Multiple Sclerosis Discovery Forum

Displaying 44 drugs.

	Name	Class types	Target	Status for MS	Administration	Commercial
[+]	Alemtuzumab	IS NP	CD52 [[435]]	Approved in the US, EU, and other countries for treating RRMS [[15222]] Used on a research basis in MS since 1991 [[783]] Approved in the EU for treating adults with RRMS (17 September 2013) [[7621]] Approved in Canada for treating adults with RRMS (13 December 2013) [[8951]] Approved in Australia for treating relapsing forms of MS (19 December 2013) [[9102]] Approved in Mexico for treating RRMS (4 February 2014) [[9747]] Approved in Brazil for treating relapsing forms of MS (21 March 2014) [[10285]] Approved in Argentina for treating adults with RRMS (30 June 2014) [[12109]] Approved in the US for treating relapsing forms of MS (14 November 2014) [[15222]]	Intravenous [[781]] Administered in two annual treatment courses, the first on five consecutive days and the second, 12 months later, on three consecutive days, according to information from the manufacturer [[6591]] Subcutaneous administration was effective and well tolerated in two patients with highly active relapsing MS [[4208]] Available in the US only through a restricted distribution program, referred to as Lemtrada REMS (Risk Evaluation and Mitigation Strategy) [[15222]]	Discovered by researchers at Cambridge University, UK [[435]] Rights were acquired by Wellcome (now GlaxoSmithKline) from British Technology Group, which undertook development in the 1990s [[6512]] Fast tracked by the US Food and Drug Administration in June, 2010 [[784]] Rights were next held by Leukosite and then Ilex Oncology, which, in 1999, formed a partnership deal with Schering (now Bayer); Ilex was bought by Genzyme in 2004 and Genzyme was bought by Sanofi in 2011 [[6512]] Clinical trials sponsored and future commercialization to be done by Genzyme (a subsidiary of Sanofi), in partnership with Bayer [[779]] Supplemental biologics license application has been submitted to the US Food and Drug Administration and a marketing authorization application has been submitted to the European Medicines Agency by Genzyme, to seek approval for use of alemtuzumab in the treatment of RRMS (12 June 2012) [[2738]] Withdrawn as a cancer drug (known as Campath/MabCampath) in the US and EU by Genzyme, a Sanofi company, so that this company can concentrate on marketing the drug for MS (as Lemtrada) and reportedly to prevent the off-label use of this drug for MS (August, 2012) [[3014]] In response to the submission of a supplemental biologics license application for approval of Lemtrada as a treatment for MS by Genzyme, the US Food and Drug Administration issued a refuse to file letter and asked that the presentation of data sets be modified (27 August 2012) [[3013]] Supplemental biologics license application, which seeks approval for the use of Lemtrada in the treatment of relapsing MS, has been accepted by the US Food and Drug Administration for review (28 January 2013) [[4732]] Response from the US Food and Drug Administration about Lemtrada approval is expected by Sanofi in the fourth quarter of 2013 and by the European regulator in the third quarter of 2013 (14 February 2013) [[4979]] Limited access to alemtuzumab (for patients who had already started treatment) has been restored by Genzyme in response to protests from doctors after withdrawal of off-label use for MS in 2012 (February 2013) [[4826]] Received a positive opinion for approval (for treating adult RRMS patients with active disease) from the Committee for Medicinal Products for Human Use of the European Medicines Agency (28 June 2013) [[6591]] Marketing authorization has been granted by the European Commission for treating adults with RRMS (17 September 2013) [[7621]] Reviewers for the US Food and Drug Administration raise concerns about serious safety issues and questions about whether the efficacy data from primary trials are adequate (8 November 2013) [[8424]] Advisory panel to the US Food and Drug Administration recommends approval, but only for individuals for whom other therapies have been unsuccessful (13 November 2013) [[8596]] Approved by Health Canada for treating adults with RRMS (13 December 2013) [[8951]] Approved by the Australian Therapeutic Goods Administration for treating relapsing forms of MS (19 December 2013) [[9102]] Supplemental Biologics License Application to the US Food and Drug Administration received a Complete Response Letter (which indicates that an application is not ready to be approved); in this case, the decision is related to how the relevant clinical trials were designed; more active comparator clinical trials would be required for approval (30 December 2013) [[9240]] Rejection by the US Food and Drug Administration will be appealed by Genzyme (30 December 2013) [[9240]] Approved by COFEPRIS, the national regulatory authority in Mexico, for treating RRMS (4 February 2014) [[9747]] Approved by ANVISA, Brazil's national health surveillance agency, for treating relapsing forms of MS (21 March 2014) [[10285]] Will receive a recommendation for funding as a treatment for adults with active RRMS by the National Health Service (NHS) in England and Wales from the National Institute for Health and Care Excellence (NICE) (4 April 2014) [[10432]]; final guidance recommending reimbursement on the NHS has been issued by NICE (27 May 2014) [[11296]] Application for approval will be resubmitted by Genzyme to the US Food and Drug Administration; the appeal of the previous negative decision will not be pursued at this time (7 April 2014) [[10489]] Supplemental Biologics License Application for approval for treating RRMS has been resubmitted to and accepted by the US Food and Drug Administration for review; supplemental analyses and additional information are included in the resubmission (30 May 2014) [[11409]] Approved by the National Administration of Drugs, Food and Medical Technology in Argentina for treating adults with RRMS (30 June 2014) [[12109]] Approved by the Scottish Medicines Consortium for use within the National Health System for Scotland for treating adults with active RRMS (7 July 2014) [[12205]] Approved by the US Food and Drug Administration for treating relapsing forms of MS (14 November 2014); use of the drug is generally limited to individuals who have inadequately responded to two or more MS drugs [[15222]] Genzyme, a Sanofi company, which markets alemtuzumab, will now be referred to instead as Sanofi Genzyme (1 January 2016) (personal communication from Ameet Khara at Sanofi Genzyme)
[+]	Amiloride	NP	Acid-sensing ion channel-1 [[4136]] Epithelial sodium channel [[12711]] [[12712]] Na+/H+ exchanger [[12713]]	Phase II trials are underway (July 2014) [[12584]] [[12599]] [[12600]]	Oral [[12643]] [[12685]]	Discovered in the late 1960s at Merck Sharp and Dohme Research Laboratories during a screen for compounds that reverse the effects of mineralocorticoids (which increase sodium and water reabsorption in the kidney) [[12658]] Approved by the US Food and Drug Administration in October 1981 [[12644]] Brand-name version was originally produced by Merck, but this company is no longer making the drug; the patent has expired and only the generic version is now produced [[12652]] Produced by Par Pharmaceutical [[12650]] Produced by Perrigo Company [[12651]] Produced by SigmaPharm Laboratories [[12654]]
[+]	ATX-MS-1467	IM	Major histocompatibility complex class II [[14248]] T cell responses to myelin basic protein [[14248]]	Phase IIa study is in progress (2014) [[14245]]	Intradermal [[14244]] Subcutaneous [[14244]]	Is being developed by Apitope (responsible for all Phase I development) in collaboration with Merck Serono (responsible beginning with Phase II studies) [[14247]] Phase I study was sponsored by Apitope Technology (Bristol) Ltd. (completed as of August, 2013) [[14244]] Phase II study is being sponsored by Merck KGaA (ongoing as of June, 2014) [[14245]]
[+]	BGC20-0134	IM	Proinflammatory and anti-inflammatory cytokines [[473]]	Phase IIa [[473]] [[791]]	Oral [[473]] [[791]]	Developed by BTG plc [[473]]
[+]	BIIB033	NP	LINGO-1 ("leucine-rich repeat and immunoglobulin-like domain–containing, Nogo receptor–interacting protein") [[377]] [[393]]	Phase I results have been published [[13242]] Phase II trial is recruiting as of May, 2014 [[13427]]	Intravenous infusion used in Phase I and Phase II trials [[486]] [[13242]] [[13427]] Subcutaneous injection used in Phase I trial [[13242]]	Discovered by Biogen Idec [[377]] Clinical trials are sponsored by Biogen Idec [[485]] [[486]] Biogen Idec, which is developing BIIB033, has changed its name to Biogen (23 March 2015) [[18038]]
[+]	Cladribine	IS IM	CD4+ T cells [[793]] DNA synthesis and repair [[793]] E-selectin [[556]] Intracellular adhesion molecule-1 [[556]] Pro-inflammatory cytokines interleukin 2 and interleukin 2R [[557]] Pro-inflammatory cytokines interleukin 8 and RANTES [[558]] Cytokine secretion [[3500]] Monocyte and lymphocyte migration [[555]]	Approved in Russia and Australia for RRMS in 2010 [[552]]	Oral [[794]] [[795]] [[559]]	Developed at Scripps Research Institute for treating hairy cell leukemia [[553]] Clinical trials for use in MS have been sponsored by EMD Serono, a division of Merck KGaA [[794]] [[795]] [[796]] [[797]] [[798]] [[800]] Rejected by the EU in January 2011 and by the US Food and Drug Administration in March 2011 [[552]]; failure to receive authorization in the EU was in part a result of concern about an associated cancer risk [[22592]] As of June 2011, Merck KGaA is no longer seeking approval for cladribine in US, and plans to withdraw the product from the market in Russia and Australia [[552]] Results of a Merck Serono-sponsored Phase III trial were published in February 2014 [[9678]] Merck KGaA plans to seek approval for cladribine from European regulators after evaluating new data (11 September 2015) [[21574]]; new analysis suggests that there is not an increased cancer risk at doses used to treat MS [[22592]]
[+]	Cyclophosphamide	IS IM	T cells, particularly CD4+ helper T cells [[934]] [[935]] B cells [[934]]	Phase III head-to-head trial is under way (as of 12 Oct 2010) [[926]] Phase III, controlled, randomized, multicenter clinical trial is planned by Accentia Biopharmaceuticals and Johns Hopkins University to study Cyrevia (high-dose Cytoxan) in MS, with the lead trial site at Johns Hopkins (press release May 2012) [[1796]]	Developed as an oral drug [[929]] Most commonly administered as monthly intravenous pulses [[929]]	Developed by ASTA Werke AG (now Baxter Healthcare) in the 1950s as a chemotherapeutic agent [[927]] [[947]] FDA-approved generic versions are made by Baxter Healthcare and Roxane Laboratories [[925]] Bristol-Myers Squibb produced Cytoxan (25 mg and 50 mg tablets), but decided to discontinue [[924]] Revimmune (high-dose pulsed cyclophosphamide in a proprietary system-of-care) was developed by researchers at Johns Hopkins University, which licensed it to Accentia Biopharmaceuticals, Inc. [[922]] Accentia Biopharmaceuticals plans controlled clinical trials of Revimmune as of May 2011 [[922]] Cytoxan for Revimmune therapy is supplied by an agreement with Baxter Healthcare Corporation [[922]]
[+]	Daclizumab	IS	Interleukin-2 receptor alpha (CD25) (high-affinity alpha subunit) [[432]] [[15077]] T cell expansion [[431]] Innate immune system [[2700]]	Phase III trials for RRMS are ongoing as of 2014 [[432]] [[11770]]	Subcutaneous [[801]] Intravenous [[431]]	Initially marketed by Hoffman-La Roche, but withdrawn in the EU in 2008 and in the US in 2009 for commercial reasons [[806]] [[807]] Trials for MS have been sponsored by Biogen Idec and AbbVie [[801]] [[11770]] Biogen Idec, which has sponsored trials for daclizumab in MS, has changed its name to Biogen (23 March 2015) [[18038]] Marketing Authorisation Application for Zinbryta for treating relapsing forms of MS in the EU has been validated by the European Medicines Agency (EMA), a step that confirms that the submission is complete and indicates that the review process by EMA's Committee for Medicinal Products for Human Use will begin (27 March 2015) [[18037]] Biologics License Application for Zinbryta for the treatment of MS has been accepted for review by the US Food and Drug Administration (29 April 2015) [[18831]]
[+]	Dalfampridine	IM	Voltage-gated potassium channels [[348]] [[384]] Degenerin/epithelial sodium channels [[4942]] L-type calcium channels that contain subunit Cavbeta3 [[14096]]	Approved in US to improve walking in patients with all forms of MS (22 January 2010) [[495]] [[497]] European Medicines Agency's Committee for Medicinal Products for Human Use gave positive opinion for marketing Fampyra (May 2011), a change from a recommendation against approval issued in January 2011 [[496]] [[503]]	First drug approved for improving walking in MS [[495]] Oral; one tablet every 12 hours (this information was provided by the manufacturer) [[494]] Is released slowly (extended release) [[493]] Recommended dose is 10 mg twice a day, according to the US Food and Drug Administration [[495]] Should not be used in MS patients with moderate or severe kidney disease (which results in blood levels of the drug that are high enough to cause seizures) [[495]] Because of associated risk of seizures that increase with higher levels of drug in the blood, and because the drug is eliminated via the kidneys, kidney function must be checked before and during treatment, according to a warning issued by the US Food and Drug Administration (23 July 2012) [[2649]]	Benefit in MS was discovered at Rush University Medical Center, where a proof-of-concept study was performed in 1983 [[13031]] Approved by the US Food and Drug Administration on 22 January 2010 [[13031]] Marketed by Acorda Therapeutics [[493]] Manufactured under license from Elan Pharma International [[493]] Commercialization outside the US is handled by Biogen Idec, which has a licensing agreement with Acorda for this purpose [[496]] [[503]] Biogen Idec, which handles commercialization of Fampyra outside the US, has changed its name to Biogen (23 March 2015) [[18038]] 4-Aminopyridine is sold under the name Avitrol as a bird poison [[504]] Patent for Ampyra sustained-release formulation is entitled to a five year patent term extension (such that the patent will now expire in 2018) under the Hatch Waxman Act, as determined by the US Patent and Trademark Office (16 October 2012) [[3770]] Patent (set to expire in 2025) that covers a range of Ampyra doses (which are less than 15 mg twice daily) for improving walking in MS has been issued to Acorda Therapeutics by the US Patent and Trademark Office (20 May 2013) [[6094]] Rush University Medical Center's royalty rights relating to worldwide sales are sold by Rush to the private equity fund Drug Royalty III for ~$42 million (12 August 2014) [[13032]]
[+]	Dimethyl fumarate	IM NP	Cytokine secretion [[341]] CD62E [[341]] Inflammation [[341]] Histone deacetylase expression [[7206]] Hydroxycarboxylic acid receptor 2 [[10837]] Nrf2 transcriptional pathway [[341]]	Tecfidera is approved in the US, EU, and other countries for treating RRMS [[5512]] [[9746]]	Oral [[583]] [[9851]] Starting dose (used for the first 7 days) for Tecfidera is 120 mg twice a day, according to information from the manufacturer [[9851]] Maintenance dose for Tecfidera is 240 mg twice a day, according to information from the manufacturer [[9851]]	Tecfidera was jointly developed by Biogen Idec and Fumapharm [[585]] Biogen Idec acquired the company Fumapharm, which has two products, Fumaderm (approved for treating psoriasis in Germany) and BG-12, in 2006 [[585]] Clinical trials for Tecfidera have been sponsored by Biogen Idec [[583]] Marketing applications from Biogen Idec for Tecfidera have been accepted by US and EU regulatory authorities for review (May 2012) [[1792]] Review time for the New Drug Application for Tecfidera has been extended 3 months by the US Food and Drug Administration (meaning a ruling would be made by the end of March 2013), because the agency needs more time to review the application; no additional studies are requested (18 October 2012) [[3767]] [[3781]] Dosing regimen (480 mg per day) for Tecfidera has been granted patent protection by the US Patent and Trademark Office (19 March 2013) [[5317]] Tecfidera is recommended to receive marketing authorization as a first-line therapy for RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency (22 March 2013) [[5367]] Tecfidera is approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]] Dimethyl fumarate in Tecfidera has been determined to be a new active substance by the European Medicines Agency's Committee for Medicinal Products for Human Use, which would mean regulatory exclusivity in the EU for ten years (22 November 2013) [[8664]] Tecfidera is approved by the European Commission as a first-line treatment for RRMS (3 February 2014) [[9746]] Initial decision is against recommendation for Tecfidera as an available treatment for RRMS through the National Health Service in England and Wales; the National Institute for Health and Care Excellence (NICE) has requested further information about cost effectiveness (19 February 2014) [[9852]]; decision is reversed and NICE now intends to recommend dimethyl fumarate for treating RRMS (11 July 2014) [[12365]] Tecfidera is approved by the Scottish Medicines Consortium as a treatment for RRMS in the National Health Service in Scotland [[10490]] Tecfidera is recommended by the National Institute for Health and Care Excellence for treating adults with RRMS; the National Health Service in England and Wales must begin funding this treatment within 3 months (27 August 2014) [[13428]] FP187, which contains dimethyl fumarate and is formulated as a controlled-release, erosion matrix tablet, is being developed for treating MS and psoriasis by Forward Pharma as of 2013 [[14441]] Biogen Idec, which markets Tecfidera, has changed its name to Biogen (23 March 2015) [[18038]] An interference between Forward Pharma and Biogen has been declared by the US Patent Office; this proceeding will decide which company was the first to invent the method of treating MS with a daily 480 mg dose of dimethyl fumarate (14 April 2015) [[18342]] Decision to grant, covering a patent application for the treatment of MS with a 480 mg daily dose of dimethyl fumarate, has been given to Forward Pharma from the European Patent Office (27 April 2015) [[18829]] Costs of introducing dimethyl fumarate for treating RRMS in Canada were calculated to be partly offset by the decreased costs associated with fewer relapses, as determined by an industry-funded budget impact model (September 2015) [[21783]] Phase III program in SPMS has been discontinued by Biogen (21 October 2015) [[23072]]
[+]	Dronabinol	NP	Cannabinoid receptor CB1 [[9525]] [[9527]] Cannabinoid receptor CB2 [[9528]]	Phase III trial for PPMS and SPMS has been completed [[6803]] [[9467]] Phase III trial for MS with muscle spasticity has been completed [[9470]]	Oral [[6803]]	Approved by the US Food and Drug Administration to treat nausea associated with chemotherapy (1985) [[9471]] Approved by the US Food and Drug Administration to stimulate appetite in individuals with HIV/AIDS (1992) [[9471]] Marinol is manufactured by Banner Pharmacaps for AbbVie Inc. [[9534]]
[+]	Estriol	IM NP	Estrogen receptor beta [[443]] T cells [[461]] Dendritic cells [[423]]	Phase II [[864]] [[865]]	Oral [[864]] Dose was set at 8 mg once daily in a clinical trial [[10842]]	Early studies were conducted at the University of California, Los Angeles [[460]] Advanced clinical trials are supported by Synthetic Biologics [[2753]] Exclusive worldwide license to patents covering the use of Trimesta for MS is held by Synthetic Biologics [[5533]] Patent covering the use of a combination of estriol and glatiramer acetate for treating MS has been issued to the Regents of the University of California by the US Patent & Trademark Office (4 April 2013) [[5533]] Patent covering the use of estriol in conjunction with a gestagen (with or without a third standard of care agent for MS) for treating MS and other autoimmune diseases has been issued to the Regents of the University of California by the US Patent & Trademark Office (10 March 2014) [[10088]] Synthetic Biologics has decided to end its estriol-related clinical trial and licensing agreements with the Regents of the University of California after two independent clinical research organizations examined Phase II trial results and found no statistically significant differences between the estriol and placebo groups (2 February 2016) [[26483]]
[+]	Fingolimod	IM NP	Sphingosine 1-phosphate receptors [[301]] Immune cell migration [[301]] Histone deacetylases [[11236]] Oligodendrocyte progenitors? [[17001]]	Approved in US, EU, and other countries for RRMS [[466]] [[467]] [[468]] [[469]] License in the EU was for adult individuals with RRMS who have not responded to interferon treatment or whose MS is severe and rapidly evolving (29 April 2014) [[11098]] License in the EU has been expanded to include individuals with RRMS who have not responded to any other disease-modifying therapy (June, 2014) [[11607]]	First oral treatment for RRMS available in US [[307]] 0.5 mg orally once daily (information provided by the manufacturer) [[470]] Decreased dosage (such that fingolimod was given every other day or every third day) did not result in clinical relapses, but did improve laboratory abnormalities (involving increased liver function tests and reduced lymphocyte counts), in a study of seven individuals [[18406]] Decreased dosage (such that fingolimod was given every other day or every third day) reversed laboratory abnormalities (involving increased liver function tests and reduced lymphocyte counts) in a study of eight individuals; although no relapses occurred, five individuals exhibited new brain lesions and one converted to SPMS [[20501]] Label has been updated to say that all patients should have an electrocardiogram before the first dose, according to information from the manufacturer (April, 2012) [[1795]] Contraindicated in the presence of specific cardiac conditions, according to information from the manufacturer [[1795]] Contraindicated in the presence of certain cardiac conditions, which were found to be present in 9.2% of individuals with MS in a retrospective cohort study involving 136,542 hospital discharges [[12603]] As a result of a drug safety communication from the US Food and Drug Administration, the label has been adjusted to indicate that one definite case, and an additional probable case, of progressive multifocal leukoencephalopathy have been reported in individuals taking fingolimod, who had not previously been exposed to immunosuppressant drugs (4 August 2015) [[20796]] To minimize fingolimod-associated risks, the European Medicines Agency has issued new recommendations for screening for progressive multifocal leukoencephalopathy and basal cell carcinoma before and during treatment (December 2015) [[24964]] Used in one individual with highly active multiple sclerosis, severe idiopathic pulmonary arterial hypertension, and coronary artery disease; treatment did not change the cardiopulmonary conditions over 9 months [[11503]] Drug-drug interactions are not observed with a combined oral contraceptive (ethinylestradiol/levonorgestrel) [[2271]]	Clinical trials have been sponsored by Novartis Pharma [[303]] [[302]] [[304]] Marketed by Novartis [[307]] Licensed from Mitsubishi Tanabe Pharma Corporation [[468]] US patent covering the process of fingolimod preparation has been granted to Mapi Pharma Ltd. of Israel, which plans to develop a generic version in anticipation of the loss of market exclusivity by Novartis (an event that will occur in 2017 in some markets) (18 February 2014) [[9853]] Positive opinion for expansion of EU label to include adult individuals with RRMS who have not responded to at least one other disease-modifying therapy has been issued by the Committee for Medicinal Products for Human Use (29 April 2014) [[11098]]; extended license has been approved by the European Commission (June, 2014) [[11607]] Under a new policy from the National Health Service in England, can now be prescribed to individuals who have not responded to beta interferons or glatiramer acetate or who are at risk for side effects of natalizumab, rather than just those who have not responded to interferon (2 July 2014) [[12110]] Endorsed by the Scottish Medicines Consortium for treating rapidly evolving, severe RRMS (October, 2014) [[14644]] Generic version Neskler has been approved by the Russian Ministry of Health (November 2014) [[25783]] Generic version Neskler has been launched in Russia and other countries in the EuroAsian Economic Union by Biointegrator after Novartis claims against Biointegrator were rejected in a series of court hearings (11 January 2016) [[25783]]
[+]	Firategrast	IM	Alpha4beta1 integrin [[1338]] [[1339]]	Phase II [[1338]] [[1339]]	Oral [[1338]] [[1339]]	Under development by GlaxoSmithKline [[2718]]
[+]	Flupirtine	NP	Neuronal potassium channels [[1342]] Membrane resting potential [[1341]] NMDA receptor channels (indirectly) [[1347]]	Phase II [[1500]]	Oral [[1499]] [[1342]]	Originally developed by Asta Medica [[1497]] [[1340]] Being developed and commercialized to treat fibromyalgia by Synthetic Biologics [[1497]] Marketed for pain indications in various European countries by Meda [[1497]]
[+]	Glatiramer acetate	IM NP	Immune cells [[343]] 26S proteasome-mediated degradation of myelin basic protein [[14142]]	Approved in US (1996), EU, and other countries for RRMS [[487]] [[488]] Approved in US (2009) and other countries for treating CIS patients in cases suggestive of MS [[487]] [[488]] Generic version has been approved in US (2015) [[18343]] Generic version has been approved in Europe (2016) [[29276]]	Involves daily subcutaneous injection, according to information from the US Food and Drug Administration [[492]] Prefilled syringes contain 20 mg glatiramer acetate in solution [[489]] [[492]] Three-times-weekly (40 mg/1 ml) subcutaneous injection has been approved by the US Food and Drug Administration [[9532]] Intramuscular version (GA Depot, which consists of microspheres containing glatiramer acetate) given once every 4 weeks is being tested in a Phase IIa study that began December, 2014 [[15983]] [[15984]] Nasal administration appears effective in experimental autoimmune encephalomyelitis mice [[5357]]	In North America, marketed by Teva Neuroscience, a subsidiary of Teva Pharmaceutical Industries [[487]] In Europe, marketed by Teva Pharmaceutical Industries and Sanofi-aventis [[487]] Sales and marketing rights in the EU have been taken back from Sanofi by Teva (May 2012) [[1768]] Teva has attempted to delay marketing approval of generic versions of Copaxone through legal measures against other companies and regulatory channels; Teva's fourth petition to US Food and Drug Administration, asking that marketing for a generic version would not be approved without clinical trials, was denied, as the previous three had been (5 December 2012) [[4142]] Application for a US patent for a Copaxone-Laquinimod mixed treatment (which would be administered via an injection) for MS has been filed by Teva (13 February 2013) [[4980]] Application for US Food and Drug Administration (FDA) approval for a 40 mg/1 ml three-times weekly dose of Copaxone has been filed by Teva (March, 2013) [[5913]] and accepted for review by the FDA (30 May 2013) [[6234]] Patent covering the use of a combination of estriol and glatiramer acetate for treating MS has been issued to the Regents of the University of California by the US Patent & Trademark Office (4 April 2013) [[5533]] US patent for a long-acting formulation (a prolonged-release version now under development that would be injected once a month rather than daily) has been granted to Mapi Pharma Ltd (6 May 2013) [[6093]] Will lose patent protection in 2014 instead of 2015 on the basis of a US appeals court ruling; Novartis and Momenta Pharmaceuticals are developing a generic version together, as are Mylan Inc and Natco Pharma (26 July 2013) [[6936]] Validity of Teva's patent protection is upheld until May 2015 by the Court of Appeal for England and Wales (29 July 2013) [[7122]] Commercialization rights in Japan have been granted to Takeda Pharmaceutical Company by Teva Pharmaceutical Industries; a New Drug Application to register the drug in Japan will be submitted by Takeda (announced 4 December 2013) [[8821]] New Drug Application for use of glatiramer acetate in Japan to prevent relapses in MS has been submitted by Takeda Pharmaceutical Company to the Japanese Ministry of Health, Labour and Welfare (25 December 2014) [[16158]] Three-times-weekly (40 mg/1 ml) Copaxone dose has been approved by the US Food and Drug Administration (28 January 2014) [[9532]] Generic version is being developed by Synthon; Phase III clinical trial is underway (March, 2014) [[10368]] [[10369]] US Supreme Court will hear Teva's appeal of the decision of a lower court that invalidated the claim of a US patent that covers the manufacture of the active ingredient in Copaxone and that expires in September 2015 (31 March 2014) [[10397]] US Supreme Court will not prevent a lower-court ruling (favoring generic versions of glatiramer acetate) from going into effect while the Supreme Court considers appeal (18 April 2014) [[10839]] US Patent to Mapi Pharma Ltd., covering "glatiramer acetate depot" (a prolonged release formulation), has been extended to December 2030 and an earlier patent has been awarded additional claims (27 May 2014) [[11295]] Abbreviated new drug application from Mylan for generic three times per week glatiramer acetate 40 mg/ml has been accepted for filing by the US Food and Drug Administration (28 August 2014) [[13429]] Three-times-weekly (40 mg/1 ml) Copaxone dose has received a positive outcome in Europe after a Positive Assessment Report from the Reference Member State’s Medicines and Healthcare Products Regulatory Agency and other EU member states (4 December 2014) [[15730]] Phase IIa study of GA Depot for treating RRMS has begun; study is being conducted by Mapi Pharma (December, 2014) [[15983]] US Supreme Court reverses a decision by the Federal Circuit Court that invalidated one of Teva's patents for Copaxone; the case has been remanded to the Federal Circuit for further review (20 January 2015) [[16574]]; the US Court of Appeals for the Federal Circuit again invalidated the patent (18 June 2015) [[19751]] Glatopa (a substitutable generic for Copaxone 20 mg), which was developed in a collaboration between Momenta Pharmaceuticals and Sandoz, has been approved by the US Food and Drug Administration for treating RRMS (16 April 2015) [[18343]] Glatopa, a generic equivalent of Copaxone 20 mg, has been launched in the US by Sandoz, as announced by Momenta Pharmaceuticals (18 Jun 2015) [[19752]] Exclusive commercialization rights in the US for the potential generic version being developed by Synthon have been acquired by Pfizer (3 August 2015) [[20667]] Copaxone (20 mg subcutaneous injection) has been approved in Japan for treating MS; the approval was obtained by Takeda Pharmaceutical Company (September 28, 2015) [[22071]] Three-times-weekly (40 mg/1 ml) Copaxone dose has been approved in Russia for treating RRMS (8 October 2015) [[22567]] Synthon's generic version (20 mg/ml) has been approved in Europe on the basis of results from the GATE trial (12 April 2016) [[29276]]
[+]	GNbAC1		MSRV-Env (envelope protein of the MS–associated retrovirus) [[8947]]	Phase IIa trial results have been published (November 2014) [[15278]]	Intravenous infusion [[8947]]	Clinical trials have been sponsored by GeNeuro SA [[8947]] [[10315]] GeNeuro enters a strategic partnership with Servier for the development and marketing of GNbAC1 (2 December 2014) [[15551]] GNbAC1 development will be carried out by GeNeuro until Phase IIb studies in MS are complete; this work will be financed by $47 million from Servier (agreement announced 2 December 2014) [[15551]] After Phase IIb studies are complete, Servier can exercise an option to license GNbAC1 for markets outside of the US and Japan; GeNeuro will retain full control of US and Japan markets (agreement announced 2 December 2014) [[15551]] Servier will cover the costs of Phase III global development (agreement announced 2 December 2014) [[15551]] Servier has exercised its option to become a minority shareholder in GeNeuro (18 December 2015) [[24962]]
[+]	Idebenone	NP	Reactive oxygen species [[8697]] [[8757]]	Phase I/II trial is recruiting as of November, 2013 [[8693]]	Oral [[8693]] Dose in clinical trial for PPMS is 2250 mg per day (750 mg dose, 3 times per day) [[8693]] [[8764]]	Initially developed in Japan, where it was licensed for treating Alzheimer's disease [[8696]] Patented by Takeda Chemical Industries, Japan [[8759]] Introduced into the Japanese market in 1986 [[8759]] Post-marketing data are available from over 8 million people [[8696]] Withdrawn from the Japanese market in 1998 because of lack of proven efficacy in Alzheimer's disease [[8773]] Under development for orphan mitochondrial and neuromuscular conditions by Santhera Pharmaceuticals [[8762]] Conditionally approved by Health Canada for the treatment of Friedreich's ataxia (24 July 2008) [[8763]] Can be obtained in some European countries on a "named patient" basis for treating Friedreich's ataxia as of November 2008 [[8773]] Clinical trial to assess use in PPMS involves a collaboration between the US National Institutes of Health (which is conducting the trial) and Santhera Pharmaceuticals (which is supplying idebenone) (24 June 2009) [[8764]] Sales in Canada for the treatment of Friedreich's ataxia were discontinued voluntarily by Santhera Pharmaceuticals after additional clinical studies (30 April 2013) [[8765]] Marketing authorization for treating Leber's hereditary optic neuropathy has been recommended by the European Medicines Agency's Committee for Medicinal Products for Human Use (26 June 2015) [[19919]] Marketing authorization for treating Leber's hereditary optic neuropathy has been granted by the European Commission (9 September 2015) [[22307]]
[+]	Imilecleucel-T	IM	Myelin-specific, autoreactive T cells [[7692]] [[7693]]	Phase II trial is ongoing as of September, 2013 [[7755]]	Subcutaneous [[7692]] [[7755]] Given 5 times per year, according to information from the manufacturer [[7692]]	Clinical trials have been sponsored by Opexa Therapeutics [[7709]] [[7755]] [[7759]] [[7760]] Tovaxin for treating SPMS has been given a Fast Track Designation by the US Food and Drug Administration (8 November 2011) [[7756]] Name for this therapy has been changed from Tovaxin to Tcelna by Opexa Therapeutics (21 May 2012) [[7757]] An agreement has been executed between Opexa Therapeutics and Merck Serono, such that Merck has been given the option for an exclusive license to develop and commercialize imilecleucel-T and Opexa has been given a $5 million payment (5 February 2013) [[7758]] The option and license agreement between Opexa Therapeutics and Merck Serono has been amended; Opexa will receive additional funding ($3 million) to support the Phase IIb Abili-T trial of imilecleucel-T (9 March 2015) [[17450]]
[+]	Interferon beta-1a	IM	Interferon beta receptor [[1071]] T cell differentiation pathways [[1071]] Pathways regulating transfer of Inflammatory cells across the blood brain barrier [[1071]]	Approved [[1063]] [[1064]]	Intramuscular [[1063]] Subcutaneous [[1064]] Plegridy dose is 125 microg injected subcutaneously once every 2 weeks, according to information from the manufacturer [[13074]] Missing a dose within the first month of observation is associated with reduced adherence to treatment and increased chance of relapse [[21584]]	Avonex was developed and is manufactured and marketed by Biogen Idec [[1063]] Rebif is manufactured by EMD Serono and is co-marketed by Serono and Pfizer in the US as of 2003 [[1064]] Plegridy (a form of interferon beta-1a that is pegylated to increase its half-life, allowing dosing less frequently) was developed by Biogen Idec [[13074]] CinnoVex was engineered and developed by the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB in Germany in a collaboration with CinnaGen in Iran [[14168]] CinnoVex has been approved as a biogeneric by the Iranian Food and Drug Administration (2006) [[14168]] CinnoVex is manufactured and marketed by CinnaGen [[1065]] Rebif Rebidose (a single-use auto-injector for interferon beta-1a) has been approved by the US Food and Drug Administration (3 January 2013) [[4437]] Biologics License Application for Plegridy has been submitted to the US Food and Drug Administration by Biogen Idec (21 May 2013) [[6231]] Biologics License Application for marketing approval of Plegridy has been accepted by the US Food and Drug Administration; a standard review timeline (about 10 months) will be used (19 July 2013) [[6894]] [[6895]] Marketing Authorisation Application for review of Plegridy in the EU has been accepted by the European Medicines Agency (19 July 2013) [[6894]] Rebif will lose patent protection at the end of 2013 [[8383]] Date for review of the Biologics License Application for marketing approval of Plegridy by the US Food and Drug Administration has been extended by three months (March 2014) [[10176]] Plegridy has been recommended for approval for treating RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency (23 May 2014) [[11227]] Plegridy has been approved in the EU for treating adults with RRMS (23 July 2014) [[12567]] Plegridy has been approved in the US for treating individuals with relapsing forms of MS (15 August 2014) [[13074]] Biogen Idec, which markets Avonex and Plegridy, has changed its name to Biogen (23 March 2015) [[18038]] Plegridy has been approved in Canada for treating adults with RRMS (13 August 2015) [[20911]] Sole rights to Rebif in the US have been taken on by EMD Serono as of 1 January 2016 [[25784]]
[+]	Interferon beta-1b	IM	T lymphocytes [[1145]] Blood-brain barrier (?) [[1135]] [[1145]] [[1147]] T cell trafficking (?) [[1145]] [[1164]] Matrix metalloproteinases [[1164]] [[1165]] [[1166]] [[1167]] Inflammatory cytokines [[1168]] Inflammasome [[1877]]	Approved in US, EU, and other countries for relapsing forms of MS [[1131]] [[1134]] [[1170]] [[1161]] Approved in EU for CIS, RRMS, and SPMS with active disease [[1131]] First disease-modifying therapy approved by the US Food and Drug Administration for use in MS (July, 1993) [[1179]] [[1161]]	For Betaseron, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer [[1170]] For Extavia, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer [[1178]] The Betaconnect autoinjector was associated with a high level of patient satisfaction in an industry-funded study involving 118 individuals with MS [[24625]]	Betaferon/Betaseron was developed by Schering AG (which operated as Berlex Laboratory in North America), a company that was taken over by Bayer HealthCare [[1177]] Betaferon/Betaseron is marketed by Bayer HealthCare [[1177]] Novartis introduced Extavia in 2009; Extavia is manufactured by Bayer HealthCare and distributed by Novartis [[1177]] [[1178]] Zist Daru Danesh Ltd (Iran) began producing ZIFERON in 2010 [[1175]] [[1176]] Mountain View Pharmaceuticals received a European patent for polyethylene glycol conjugates of interferon beta-1b with enhanced biological potency (press release, June 2012) [[2104]] Filing of a supplemental Biologics License Application by Bayer for Betaconnect, a new means of delivering Betaseron, has been accepted by the US Food and Drug Administration (22 April 2015) [[18495]] Betaconnect, the first electronic autoinjector for use in treating RRMS, has been approved by the US Food and Drug Administration; this device is used for delivering Betaseron (September 25, 2015) [[22069]]
[+]	Laquinimod	IM NP	NFkB-mediated inflammatory pathways [[567]] T helper cell response [[567]] B cells [[2675]] Dendritic cells [[5351]] Microglial activation [[14871]]	Phase III trial for treating RRMS has been completed (press release 2011; publ 2012) [[809]] [[883]] Received a negative opinion for use in treating RRMS from the Committee for Medicinal Products for Human Use of the European Medicines Agency (24 January 2014) [[9529]]	Oral dose of 0.6 mg per day has been used in clinical trials for RRMS [[809]] Tolerability was established at 0.1 to 1.2 mg per day by unpublished Phase I studies [[560]]	Developed by Active Biotech [[813]] Licensed to Teva Pharmaceutical Industries for development and commercialization, through an agreement with Active Biotech [[813]] Granted fast-track review status by the US Food and Drug Administration in 2009 [[818]] [[348]] After a meeting with the US Food and Drug Administration, Teva decided that filing a New Drug Application would be premature and that another clinical trial should be undertaken (2 November 2011) [[9530]] Validation process for marketing authorization for RRMS has been completed by the European Medicines Agency, indicating that the formal scientific review process can begin, according to Active Biotech (17 July 2012) [[2565]] Application for a US patent for a Copaxone-Laquinimod mixed treatment (which would be administered via an injection) for MS has been filed by Teva (13 February 2013) [[4980]] Decision about whether to approve laquinimod by the Committee for Medicinal Products for Human Use of the European Medicines Agency is expected in January, 2014 (20 December 2013) [[9105]] Received a negative opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency, which indicated that laquinimod should not receive marketing authorization in the EU because of the risk-benefit profile (24 January 2014) [[9529]] Opinion recommending against approval for treating RRMS in the EU is confirmed by the Committee for Medicinal Products for Human Use, but Teva and Active Biotech plan to continue clinical development (23 May 2014) [[11226]]
[+]	Masitinib	IM	KIT (a stem cell factor, also called c-KIT) receptor as well as select other tyrosine kinases [[1334]] Mast cells [[1334]]	Phase III [[1378]] [[1381]]	Oral [[1378]]	Under development by AB Science [[1378]] Trials in a variety of non-life-threatening conditions, including MS, have been halted by French regulators because of the risk of adverse events that might be fatal (2012) [[20145]]
[+]	MEDI-551	IS	CD19, a B cell-specific antigen that is part of the B cell receptor complex and that functions in determining the threshold for B cell activation [[11914]] B cells [[11914]] Plasmablasts, B cells that express CD19 (but not CD20) and that secrete large quantities of antibodies; depletion of plasmablasts may be useful in autoimmune diseases involving pathogenic autoantibodies [[11914]]	Phase I trial for relapsing forms of MS is underway as of June 2014 [[11917]] Phase II/III trial for neuromyelitis optica and neuromyelitis optica spectrum disorders is underway as of October 2015 [[24768]]	Intravenous [[11917]] Subcutaneous [[11917]]	Developed by MedImmune [[11914]] Clinical trial for RRMS sponsored by MedImmune [[11917]] Clinical trial for neuromyelitis optica and neuromyelitis optica spectrum disorders sponsored by MedImmune [[24768]]
[+]	Minocycline	IM NP	T cells [[6953]] Microglia [[6953]] Leukocyte migration [[6953]] Matrix metalloproteinases [[6953]] [[6954]]	Phase III trial is underway (as of July, 2013) [[6986]]	Oral [[6938]] Available as pellet-filled capsules and an oral suspension [[6942]]	Arestin is marketed by Orapharma as a topical sustained-release formulation for periodontal disease [[6943]] Dynacin is marketed by Par Pharmaceuticals [[6946]] Minocin is marketed and distributed by Triax Pharmaceuticals [[6938]] Minocin is manufactured by Patheon Pharmaceuticals for Triax Pharmaceuticals [[6938]] Myrac is marketed by Glade Pharmaceuticals [[6948]] Solodyn is marketed by Medicis for treating acne [[6945]] Ximino is marketed by Ranbaxy Laboratories for treating acne [[6949]] [[6950]]
[+]	MIS416	IM	Innate immune system [[13783]] [[9622]] Pathogen-associated molecular pattern recognition receptors of the innate immune system [[13783]] Myeloid cells of the innate immune system, which might be able to remodel the deregulated immune system activity that occurs in SPMS [[13783]] [[14089]]	Phase II trial is underway (2014) [[13757]]	Intravenous [[13756]] [[13757]]	Designed and manufactured by Innate Immunotherapeutics [[13859]] Manufacture as a medicine is approved by Medsafe, the New Zealand medicines regulator (2008) [[13875]] Clinical trials have been sponsored by Innate Immunotherapeutics [[13756]] [[13757]]
[+]	Mitoxantrone	IS	T cells [[511]] B cell proliferation [[511]] Macrophages [[511]] Antigen presenting cells [[518]] Pro-inflammatory cytokines, including interleukin-10 [[505]] Microglia [[508]] DNA [[519]]	Approved in US, EU, and other countries for RRMS, SPMS, and PRMS [[511]]	Recommended administration is as a short intravenous infusion every 3 months, according to information from the US Food and Drug Administration [[920]] Cumulative lifetime dose should be limited [[511]]	Marketed by EMD Serono, Inc. [[917]]
[+]	Mycophenolate mofetil	IS	Purine synthesis [[597]] [[457]]	Phase II [[425]] [[599]]	Oral [[600]]	Manufactured by Genentech [[597]]
[+]	Naltrexone	IM	Opioid receptors [[9776]] [[9971]] Toll-like receptor 4 [[10092]]	Phase II [[9937]]	Given at low doses (3 to 4.5 mg per day) in oral form when used off-label for MS or in clinical studies for MS [[9935]] [[9943]] "Low-dose naltrexone" (or "LDN") indicates daily doses that are about one tenth those used for opioid addiction [[9776]] Low-dose naltrexone causes analgesia and anti-inflammatory effects that have not been observed at higher doses [[9776]] Depade (for alcohol and opioid dependence) is supplied as 25, 50, and 100 mg tablets and is taken orally once daily [[9973]] ReVia (for alcohol and opioid dependence) is supplied as 50 mg tablets and is taken orally once daily [[9973]] Vivitrol (for alcohol and opioid dependence) is given at a dose of 380 mg, administered by intramascular injection once per month, according to information from the manufacturer [[9942]]	Initially synthesized at Endo Laboratories in 1963; received US patent protection in 1967 as Endo 1639A [[9972]] [[9973]] Rights acquired by DuPont in 1969, when DuPont purchased Endo Laboratories [[9972]] Development as a treatment for opioid and alcohol dependence was supported by the US National Institute on Drug Abuse and the US National Institute on Alcohol Abuse and Alcoholism [[9972]] Approved by the US Food and Drug Administration as a treatment for opioid addiction in 1984 and marketed by DuPont with trade name Trexan [[9972]] [[9973]] Approved by the US Food and Drug Administration as a treatment for alcohol use disorders in 1994, at which time DuPont changed the trade name to ReVia [[9973]] ReVia, as well as a generic version, are manufactured by Barr Pharmaceuticals [[9973]] Manufactured under the trade name Depade by Mallinckrodt [[9973]] Injectable form Vivitrol was approved by the US Food and Drug Administration for treating alcohol and opioid dependence in 2006 and 2010 [[9939]] [[9940]] Vivitrol is manufactured by Alkermes, Inc. [[9939]] [[9942]] Proprietary and legal rights for LDN (US) / Lodonal (outside of US), which has been used as an immune modulator for treating autoimmune diseases, viral infections, and cancer in clinical trials and through off-label prescription use, are held by Immune Therapeutics, Inc. [[16576]] [[16577]] Immune Therapeutics, Inc. has signed an agreement with KRS Global Biotechnology, Inc. to compound, package, and distribute naltrexone tablets in various strengths; the tablets will be prepared for shipment in the US (23 January 2015) [[16577]] Immune Therapeutics, Inc. plans to use payments from KRS Global Biotechnology, Inc. to fund the biotechnology company Cytocom Inc. to undertake clinical trials with low-dose naltrexone in conditions including MS (23 January 2015) [[16577]]
[+]	Natalizumab	IM	α4 integrins [[300]] Leukocyte trafficking [[379]]	Approved in the US for treating relapsing forms of MS (November, 2004) [[300]] [[593]] [[18832]] Approved in the EU for treating highly active RRMS (June, 2006) [[18832]]	300 mg via intravenous infusion every four weeks (this information was provided by the manufacturer) [[592]] Extending the dose schedule (from 4 weeks to 5 to 8 weeks) did not reduce efficacy and was not associated with progressive multifocal leukoencephalopathy, as shown in a retrospective analysis involving 1964 individuals (meeting report, April 2015) [[18494]]; further analysis indicated that an 8-week dosing interval might reduce relapse rates and MRI lesions as compared with the 4-week interval (meeting report, October 2015) [[22569]] Review to assess whether the current approach for managing the risk of progressive multifocal leukoencephalopathy needs to be revised has been requested by the European Commission (May 2015) [[18832]]; new guidelines have been issued by the European Medicines Agency (February 2016) [[26715]]	Jointly developed by Elan Pharmaceuticals and Biogen Idec [[379]] Clinical trials sponsored by Biogen Idec and Elan Pharmaceuticals [[391]] [[397]] [[390]] Manufactured by Biogen Idec [[592]] Distributed by Elan Pharmaceuticals [[592]]; Biogen Idec will take full control of Tysabri in 2013 [[4904]] Available only through a special restricted distribution program (TOUCH), because of the risk of progressive multifocal leukoencephalopathy [[592]] Marketing applications for first-line use in anti-JC virus antibody negative MS patients have been submitted to the US Food and Drug Administration and the European Medicines Agency by Biogen Idec and Elan (16 January 2013) [[4629]] Full rights for and control of Tysabri will be acquired by Biogen Idec from Elan Pharmaceuticals for cash ($3.25 billion) and future contingent payments; the deal is expected to close by the end of the second quarter of 2013 (6 February 2013) [[4904]] Using some of the proceeds from the Tysabri restructuring, Elan Corporation will repurchase $1 billion of stock after the restructuring transaction with Biogen Idec is closed (22 February 2013) [[5085]] Full rights for and control of Tysabri have been purchased by Biogen Idec from Elan Pharmaceuticals (2 April 2013) [[5532]] Biogen Idec, which markets Tysabri, has changed its name to Biogen (23 March 2015) [[18038]]
[+]	Ocrelizumab	IS	B cells [[432]] CD20 [[432]]	Phase III trials [[655]] [[875]] [[876]]	Intravenous [[655]] [[875]] [[876]] [[878]]	Clinical trials have been funded by Hoffmann-La Roche Ltd and Biogen Idec [[5528]] Genentech, a wholly-owned member of the Roche Group, is now fully responsible for development and commercialization of ocrelizumab in MS; Biogen Idec will receive royalties on sales of ocrelizumab in the US (21 October 2010) [[23294]] Biogen Idec, which originally funded trials for ocrelizumab, has changed its name to Biogen (23 March 2015) [[18038]] Granted Breakthrough Therapy Designation by the US Food and Drug Administration for treating PPMS; this designation aims to speed the development and review of ocrelizumab (17 February 2016) [[26945]]
[+]	Ofatumumab	IS	B cells [[432]] CD20 [[432]]	Phase I/II trial is ongoing [[432]] [[648]] [[649]] Phase II trial is ongoing [[645]] [[651]] [[8042]]	Intravenous [[648]] Subcutaneous [[645]] [[8042]]	Marketed and developed by Genmab together with GlaxoSmithKline (2013) [[7637]] Clinical trial conducted by GlaxoSmithKline [[8042]] Plans for a Phase III trial for testing the subcutaneous formulation in RRMS, beginning in 2015, have been announced by Genmab after a decision was made by its partner GlaxoSmithKline (30 May 2014) [[11410]] Plans for filing an Investigational New Drug Application for a pivotal study of the subcutaneous formulation in neuromyelitis optica have been announced by Genmab after a decision was made by its partner GlaxoSmithKline (30 May 2014) [[11410]] All remaining rights for development as a treatment for MS and other autoimmune conditions have been acquired by Novartis from GlaxoSmithKline (21 August 2015); Novartis had obtained the rights for oncology indications previously [[21072]]
[+]	ONO-4641	IM	Sphingosine 1-phosphate receptor [[626]] [[428]]	Phase II [[626]]	Oral [[626]] [[428]]	Discovered by Ono Pharmaceutical Co. [[626]] Developed by Ono Pharmaceutical Co.for commercialization in Japan, Korea, and Taiwan [[626]] Licensed to Merck Serono for development and commercialization outside of Japan, Korea, and Taiwan (October 2011) [[626]] [[11845]] License agreement between Merck KGaA and Ono Pharmaceutical has been terminated because the drug does not meet Merck's conditions for continued investment (17 June 2014) [[11845]]
[+]	Ozanimod		Sphingosine-1-phosphate receptors S1P1R and S1P5R [[28138]]	Positive Phase II results have been published (February 2016) [[26787]] Phase III trial is underway as of December 2014 [[15985]] [[15986]]	Oral [[3775]] [[3776]]	Discovered at the National Institute of Health’s Molecular Libraries Probe Production Center at The Scripps Research Institute [[3777]] Relevant patents were exclusively licensed to Receptos from The Scripps Research Institute [[3777]] Developed by Receptos [[3777]] Phase I, II, and III clinical trials sponsored by Receptos [[3777]] [[8906]] Composition of matter patents covering ozanimod have been issued by the US Patent and Trademark Office to Receptos, which have an initial term that extends to May 2029 (13 August 2013) [[7265]] Phase III trial will be initiated (5 December 2013) [[8906]] Receptos will be acquired by Celgene; this transaction should close in 2015 (14 July 2015) [[20496]]
[+]	Phenytoin	NP	Sodium channels [[10458]] [[10459]]	Results from a Phase II trial for optic neuritis, which is often associated with MS, have been published (2016) [[26174]]	Intravenous [[10867]] Intramuscular (less favored option) [[10867]] Oral [[10867]] [[10868]]	First synthesized at the University of Kiel in 1908 [[10866]] Synthesized as a phenobarbital analog at Parke-Davis in the 1920s in an effort to identify sleep-inducing (hypnotic) drugs, although it was found to lack such activity [[10866]] Found to exhibit potent anticonvulsant activity in animal studies at Parke-Davis in 1936 [[10866]] Marketed as Dilantin by Parke, Davis and Company as an anticonvulsant treatment beginning in 1938 [[10866]] Dilantin was approved by the US Food and Drug Administration on 6 January 1953 [[10874]] Continued as a first-line treatment for epilepsy until the 1980s [[10866]] Dilantin is produced by Parke-Davis, a division of Pfizer [[10867]] Phenytek is produced by Mylan Bertek Pharmaceuticals [[10868]]
[+]	Raltegravir		Retroviral integrase [[9219]] Herpesvirus DNA packaging terminase [[9220]]	Phase II study is underway (as of 2013) [[8957]]	Oral [[9203]] 400 mg tablet twice daily, according to information from the manufacturer [[9203]]	Received accelerated approval for treating HIV-1 (in combination with other drugs) from the US Food and Drug Administration (12 October 2007) [[8955]] Clinical trials for efficacy in treating HIV have been sponsored by Merck [[9200]] [[9201]] Distributed by Merck [[8955]]
[+]	Riluzole	NP	Glutamatergic neurotransmission [[13362]] [[13306]] Glutamate uptake and release [[13363]] [[13371]] [[13372]] [[13373]] Voltage-gated sodium channels [[13365]] [[13367]] [[13375]] Protein kinase C [[13369]]	Phase II trial is underway as of 2014 [[12584]] Phase II trial data have been published (May 2014) [[14874]]	Oral [[13304]]	Synthesized by scientists at Rhône-Poulenc Rorer [[13305]] When approved by the US Food and Drug Administration in 1995, was manufactured by Rhône-Poulenc Rorer Inc. [[13301]] Marketed by sanofi-aventis after Rhone-Poulenc Rorer merged with Hoechst Marion Roussel to create Aventis (December 1999) and Aventis was acquired by Sanofi-Synthelabo to create sanofi-aventis (31 December 2004) [[13303]] [[13304]] Full commercial rights in the US are acquired by Covis Pharma from Sanofi [the new name of sanofi-aventis as of 2011 [[13303]]]; Sanofi retains existing rights outside the US (4 April 2013) [[13302]]
[+]	Rituximab	IS	B cells [[481]] CD20 [[481]]	Results from Phase II trials for RRMS have been published (2009, 2010) [[359]] [[352]] Used off-label to treat MS [[345]]	Intravenous infusion [[388]] Example of frequency of intravenous infusions in clinical trials is two 1000 mg infusions every 24 weeks [[359]] Results presented at a meeting indicate that subcutaneous administration is a non-inferior alternative to intravenous infusion, which would allow administration over 5 minutes rather than 2.5 hours (8 December 2012) [[4141]] Subcutaneous formulation is approved by the European Commission for treating non-Hodgkin lymphoma, allowing administration over 5 minutes (28 March 2014) [[10370]]	Discovered by Biogen Idec [[484]] Co-marketed by Genentech and Biogen Idec in the US [[484]] Biogen Idec, which co-markets Rituxan in the US, has changed its name to Biogen (23 March 2015) [[18038]] Co-marketed by Chugai and Zenyaku Kogyo Co. Ltd in Japan [[484]] Marketed by Roche as MabThera elsewhere in the world [[484]] Biosimilar version has been launched by Intas Pharmaceuticals in India (May 2013) [[5912]]
[+]	RTL1000	IM NP	T cell receptors [[427]] T cell proliferation [[430]] Cytokine secretion [[430]]	Phase I completed [[427]]	Intravenous [[427]] [[624]]	Invented by researchers at Oregon Health and Science University and the Portland Veteran Affairs Medical Center [[622]] Under development by Artielle ImmunoTherapeutics [[623]]
[+]	Secukinumab	IS	Interleukin 17A, a proinflammatory cytokine that is produced by T helper 17 cells and that is associated with autoimmune diseases [[8226]] [[8227]] [[8242]]	Phase II trials are underway [[8243]] [[8244]]	Intravenous; doses ranged from 3 to 10 mg per kg, given as a 2-hour intravenous infusion either once or twice (3 weeks apart) in clinical studies [[8225]] Given in monthly subcutaneous injections (25 mg to 300 mg) in a clinical trial for rheumatoid arthritis [[8235]]	Developed by Novartis Pharmaceuticals [[8248]] Clinical trials have been sponsored by Novartis Pharmaceuticals [[8243]] [[8244]] [[8245]] Approved in Japan for treating adults with psoriasis or psoriatic arthritis (26 December 2014) [[24815]] Approved in the US and EU for treating moderate-to-severe plaque psoriasis (early 2015) [[24815]]
[+]	Simvastatin	IM	3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (part of the mevalonate pathway, which functions in cholesterol and isoprenoid synthesis, which in turn plays a role in protein isoprenylation) [[11156]] Protein prenylation [[11155]] Expression of a variety of immunoregulatory molecules, including major histocompatibility class II and class I molecules [[11156]] [[11157]] Th17 cell differentiation [[11287]] Leukocyte-endothelial cell adhesion [[11160]]	Phase III [[11147]] [[11285]]	Oral [[11288]] In general, doses range from 5 to 40 mg per day for treating dyslipidemia [[11288]] In trials for MS, doses range from 40 to 80 mg per day [[11145]] [[11147]] [[11148]] [[11149]] [[11150]] [[11151]] [[11284]] [[11285]]	Discovered by scientists at Merck in 1985 [[11289]] Approved by the US Food and Drug Administration in 1991 for conditions related to coronary heart disease [[11288]] Marketed by Merck as Zocor [[11288]] Loses US patent protection, allowing generic versions to be sold (23 June 2006) [[11294]]
[+]	Siponimod	IM	Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P5 [[7168]] B cell distrubution [[7168]] T cell distribution [[7168]]	Phase III trial is underway as of July, 2013 [[7172]]	Oral [[7168]]	Clinical trials have been sponsored by Novartis Pharma [[7168]] [[7174]] [[7171]] [[6418]] [[7175]]
[+]	Teriflunomide	IS IM	Dihydroortate dehydrogenase [[411]] [[410]] Pyrimidine synthesis [[410]] Lymphocyte proliferation [[401]]	Approved in the US, EU, and other countries for RRMS [[3139]] [[4011]] [[5779]] [[7563]] [[8613]] [[10089]]	Oral [[341]]	Clinical trials have been sponsored by Sanofi-Aventis and Genzyme, a Sanofi company [[578]] [[580]] [[2006]] Marketing authorization application has been filed with the European Medicines Agency by Genzyme (23 February 2012) [[2108]] Approved by the US Food and Drug Administration as a once-daily, oral treatment for RRMS, on the basis of efficacy data from the TEMSO trial (12 September 2012) [[3139]] Approved by the Australian Therapeutic Goods Administration as a once-daily, oral treatment for relapsing forms of MS (21 November 2012) [[4011]] Given a recommendation for approval for adults with RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency, but was not recommended to receive a new active substance designation (22 March 2013) [[5366]] Approved by the National Administration of Drugs, Food and Medical Technology (Argentina) for treating relapsing forms of MS (8 April 2013) [[5779]] Received a positive opinion for a new active substance designation from the Committee for Medicinal Products for Human Use of the European Medicines Agency, reversing an earlier decision (28 June 2013) [[6591]] Planned registration and launch in MENA (Middle East and North Africa) will be handled by a partnership between Genpharm and Genzyme (5 August 2013) [[7124]] Approved by the European Commission as a once-daily, oral treatment for adults with RRMS (30 August 2013) [[7563]] Approved by Health Canada as a once-daily, oral treatment for RRMS (20 November 2013) [[8613]] Approved for use by the National Health Service in England and Wales as a treatment for adults with RRMS (January 2014) [[10102]] Approved for use as a treatment for adults with RRMS in Northern Ireland (February 2014) [[10102]] Approved for use by the National Health Service in Scotland as a treatment for adults with RRMS (10 March 2014) [[10089]] [[10102]] Inclusion of TOWER and TOPIC clinical trial data about efficacy and safety on the US label has been approved by the US Food and Drug Administration (20 October 2014) [[14788]] Genzyme, a Sanofi company, which markets teriflunomide, will now be referred to instead as Sanofi Genzyme (1 January 2016) (personal communication from Ameet Khara at Sanofi Genzyme)
[+]	Ustekinumab	IM	Subunit P40 on cytokines interleukin 12 and interleukin 23 [[437]]	Discontinued after Phase II trials showed a lack of efficacy [[625]]	Subcutaneous injection [[625]]	Clinical trials have been sponsored by Centocor, a subsidiary of Johnson & Johnson [[452]] [[625]] Centocor merges with Ortho Biotech to become Centocor Ortho Biotech Inc. (2008) [[13539]] Approved by the US Food and Drug Administration for treating plaque psoriasis (25 September 2009) [[13538]] Manufactured by Centocor Ortho Biotech Inc. at the time of approval for treating plaque psoriasis (25 September 2009) [[13538]] Before June 2011, marketed by Centocor Ortho Biotech Inc. in the US and Janssen-Ortho, Inc. outside the US [[619]] [[437]] [[13537]] Centocor Ortho Biotech Inc. changes its name to Janssen Biotech, Inc. (22 June 2011) [[13537]] Marketed by Janssen Biotech, Inc. as of 2011 [[13537]] [[13540]]

	Name	Trade name	Synonyms	Systematic name
[+]	Alemtuzumab	Lemtrada [[779]]	Alemtuzumab [[465]] Campath [[465]] Campath 1H [[465]] Campath 1H/LDP03 [[465]] "Campath" refers to the Department of Pathology at Cambridge University [[6512]] LDP-03 [[465]] UNII-3A189DH42V [[465]] ALEM [[432]] Lemtrada [[779]]	Immunoglobulin G1, anti-(human CD52 (antigen)) (human-rat monoclonalCAMPATH-1H gamma1-chain), disulfide with human-rat monoclonal CAMPATH-1H light chain, dimer [[465]]
[+]	Amiloride	Midamor [[12650]]	Amilorida [[12583]] Amiloride [[12583]] Amiloridum [[12583]] Amipramidin [[12583]] Amipramizid [[12583]] CCRIS 6545 [[12583]] EINECS 220-024-7 [[12583]] Guanamprazin [[12583]] N-Amidino-3,5-diamino-6-chloropyrazinecarboxamide [[12583]] N-Amidino-3,5-diamino-6-chlorpyrazincarboxamid [[12583]] UNII-7DZO8EB0Z3 [[12583]]	Pyrazinecarboxamide, 3,5-diamino-N-(aminoiminomethyl)-6-chloro- [[12583]]
[+]	ATX-MS-1467		M2736 [[20798]]
[+]	BGC20-0134	Pleneva [[473]]
[+]	BIIB033	Opicinumab [[29068]]	Anti-LINGO-1 antibody [[485]] Anti-LINGO-1 mAb [[16280]] Li81 [[10729]]
[+]	Cladribine	Movectro (in Australia and Russia) [[552]]	2-CdA [[465]] 2-Chloro-2'-deoxy-beta-adenosine [[465]] 2-Chloro-2'-deoxyadenosine [[465]] 2-Chloro-6-amino-9-(2-deoxy-beta-D-erythropentofuranosyl)purine [[465]] 2-Chlorodeoxyadenosine [[465]] Adenosine, 2-chloro-2'-deoxy- [[465]] BRN 0624220 [[465]] CCRIS 9374 [[465]] CdA [[554]] Chlorodeoxyadenosine [[465]] Cladarabine [[465]] Cladribine [[465]] HSDB 7564 [[465]] Leustatin [[465]] Movectro [[552]] NSC 105014 [[465]] NSC 105014-F [[465]] RWJ 26251 [[465]] UNII-47M74X9YT5 [[465]]	2-chlorodeoxyadenosine [[465]]
[+]	Cyclophosphamide	Clafen [[923]] Cyrevia [[1725]] Cytoxan [[927]] Endoxan [[927]] Neosar [[927]] Procytox [[927]] Revimmune [[927]]	(+-)-Cyclophosphamide [[465]] (RS)-cyclophosphamide [[465]] 1-Bis(2-chloroethyl)amino-1-oxo-2-aza-5-oxaphosphoridin [[465]] 2-(Bis(2-chloroethyl)amino)-2H-1,3,2-oxazaphosphorine 2-oxide [[465]] 2-(Bis(2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazophosphorine 2-oxide [[465]] 4-27-00-09750 [[465]] 4-Hydroxy-cyclophosphan-mamophosphatide [[465]] AI3-26198 [[465]] ASTA B518 [[465]] B 518 [[465]] BRN 0011744 [[465]] Bis(2-chloroethyl)phosphoramide cyclic propanolamide ester [[465]] CB 4564 [[465]] CCRIS 188 [[465]] Ciclofosfamida [[465]] Ciclophosphamide [[465]] Clafen [[465]] Claphene [[465]] CTX [[928]] Cy [[927]] Cyclophosphamid [[465]] Cyclophosphamidum [[465]] Cyclophosphan [[465]] Cyclophosphane [[465]] Cyclophosphanum [[465]] Cyclophosphoramide [[465]] Cyclostin [[465]] Cyklofosfamid [[465]] Cytophosphan [[465]] Cytophosphane [[465]] Cytoxan [[465]] EINECS 200-015-4 [[465]] Endoxan [[465]] Endoxan R [[465]] Endoxan-asta [[465]] Endoxana [[465]] Endoxanal [[465]] Genoxal [[465]] HSDB 3047 [[465]] Lyophilized cytoxan [[465]] N,N-Bis(2-chloroethyl)-N',O-propylenephosphoric acid ester diamide [[465]] N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2- oxide [[465]] N,N-Bis-(beta-chloroethyl)-N',O-propylenephosphoric acid ester diamide [[465]] N,N-Bis(beta-chloroethyl)-N',O-trimethylenephosphoric acid ester diamide [[465]] N,N-Bis-(beta-chloraethyl)-N',O-propylen-phosphorsaeure-ester-diamid [[465]] N,N-Di(2-chloroethyl)-N,O-propylene-phosphoric acid ester diamide [[465]] NCI-C04900 [[465]] NSC 26271 [[465]] NSC-26271 [[465]] Neosar [[465]] Phosphorodiamidic acid, N,N-bis(2-chloroethyl)-N'-(3- hydroxypropyl)-, intramol. ester [[465]] Procytox [[465]] RCRA waste number U058 [[465]] Revimmune [[927]] SK 20501 [[465]] Sendoxan [[465]] UNII-6UXW23996M [[465]] Zyklophosphamid [[465]]	2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-, 2-oxide [[465]] 2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-, 2-oxide (9CI) [[465]] 2H-1,3,2-Oxazaphosphorine, 2-(bis(2-chloroethyl)amino)tetrahydro-, 2- oxide [[465]]
[+]	Daclizumab	Zinbryta (Biogen) [[13746]] [[18038]] Zenapax (Hoffmann-La Roche) [[807]]; refers to an earlier formulation used for inhibiting rejection of organ transplants, which is distinct from daclizumab high yield process (HYP) [[15077]]	Anti-Tac [[454]] DAC [[432]] Dacliximab [[465]] Daclizumab [[465]] Daclizumab high yield process [[15077]] Daclizumab HYP [[15077]] Ro 24-7375 [[465]] UNII-CUJ2MVI71Y [[465]]	Immunoglobulin G 1 (human-mouse monoclonal clone 1H4 gamma-chain anti- human interleukin 2 receptor), disulfide with human-mouse monoclonal clone 1H4 light chain, dimer [[465]]
[+]	Dalfampridine	Ampyra [[493]] Fampyra (EU) [[496]]	4-AP [[465]] 4-Aminopyridine [[465]] 4-Pyridinamine [[465]] 4-Pyridylamine [[465]] 5-22-09-00106 (Beilstein Handbook Reference) [[465]] AI3-52547 [[465]] Amaya [[465]] Amino-4 pyridine [[465]] Ampyra [[465]] Avitrol [[465]] Avitrol 200 [[465]] BIIB041 [[18648]] BRN 0105782 [[465]] Caswell No. 038 [[465]] Compound 1861 [[465]] Dalfampridine [[465]] EINECS 207-987-9 [[465]] EL-970 [[465]] EPA Pesticide Chemical Code 069201 [[465]] Fampridine [[465]] Fampyra [[496]] HSDB 6037 [[465]] Mi-W-3 [[465]] NSC 15041 [[465]] Neurelan [[465]] Phillips 1861 [[465]] Pimadin (free base) [[465]] Prc 1237 [[465]] RCRA waste number P008 [[465]] UNII-BH3B64OKL9 [[465]] VMI 10-3 [[465]] gamma-Aminopyridine [[465]] p-Aminopyridine [[465]]	4-Pyridinamine [[465]] 4-Pyridylamine [[465]] Pyridine, 4-amino- [[465]]
[+]	Dimethyl fumarate	Tecfidera [[5317]] A mixture of dimethyl fumarate and salts of monoethylfumarate is marketed in Germany as Fumaderm [[380]]	2-Butenedioic acid, dimethyl ester, (E)- [[465]] 4-02-00-02205 (Beilstein Handbook Reference) [[465]] AI3-07872 [[465]] AZL O 211089 [[465]] Allomaleic acid dimethyl ester [[465]] BG 00012 [[465]] BG-12 [[341]] BG 12 [Fumarate] [[465]] BG 12 compound [[465]] BG-00012 [[465]] BG00012 [[465]] BRN 0774590 [[465]] Boletic acid dimethyl ester [[465]] Dimethyl fumarate [[465]] Dimethyl trans-ethylenedicarboxylate [[465]] Dimethylester kyseliny fumarove [[465]] Dimethylester kyseliny fumarove [Czech] [[465]] Dimethylfumarate [[465]] DMF [[341]] EINECS 210-849-0 [[465]] Ethylene, 1,2-bis(methoxycarbonyl)-, trans- [[465]] FAG 201 [[465]] FAG201[[465]] FP187 [[14441]] Fumaderm [[465]] Fumaric acid, dimethyl ester [[465]] HSDB 7725 [[465]] Methyl fumarate [[465]] NSC 167432 [[465]] NSC 25942 [[465]] TL 353 [[465]] UNII-FO2303MNI2 [[465]] trans-1,2-Ethylenedicarboxylic acid dimethyl ester [[465]] trans-Butenedioic acid dimethyl ester [[465]]	2-Butenedioic acid (2E)-, 1,4-dimethyl ester [[465]] 2-Butenedioic acid (2E)-, dimethyl ester [[465]] 2-Butenedioic acid (E)-, dimethyl ester [[465]] 2-Butenedioic acid, dimethyl ester, (E)- [[465]] Dimethyl fumarate [[465]] Fumaric acid, dimethyl ester (8CI) [[465]]
[+]	Dronabinol	Marinol [[9534]]	(-)-delta(sup 1)-3,4-trans-Tetrahydrocannabinol [[9469]] (-)-delta9-trans-Tetrahydrocannabinol [[9469]] (6aR,10aR)-6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo(b,d)pyran-1-ol [[9469]] (l)-delta(sup 1)-Tetrahydrocannabinol [[9469]] 1-trans-delta(sup 9)-Tetrahydrocannabinol [[9469]] 1-trans-delta-9-Tetrahydrocannabinol [[9469]] 3-Pentyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-dibenzo(b,d)pyran-1-ol [[9469]] 6,6,9-Trimethyl-3-pentyl-7,8,9,10-tetrahydro-6H-dibenzo(b,d)pyran-1-ol [[9469]] 6H-Dibenzo(b,d)pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-, (6aR-trans)- [[9469]] Abbott 40566 [[9469]] Cannabinol, 1-trans-delta(sup 9)-tetrahydro- [[9469]] Cannabinol, delta1-tetrahydro- [[9469]] CCRIS 4726 [[9469]] Δ9-Tetrahydrocannabinol [[6803]] Δ9-THC [[9470]] delta(9)-Tetrahydrocannibinol [[9469]] delta(sup 1)-Tetrahydrocannabinol [[9469]] delta(sup 1)-Thc [[9469]] delta(sup 9)-Tetrahydrocannabinol [[9469]] delta(sup 9)-Thc [[9469]] delta-9 Tetrahydrocannabinol [[9469]] delta-9-THC [[9475]] delta1-Tetrahydrocannabinol [[9469]] delta1-Tetrahydrocannabinol (VAN) [[9469]] delta1-THC [[9469]] delta9-Tetrahydrocannabinol (VAN) [[9469]] delta9-THC [[9469]] Deltanyne [[9469]] Dronabinolum [[9469]] HSDB 6471 [[9469]] l-delta1-trans-Tetrahydrocannabinol [[9469]] Marinol [[9469]] Namisol [[9469]] NSC 134454 [[9469]] QCD 84924 [[9469]] QCD-84924 [[9469]] SP 104 [[9469]] Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo(b,d)pyran-1-ol [[9469]] Tetrahydrocannabinol [[9469]] Tetrahydrocannabinols (-)-delta1-3,4-trans-form [[9469]] THC [[9469]] UNII-7J8897W37S [[9469]]	1-trans-delta9-Tetrahydrocannabinol [[9469]] 6H-Dibenzo(b,d)pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-, (6aR,10aR)- [[9469]] 6H-Dibenzo(b,d)pyran-1-ol, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-, (6aR-trans)- [[9469]]
[+]	Estriol	Trimesta [[864]]	(16alpha,17beta)-Estra-1,3,5(10)-triene-3,16,17-triol [[465]] (16alpha,17beta)-Oestra-1,3,5(10)-triene-3,16,17-triol [[465]] 1,3,5-Estratriene-3beta,16alpha,17beta-triol [[465]] 1,3,5-Oestratriene-3beta,16alpha,17beta-triol [[465]] 16-alpha,17-beta-Estriol [[465]] 16-alpha,17-beta-Oestriol [[465]] 16-alpha-Hydroxyestradiol [[465]] 16-alpha-Hydroxyoestradiol [[465]] 16alpha,17beta-Estriol [[465]] 16alpha,17beta-Oestriol [[465]] 16alpha-Hydroxy-17beta-estradiol [[465]] 16alpha-Hydroxyestradiol [[465]] 16alpha-Hydroxyoestradiol [[465]] 3,16-alpha,17-beta-Estriol [[465]] 3,16-alpha,17-beta-Oestriol [[465]] 3,16-alpha,17-beta-Trihydroxy-delta-1,3,5-estratriene [[465]] 3,16-alpha,17-beta-Trihydroxy-delta-1,3,5-oestratriene [[465]] 3,16-alpha,17-beta-Trihydroxyestra-1,3,5(10)-triene [[465]] 3,16-alpha,17-beta-Trihydroxyoestra-1,3,5(10)-triene [[465]] 3,16alpha,17beta-Estriol [[465]] 3,16alpha,17beta-Trihydroxy-1,3,5(10)-estratriene [[465]] 3,16alpha,17beta-Trihydroxy-delta-1,3,5-oestratriene [[465]] 4-06-00-07550 (Beilstein Handbook Reference) [[465]] A 13610 [[465]] Aacifemine [[465]] BRN 2508172 [[465]] CCRIS 284 [[465]] Destriol [[465]] Deuslon-A [[465]] EINECS 200-022-2 [[465]] Estra-1,3,5(10)-trien-3,16alpha,17beta-triol [[465]] Estra-1,3,5(10)-triene-3,16alpha,17beta-triol [[465]] Estratriol [[465]] Estriol [[465]] Estriol, unconjugated [[465]] Estriolo [[465]] Estriolo [Italian] [[465]] Follicular hormone hydrate [[465]] Gynaesan [[465]] HSDB 3590 [[465]] Hemostyptanon [[465]] Holin [[465]] Hormomed [[465]] Hormonin [[465]] Klimoral [[465]] NSC 12169 [[465]] NSC-12169 [[465]] OE3 [[465]] Oestra-1,3,5(10)-triene-3,16-alpha,17-beta-triol [[465]] Oestra-1,3,5(10)-triene-3,16alpha,17beta-triol [[465]] Oestratriol [[465]] Oestriol [[465]] Oestriolum [[465]] Orestin [[465]] Orgastyptin [[465]] Ortho-Gynest [[465]] Overstin [[465]] Ovestin [[465]] Ovestrion [[465]] Stiptanon [[465]] Synapause [[465]] Theelol [[465]] Thulol [[465]] Tridestrin [[465]] Trihydroxyestrin [[465]] Trihydroxyoestrin [[465]] Triodurin [[465]] Triovex [[465]] UNII-FB33469R8E [[465]] Trimesta [[864]]	Estra-1,3,5(10)-triene-3,16,17-triol, (16alpha,17beta)- [[465]]
[+]	Fingolimod	Gilenya [[307]] Neskler (generic version marketed in Russia) [[25783]]	2-Amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol [[465]] FTY-720 [[465]] FTY720 [[465]] Fingolimod [[465]] Gilenia [[465]] Gilenya [[465]] Neskler [[25783]] TDI-132 [[4978]] UNII-3QN8BYN5QF [[465]]	1,3-Propanediol, 2-amino-2-(2-(4-octylphenyl)ethyl)- [[303]]
[+]	Firategrast	N/A	Firategrast [[465]] SB 683699 [[465]] SB-683699 [[465]] UNII-OJY3SK9H5F [[465]]	1,1'-Biphenyl)-4-propanoic acid, alpha-((2,6-difluorobenzoyl)amino)-4'-(ethoxymethyl)-2',6'-dimethoxy-, (alphaS)- [[465]] 2S)-2-((2,6-Difluorobenzoyl)amino)-3-(4'-(ethoxymethyl)-2',6'-dimethoxybiphenyl-4- yl)propanoic acid [[465]]
[+]	Flupirtine	Effirma (US) [[1497]] Katadolon (Brazil, Germany, Latvia, Estonia, Slovakia, Lithiania, Russian Federation) [[1498]] Awegal (Germany) [[1498]] Efiret (Italy) [[1498]] Metanor (Portugal) [[1498]] Trancolong (Germany) [[1498]] Trancopal Dolo (Germany) [[1498]]	EINECS 260-503-8 [[465]] Flupirtine [[465]] Flupirtino [[465]] Flupirtino [INN-Spanish][[465]] Flupirtinum [[465]] Flupirtinum [INN-Latin] [[465]] UNII-MOH3ET196H [[465]] Effirma (US) [[1497]] Katadolon (Brazil, Germany, Latvia, Estonia, Slovakia, Lithiania, Russian Federation) [[1498]] Awegal (Germany) [[1498]] Efiret (Italy) [[1498]] Metanor (Portugal) [[1498]] Trancolong (Germany) [[1498]] Trancopal Dolo (Germany) [[1498]]	Carbamic acid, (2-amino-6-(((4-fluorophenyl)methyl)amino)-3-pyridinyl)-, ethyl ester [[465]]
[+]	Glatiramer acetate	Copaxone [[490]] Glatopa (generic) [[18343]] Polimunol (Synthon; marketed in Argentina as a generic version as of May 2014) [[25147]]	COP-1 [[465]] Copaxone [[490]] Copolymer-1 [[465]] GA [[343]] GA Depot [[15983]] Glatopa [[18343]] L-Glutamic acid peptide with L-alanine, L-lysine and L-tyrosine, acetate (salt) [[465]] GTR [[10369]] M356 [[18343]] UNII-5M691HL4BO [[465]]	L-Glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt) [[465]]
[+]	GNbAC1
[+]	Idebenone	Avan (Takeda Chemical Industries, Japan) [[8759]] Catena (Santhera Pharmaceuticals, Switzerland) [[8762]] Cerestabon [[8774]] Daruma [[8774]] Mnesis [[8774]] Raxone (Santhera Pharmaceuticals, Switzerland) [[8762]] Sovrima (Santhera Pharmaceuticals, Switzerland) [[8773]]	6-(10-Hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone [[465]] BRN 2001459 [[465]] CV 2619 [[465]] Hydroxydecyl-ubiquinone [[8757]] Idebenona [[465]] Idebenonum [[465]] SNT MC17 [[8774]] UNII-HB6PN45W4J [[465]]	2,5-Cyclohexadiene-1,4-dione, 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl- [[465]] 2,5-Cyclohexadiene-1,4-dione, 5,6-dimethoxy-2-(10-hydroxydecyl)-3-methyl- [[465]] 2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-p-benzoquinone [[465]]
[+]	Imilecleucel-T	Tcelna [[7692]] Tovaxin (former name for Tcelna) [[7692]]		N/A
[+]	Interferon beta-1a	Avonex [[1063]] Rebif [[1064]] CinnoVex (approved as a generic in Iran) [[1065]] [[14168]] Plegridy (peginterferon beta-1a) [[5316]]	Avonex [[465]] BIIB017 (PEGylated interferon beta-1a) [[12800]] CinnoVex [[1065]] Genfaxon [[14786]] Interferon beta-1a [[465]] Neoferon [[465]] Recombinant human interferon beta 1a [[465]] UNII-XRO4566Q4R [[465]] Rebif [[1064]]	Interferon beta1 (human fibroblast protein moiety) [[465]]
[+]	Interferon beta-1b	Betaseron (in the US) [[1134]] [[1179]] Betaferon (in Europe) [[1134]] Extavia [[1160]] ZIFERON [[1175]]	17-L-Serine-2-166-interferon beta1 (human fibroblast reduced) [[465]] BAY 86-5046 [[465]] BAY86-5046 [[465]] Betaferon [[465]] Betaseron [[465]] DRG-0054 [[465]] Extavia [[465]] IFN-beta (sub ser) [[465]] IFNB-1b [[1192]] IFNbeta-1b [[1141]] Interferon beta-1b [[465]] Interferon-1b [[465]] UNII-TTD90R31WZ [[465]] ZIFERON [[1175]]	2-166-Interferon beta1 (human fibroblast reduced), 17-L-serine- [[465]] Interferon beta1, 17-L-serine-, (2S-(2R,5R))- [[465]]
[+]	Laquinimod	Nerventra [[9529]]	5-Chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide [[465]] ABR 215062 [[465]] ABR-215062 [[465]] N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide [[465]] N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide [[465]] UNII-908SY76S4G [[465]]	3-Quinolinecarboxamide, 5-chloro-N-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phenyl- [[465]]
[+]	Masitinib	N/A	4-((4-Methylpiperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)-1,3-thiazol-2-yl)amino)phenyl)benzamide [[465]] AB 1010 [[465]] AB-1010 [[465]] AB1010 [[465]] Masitinib [[465]] UNII-M59NC4E26P [[465]]	4-((4-Methylpiperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)-1,3-thiazol-2-yl)amino)phenyl)benzamide [[465]]
[+]	MEDI-551		MEDI 551 [[11913]]
[+]	Minocycline	Arestin (US) [[6943]] Dynacin (US) [[6946]] Minocin (US) [[6938]] Myrac (US) [[6948]] Solodyn (US) [[6945]] Ximino (US) [[6949]] Akamin (Australia) [[6942]] Borymycin (Philippines, Singapore, Taiwan) [[6942]] Cyclimycin (South Africa) [[6942]] Cynomycin (India) [[6942]] Klinomycin (Germany) [[6942]] Lederderm (Germany) [[6942]] Mestacine (France) [[6942]] Micromycin (Mexico) [[6942]] Minaxen (Hong Kong) [[6942]] Mino-50 (Belgium) [[6942]] Minocin G (Taiwan) [[6942]] Minocin MR (Hong Kong) [[6942]] Minoclin (Israel) [[6942]] Minoclir 50 (Germany) [[6942]] Minocyclin 50 Stada (Germany) [[6942]] Minoderm (Brazil) [[6951]] Minogalen (Germany) [[6942]] Minoline (Taiwan) [[6942]] Minomycin (Japan, South Africa) [[6942]] Minotab 50 (New Zealand, South Africa) [[6942]] Mino-Wolff (Germany) [[6942]] Mynocine (France) [[6942]] Romin (South Africa) [[6942]] Skinocyclin (Germany) [[6942]] Spicline (France) [[6942]] Vectrin (Ireland) [[6947]]	4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a- tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide [[465]] 7-Dimethylamino-6-demethyl-6-deoxytetracycline [[465]] Borymycin [[465]] BRN 3077644 [[465]] CL 59806 [[465]] HSDB 3130 [[465]] Minociclina [[465]] Minociclina [INN-Spanish] [[465]] Minocyclin [[465]] Minocycline hydrochloride [[6938]] Minocyclinum [[465]] Minocyclinum [INN-Latin] [[465]] Minocyn [[465]] Minoz [[465]] NSC 141993 [[465]] Tri-minocycline [[465]] UNII-FYY3R43WGO [[465]]	2-Naphthacenecarboxamide, 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4S,4aS,5aR,12aS)- [[465]] 2-Naphthacenecarboxamide, 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4S- (4alpha,4aalpha,5aalpha,12aalpha))- [[465]]
[+]	MIS416
[+]	Mitoxantrone	Novantrone [[917]]	MTX [[505]] 1,4-Bis(2-(2-hydroxyethylamino)ethyl)amino)-5,8-dihydroxyanthraquinone [[465]] 1,4-Dihydroxy-5,8-bis(2-((2-hydroxyethyl)amino)ethylamino)-9,10-anthracenedione [[465]] 1,4-Dihydroxy-5,8-bis(5-hydroxy-3-azapentylamino)anthrachinon [[465]] 5,8-Bis((2-((2-hydroxyethyl)amino)ethyl)amino)-1,4-dihydroxyanthraquinone [[465]] BRN 2795126 [[465]] CCRIS 7604 [[465]] DHAQ [[465]] Dihydroxyanthraquinone [[465]] Mitoxanthrone [[465]] Mitoxantrona [[465]] Mitoxantrona [INN-Spanish] [[465]] Mitoxantronum [[465]] Mitoxantronum [INN-Latin] [[465]] NSC 279836 [[465]] Novantron [[465]] UNII-BZ114NVM5P [[465]] Mitoxantrone hydrochloride [[918]]	9,10-Anthracenedione, 1,4-dihydroxy-5,8-bis((2-((2 hydroxyethyl)amino)ethyl)amino)- (9CI) [[465]] Anthraquinone, 5,8-bis((2-((2- hydroxyethyl)amino)ethyl)amino)-1,4-dihydroxy- [[465]]
[+]	Mycophenolate mofetil	CellCept [[597]]	CellCept [[465]]	4-Hexenoic acid, 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-ethyl-, 2-(4-morpholinyl)ethyl ester, (E) [[465]]
[+]	Naltrexone	Lodonal (outside of US) (for use off-label as an immune modulator) [[16576]] Depade (for treating alcohol and opioid dependence) [[9973]] ReVia (for treating alcohol and opioid dependence) [[9973]] Vivitrol (for treating alcohol and opioid dependence) [[9939]] [[9940]]	17-(Cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one [[9934]] 17-(Cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan-6-one [[9934]] BRN 3596648 [[9934]] CCRIS 3506 [[9934]] Celupan [[9934]] Depade [[9934]] EINECS 240-649-9 [[9934]] EN-1639A [as hydrochloride] [[9934]] Endo 1639A [[9972]] HSDB 6750 [[9934]] LDN (low-dose naltrexone) [[9935]] Lodonal [[16576]] N-Cyclopropylmethyl-14-hydroxydihydromorphinone [[9934]] N-Cyclopropylmethylnoroxymorphone [[9934]] Naltrexona [[9934]] Naltrexonum [[9934]] ReVia [[9934]] UM-792 [[9934]] UNII-5S6W795CQM [[9934]] Vivitrex [[9934]] Vivitrol [[9934]]	Morphinan-6-one, 17-(cyclopropylmethyl)-4,5-alpha-epoxy-3,14-dihydroxy- [[9934]] Morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-, (5alpha)- [[9934]]
[+]	Natalizumab	Tysabri [[588]]	Antegren [[465]] Immunoglobulin G4 (human-mouse monoclonal AN100226 4-chain anti- human integrin 4), disulfide with human-mouse monoclonal AN100226 light chain, dimer [[465]] Natalizumab [[465]] Tysabri [[465]] UNII-3JB47N2Q2P [[465]]	Immunoglobulin G4, anti-(human integrin alpha4) (human-mouse monoclonal AN100226 gamma4-chain), disulfide with human-mouse monoclonal AN100226 light chain, dimer [[465]]
[+]	Ocrelizumab	Ocrevus [[26945]]	Ocrelizumab [[465]] PR070769 [[465]] PRO-70769 [[465]] UNII-A10SJL62JY [[465]] rhuMAb 2H7 [[465]] OCRE [[432]]	Immunoglobulin G1, anti (human CD20 (antigen)) (human mouse monoclonal 2H7 γ1 chain), disulfide with human mouse monoclonal 2H7 κ chain, dimer [[653]]
[+]	Ofatumumab	Arzerra [[645]]	Arzerra [[465]] GSK 1841157 [[465]] GSK1841157 [[465]] HuMax-CD20 [[465]] Ofatumumab [[465]] UNII-M95KG522R0 [[465]]	Immunoglobulin G1, anti-(human CD20 (antigen))(human monoclonal HuMax- CD20 heavy chain), disulfide with human monoclonal HuMax-CD20 kappa- chain, dimer [[465]]
[+]	ONO-4641	Ceralifimod [[11845]]	MSC2430913A [[628]] ONO 4641 [[11846]] ONO4641 [[11846]]
[+]	Ozanimod		RPC1063 [[3777]]
[+]	Phenytoin	Dilantin [[10867]] Phenytek [[10868]]	5,5-Diphenyl-2,4-imidazolidinedione [[10865]] 5,5-Diphenylhydantoin [[10865]] 5,5-Diphenylimidazolidin-2,4-dione [[10865]] 5,5-Dwufenylohydantoina [[10865]] AI3-52498 [[10865]] Aleviatin [[10865]] Auranile [[10865]] Causoin [[10865]] CCRIS 515 [[10865]] Comitoina [[10865]] Convul [[10865]] Danten [[10865]] Dantinal [[10865]] Dantoinal [[10865]] Dantoinal klinos [[10865]] Dantoine [[10865]] Denyl [[10865]] Di-Hydan [[10865]] Di-Lan [[10865]] Di-Phetine [[10865]] Didan TDC 250 [[10865]] Difenilhidantoina [[10865]] Difenin [[10865]] Difetoin [[10865]] Difhydan [[10865]] Dihycon [[10865]] Dihydantoin [[10865]] Dilabid [[10865]] Dilantin [[10865]] Dilantin acid [[10865]] Dilantin-125 [[10865]] Dilantin-30 [[10865]] Dilantine [[10865]] Dillantin [[10865]] Dintoin [[10865]] Dintoina [[10865]] Diphantoin [[10865]] Diphedal [[10865]] Diphedan [[10865]] Diphenin [[10865]] Diphenine [[10865]] Diphentyn [[10865]] Diphenylan [[10865]] Diphenylhydantoin [[10865]] Diphenylhydantoine [[10865]] Ditoinate [[10865]] DPH [[10865]] EINECS 200-328-6 [[10865]] Ekko [[10865]] Elepsindon [[10865]] Enkelfel [[10865]] Epamin [[10865]] Epasmir "5" [[10865]] Epdantoine simple [[10865]] Epelin [[10865]] Epifenyl [[10865]] Epihydan [[10865]] Epilan D [[10865]] Epilan-D [[10865]] Epilantin [[10865]] Epinat [[10865]] Epised [[10865]] Eptal [[10865]] Fenantoin Mn Pharma [[10865]] Fenidantoin "s" [[10865]] Fenitoina [[10865]] Fentoin [[10865]] Fenylepsin [[10865]] Fenytoin Dak [[10865]] Fenytoine [[10865]] Gerot-epilan-D [[10865]] Hidan [[10865]] Hidantal [[10865]] Hidantilo [[10865]] Hidantina [[10865]] Hidantina senosian [[10865]] Hidantina vitoria [[10865]] Hidantomin [[10865]] HSDB 3160 [[10865]] Hydantal [[10865]] Hydantoinal [[10865]] Ictalis simple [[10865]] Idantoil [[10865]] Idantoin [[10865]] Iphenylhydantoin [[10865]] Kessodanten [[10865]] Labopal [[10865]] Lehydan [[10865]] Lepitoin [[10865]] Lepsin [[10865]] Minetoin [[10865]] NCI-C55765 [[10865]] Neos-hidantoina [[10865]] Neosidantoina [[10865]] Novantoina [[10865]] Novophenytoin [[10865]] NSC 8722 [[10865]] OM hidantoina simple [[10865]] OM-Hydantoine [[10865]] Oxylan [[10865]] Phanantin [[10865]] Phanatine [[10865]] Phenatine [[10865]] Phenatoine [[10865]] Phenhydanin [[10865]] Phentoin [[10865]] Phentytoin [[10865]] Phenytoin AWD [[10865]] Phenytoin-Gerot [[10865]] Phenytoine [[10865]] Phenytoinum [[10865]] Ritmenal [[10865]] Saceril [[10865]] Sanepil [[10865]] Silantin [[10865]] Sinergina [[10865]] Sodanthon [[10865]] Sodantoin [[10865]] Sodanton [[10865]] Sodium diphenylhydantoinate [[10866]] Solantin [[10865]] Sylantoic [[10865]] Thilophenyl [[10865]] TOIN [[10865]] Toin unicelles [[10865]] UNII-6158TKW0C5 [[10865]] Zentronal [[10865]] Zentropil [[10865]]	2,4-Imidazolidinedione, 5,5-diphenyl- [[10865]] Hydantoin, 5,5-diphenyl- [[10865]]
[+]	Raltegravir	Isentress [[8955]]	MK 0518 [[465]] MK-0518 [[9200]] N-(2-(4-(4-Fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide [[465]] UNII-22VKV8053U [[465]]	4-Pyrimidinecarboxamide, N-((4-fluorophenyl)methyl)-1,6-dihydro-5-hydroxy-1-methyl-2-(1-methyl-1-(((5-methyl-1,3,4-oxadiazol-2-yl)carbonyl)amino)ethyl)-6-oxo- (9CI) [[465]]
[+]	Riluzole	Rilutek [[13301]]	2-Amino-6-(trifluoromethoxy)benzothiazole [[12916]] 2-Amino-6-trifluoromethoxy benzothiazole [[13362]] 2-Benzothiazolamine, 6-(trifluoromethoxy)- [[12916]] Amino-2 trifluoromethoxy-6 benzothiazole [[12916]] Rilutek [[12916]] Riluzol [[12916]] Riluzolum [[12916]] RP 54274 [[12916]] PK 26124 [[13362]] UNII-7LJ087RS6F [[12916]]	2-Benzothiazolamine, 6-(trifluoromethoxy)- [[12916]] Benzothiazole, 2-amino-6-trifluoromethoxy- [[12916]]
[+]	Rituximab	Rituxan [[481]] MabThera [[484]] MabThera SC (subcutaneous version) [[10370]] Mabtas (biosimilar version) [[5912]]	HSDB 7455 [[465]] IDEC-102 [[465]] Immunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 gamma1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC- C2B8 kappa-chain, dimer [[465]] Mabtas [[5912]] Mab Thera [[465]] MabThera [[484]] Rituxan [[465]] Rituximab [[465]] UNII-4F4X42SYQ6 [[465]]	Immunoglobulin G1, anti-(human CD20 (antigen)(human-mouse monoclonal IDEC-C2B8 gamma1-chain), disulfide with human-mouse monoclonal IDEC- C2B8 kappa-chain, dimer [[465]]
[+]	RTL1000
[+]	Secukinumab	Cosentyx [[24815]]	AIN 457 [[465]] AIN457 [[465]] UNII-DLG4EML025 [[465]]	Immunoglobulin G1, anti-(human interleukin-17A (IL-17, cytotoxic T- lymphocyte-associated antigen 8)) [[465]] Human monoclonal AIN457 gamma1 heavy chain (230-215')-disulfide with human monoclonal AIN457 kappa light chain dimer (236-236'':239-239'')-bisdisulfide [[465]]
[+]	Simvastatin	ZOCOR [[11288]]	2,2-Dimethylbutyric acid, 8-ester with (4R,6R)-6-(2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl)ethyl)tetrahydro-4-hydroxy-2H-pyran-2-one [[11152]] BRN 4768037 [[11152]] Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester, (1S-(1alpha,3alpha,7beta,8beta(2S,4S),8abeta))- [[11152]] CCRIS 7558 [[11152]] Cholestat [[11152]] Coledis [[11152]] Colemin [[11152]] Corolin [[11152]] Denan [[11152]] DRG-0320 [[11152]] HSDB 7208 [[11152]] L 644128-000U [[11152]] Labistatin [[11152]] Lipex [[11152]] Lodales [[11152]] Medipo [[11152]] MK 0733 [[11152]] MK-0733 [[11152]] MK-733 [[11152]] Nivelipol [[11152]] Pantok [[11152]] Rechol [[11152]] Rendapid [[11152]] Simovil [[11152]] Simvastatina [[11152]] Simvastatine [[11152]] Simvastatinum [[11152]] Sinvacor [[11152]] Sivastin [[11152]] Synvinolin [[11152]] UNII-AGG2FN16EV [[11152]] Vasotenal [[11152]] Velostatin [[11152]] Zocor [[11152]] Zorced [[11152]] Zosta [[11152]]	Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-((2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester [[11152]] Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester, (1S-(1alpha,3alpha,7beta,8beta(2S,4S),8abeta))- [[11152]]
[+]	Siponimod		BAF312 [[7168]] [[7174]] BAF 312 [[465]] UNII-RR6P8L282I [[465]]	(1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethylbenzyloxyimino]-ethyl}-2-ethylbenzyl)-azetidine-3-carboxylic acid) [[7168]]
[+]	Teriflunomide	Aubagio [[465]] Leflunomide (the prodrug from which teriflunomide is derived), is marketed by Sanofi Aventis US as Arava [[582]]	(Z)-2-Cyano-alpha'alpha'alpha-trifluoro-3-hydroxy-p-crotonotoluidide [[465]] 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-butenamide [[465]] A 771726 [[465]] A77 1726 [[465]] A771726 [[465]] Active metabolite of leflunomide [[465]] Aubagio [[465]] Flucyamide [[465]] HMR 1726 [[465]] HMR1726 [[22570]] Malononitrilamide [[465]] N-(4-Trifluoromethylphenyl)-2-cyano-2-hydroxycrotonamide [[465]] RS-61980 [[411]] SU 20 [[465]] Teriflunomide [[465]] UNII-1C058IKG3B [[465]]	2-Butenamide, 2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl) [[465]]
[+]	Ustekinumab	Stelara [[452]]	CNTO 1275 [[465]] Stelara [[465]] UNII-FU77B4U5Z0 [[465]] Ustekinumab [[465]] USTE [[432]]	Immunoglobulin G1, anti-(human interleukin 12 p40 subunit) (human monoclonal CNTO 1275 gamma1-chain), disulfide with human monoclonal CNTO 1275 kappa-chain, dimer [[465]]

	Name	Class types	Target	Properties	Mechanism/Effects (Human)	Mechanism/Effects (Animal)
[+]	Alemtuzumab	IS NP	CD52 [[435]]	Molecular weight, ~150 kDa [[465]] Produced in mammalian cell (Chinese hamster ovary) suspension culture in medium containing neomycin [[781]] Recombinant DNA-derived humanized monoclonal antibody directed against the 21-28 kD cell surface glycoprotein, CD52 [[781]] Humanized IgG1 kappa antibody with human variable framework and constant regions, and complementarity-determining regions from a murine (rat) monoclonal [[781]] Y-shaped molecule with two 24 kDa light polypeptide chains and two 55 kDa heavy polypeptide chains [[436]] Half life is approximately 288 hours, or 12 days [[782]] Terminal half-life in patients undergoing bone marrow transplants to prevent graft versus host disease and transplant rejection was 15-21 days [[462]] In patients with chronic lymphocytic leukemia (CLL), terminal half life of injected drug was longer in those with undetectable CLL cells, and shorter in those with a substantial tumor burden, with an average of 6.1 days [[459]] Complex pharmacokinetics with non-linear elimination; clearance reduces with repeated administration and the half-life recorded varies with dose given and period after treatment [[783]] Affinity constants for binding to CD52 have been determined [[780]] [[781]]	Swiftly and fully depletes CD52-bearing cells, which include T and B lymphocytes, natural killer cells, dendritic cells, most monocytes and macrophages, and cells of the male reproductive system [[435]] Depletes cells that cause antibody-mediated cytotoxicity, suggesting that immune-cell depletion occurs via complement-dependent cytotoxicity [[435]] Does not target erythrocytes, platelets, or bone marrow stem cells [[780]] Depletes B lymphocyte levels, which return to baseline 3 months after treatment; levels rise to 165% 1 year after treatment; immature transitional B lymphocytes predominate at 1 month, but mature naïve B lymphocytes overtake them after 3 months; B-cell-activating factor, which helps spur this transition, also surges in that timeframe, remaining elevated by 33% for at least 12 months [[442]] Depletes memory B cells, which recover to only 25% of normal levels in a year [[432]] Depletes effector T cells; counts recover slowly, with CD4+ depletion lasting a median of 61 months and CD8+ cells lasting 30 months, but regulatory T cells expressing FoxP3 recover much quicker [[420]] A single course of the drug depletes lymphocytes; in patients with progressive MS (n=36), B cell counts recovered to the lower limit of the normal range in about 8 months and T cell subset counts recovered after 3 years, but usually not to values at the baseline [[4209]] Depletes circulating CD4+ lymphocytes almost completely by day 7 after initiation of treatment, after which CD4+CD25+CD127[low] regulatory T cells expand preferentially among this cell subset (peaking at month 1), followed by CD4+ cells that express transforming growth factor beta 1, interleukin 10 (IL-10), and IL-4 (which peak at month 3), as shown by studies of participants in the CARE-MS II trial [[8410]] Depletes circulating CD4+ lymphocytes almost completely by day 7 after initiation of treatment, and whereas some CD4+ cell populations expand in the first several months, levels of T helper cells Th1 and Th17 are decreased at months 12 and 24 versus baseline, as shown by studies of participants in the CARE-MS II trial [[8410]] Depletes circulating CD4+ lymphocytes almost completely by day 7 after initiation of treatment, which is followed by a slow increase in serum levels of interleukin 7 (IL-7) and IL-4 and decreases in serum levels of IL-17A, IL-17F, IL-21, IL-22, and interferon gamma, as shown by studies of participants in the CARE-MS II trial [[8410]] Depletes CD19+, CD8+, and CD4+ cell counts, which recover over a median of 3, 19.5, and 32 months, respectively (based on a study of 108 individuals); the time to recovery of any of these populations does not correlate with disease activity or disability accumulation [[11105]] Causes complement-dependent cytolysis of T lymphocytes in vitro, such that the population that remains has an increased proportion of regulatory T cells [[8209]] Mediates an increase in the frequency of regulatory T cells (in a population of T lymphocytes) in vitro, and these regulatory T cells inhibit the allogeneic response of autologous T cells in a manner that requires cell-cell contact and interleukin 2 [[8209]] Persistently increases levels of mRNAs encoding anti-inflammatory cytokines interleukin 10 (IL-10), IL-27, and transforming growth factor beta, as shown by analysis of peripheral blood from 29 participants from the CARE-MS I and CARE-MS II trials at months 1, 6, 12, 18, and 24 [[26136]] Persistently decreases levels of mRNAs encoding Th1 and Th2-related proinflammatory molelcules, as shown by analysis of peripheral blood from 29 participants from the CARE-MS I and CARE-MS II trials at months 1, 6, 12, 18, and 24 [[26136]] Persistently decreases the percentage of CD4+ cells, but does not affect percentages of Th1 and Th17 cells, as shown by analysis of peripheral blood from 29 participants from the CARE-MS I and CARE-MS II trials at months 1, 6, 12, 18, and 24 [[26136]] Increases the percentage of regulatory T (Treg) cells at month 24, and this increase was associated with increased Treg cell suppressive activity against Th1 and Th17 cells specific for myelin basic protein, as shown by analysis of peripheral blood from 29 participants from the CARE-MS I and CARE-MS II trials at months 1, 6, 12, 18, and 24 [[26136]] Does not appear to affect immunocompetency in individuals with MS, such that serum antibodies that recognize common viruses are present after treatment and vaccine responses to several types of antigens (T-cell-dependent recall antigens, a T-cell-dependent novel antigen, and T-cell-independent antigens) are normal, as shown by a historically controlled pilot study [[7136]] Causes thyroid autoimmunity in MS patients with increased levels of interleukin 21 (IL-21) because that cytokine drives production of self-reactive T cells, which suggests that IL-21 serum levels and genetic analysis may predict risk of thyroid autoimmunity [[442]] Can lead to autoimmunity, which positively correlates with high baseline serum levels of interleukin 21 (IL-21), but only one enzyme linked immunosorbent assay kit for testing IL-21 levels appears useful for predicting autoimmunity [[9079]] May trigger neuroprotective autoimmunity, based on long-term followup of CAMMS223 (Phase II) trial, in which treated patients showed improvement long after drug administration [[420]] Enhances production of brain-derived neurotrophic factor and ciliary neurotrophic factor in lymphocytes, as determined by analysis of lymphocytes derived from treated versus untreated patients [[790]] Causes adverse autoimmune effects only in patients with MS and other immune-mediated diseases [[436]] Promotes the development of other autoimmune diseases when used to treat MS, possibly because CD52 T cells (which are depleted by alemtuzumab) normally suppress other T cells [[6514]] Improves contrast sensitivity in vision tests in patients with early, untreated RRMS [[5147]] Reduces the risk of acute rejection after kidney transplant compared to the standard (basiliximab-based) treatment, as shown in a randomized clinical trial [[12912]]	Transiently increases serum cytokines and depletes B and T lymphocytes nearly completely in peripheral blood, but less profoundly in lymphoid organs (perhaps explaining the relatively low infection rate in treated patients), in a transgenic mouse model expressing human CD52 [[4211]] Has only a minimal effect on innate immune cells and memory responses, and causes a transient decrease in primary adaptive immune responses, in a human CD52 transgenic mouse model [[6403]] Monoclonal antibody against mouse CD52, which exhibits pharmacodynamics similar to those of alemtuzumab, reduces the severity of murine experimental autoimmune encephalomyelitis [[20503]] Monoclonal antibody against mouse CD52, which exhibits pharmacodynamics similar to those of alemtuzumab, reduces the level of pro-inflammatory cytokines, autoreactive T cells, and lymphocytes infiltrating the central nervous system in a murine experimental autoimmune encephalomyelitis [[20503]] Monoclonal antibody against mouse CD52, which exhibits pharmacodynamics similar to those of alemtuzumab, reduces demyelination and loss of axons in the central nervous system in a murine experimental autoimmune encephalomyelitis [[20503]] Monoclonal antibody against mouse CD52, which exhibits pharmacodynamics similar to those of alemtuzumab, improves axonal conductance in the spinal cord in a murine experimental autoimmune encephalomyelitis [[20503]]
[+]	Amiloride	NP	Acid-sensing ion channel-1 [[4136]] Epithelial sodium channel [[12711]] [[12712]] Na+/H+ exchanger [[12713]]	Composed of a substituted pyrazine ring attached to an acylguanidine group [[12644]] Molecular weight of amiloride HCl is 302.12 [[12685]] Biologically active form is positively charged [[12644]] Is a weak base [[12644]] Blocks sodium transport selectively [[12643]] Activity begins about 2 hours after oral administration [[12644]] Levels in serum peak 3 hours after administration [[12643]] Half-life in serum is 6 hours [[12643]] 20 mg oral dose has a biological half-life of 9.6 hours [[12644]] Excreted in the urine and feces in an unmetabolized form [[12643]]	Idea for use in MS comes from observations linking the acid-sensing ion channel 1 (ASIC1), an amiloride target that is permeable to Na+ and Ca2+, with a potential role in neurodegeneration; ASIC1 is overproduced in MS lesions and overaccumulation of Na+ and Ca+ in axons appears to contribute to neurodegeneration [[4764]] [[4136]] Is a diuretic [[12644]] Decreases both systolic and diastolic blood pressure [[12644]] Reversibly inhibits Na+ influx in the kidney [[12644]] Increases the output of urine and the excretion of Na+ and HCO3- but decreases the excretion of K+ [[12644]] Increases urinary pH because of increased HCO3- excretion [[12644]] Inhibits the epithelial Na+ channel, which is probably formed of three distinct but homologous subunits (alpha, beta, gamma ENaC or delta, beta, gamma ENaC), as shown by expression of the human subunits in Xenopus oocytes [[12712]] Inhibits the Na+/H+ exchanger [[12713]]	Reduces the severity of experimental autoimmune encephalomyelitis in mice, even when treatment is started at the peak of disease [[4136]] Ability to reduce the severity of experimental autoimmune encephalomyelitis depends on the presence of ASIC1 (acid-sensing ion channel-1), as shown by experiments with Asic1-/- mice [[4136]] Strongly reduces axonal degeneration in the dorsal corticospinal tract, dorsal column, and optic nerve in experimental autoimmune encephalomyelitis mice [[4136]] Decreases axonal injury under acid conditions (pH 6.5), as shown by studies involving optic nerve and retinal explants from mice [[4136]] Protects both neurons and myelin against damage in an acute experimental autoimmune encephalomyelitis model [[4137]] Inhibits transepithelial Na+ transport in tissues such as skin and urinary bladder in amphibians, acting rapidly at the apical side of the epithelium where passive Na+ entry occurs [[12658]] Has been shown to inhibit Na+ influx reversibly and rapidly in a wide variety of species, cell types, and tissues [[12644]] Binds and inhibits the epithelial Na+ channel, which is formed of three distinct but homologous subunits (alpha, beta, and gamma ENaC), as shown by expression of the rat subunits in Xenopus oocytes [[12711]] Inhibits the Na+/H+ exchanger [[12713]]
[+]	ATX-MS-1467	IM	Major histocompatibility complex class II [[14248]] T cell responses to myelin basic protein [[14248]]	Is a peptide vaccine [[14248]] Consists of equal parts of 4 synthetic, soluble peptides derived from human myelin basic protein [[14248]] Peptides that make up the vaccine represent immunodominant disease-associated myelin basic protein epitopes in individuals with MS with certain human leukocyte antigen haplotypes (DRB11501 and DQB10602) [[14246]] Targets major histocompatibility complex class II [[14248]]	Based on the idea that vaccination with fragments of an MS autoantigen, myelin basic protein, will result in tolerance to those antigens in a process involving negative feedback control of the autoimmune reaction [[14671]] [[14672]] Reduces T cell proliferation induced by myelin basic protein [[14248]]	Promotes the re-establishment of self-tolerance to myelin peptides from the central nervous system in experimental autoimmune encephalomyelitis models [[14246]] Delays the onset and reduces the severity of experimental autoimmune encephalomyelitis (EAE) when given before EAE is induced in Lewis rats [[14246]] Halts the progression of experimental autoimmune encephalomyelitis when given either therapeutically or at onset of disease in double-transgenic mice that express human leukocyte antigen DR15 and human myelin basic protein-specific T cell receptor [[14246]] Reduces neurological deficits to a greater extent than myelin basic protein [82-98] or glatiramer acetate in an experimental autoimmune encephalomyelitis model [[14246]] Reduces infiltration of the brain by CD4+, CD8+ T cells, B cells, and activated macrophages, and reduces microglial activation, in experimental autoimmune encephalomyelitis double-transgenic mice (which express human leukocyte antigen DR15 and human myelin basic protein-specific T cell receptor) [[14246]] Increases interleukin 10 (IL-10) levels and reduces IL-17, IL-2, and tumor necrosis factor-alpha levels in experimental autoimmune encephalomyelitis double-transgenic mice (which express human leukocyte antigen DR15 and human myelin basic protein-specific T cell receptor) [[14246]] Inhibits experimental autoimmune encephalomyelitis in a dose-dependent manner in a humanized mouse model [(Ob x DR2)F1], which expresses MS-associated histocompatibility antigen HLA-DR2b as well as a human T-cell receptor specific for a DR2b-bound peptide from myelin basic protein [[17758]] Inhibits experimental autoimmune encephalomyelitis in a humanized mouse model when given either before or after the onset of disease [[17758]] Inhibits experimental autoimmune encephalomyelitis (EAE) when given after disease onset in a humanized mouse model, reducing the mean maximum EAE score as well as the duration of disease, whereas glatiramer acetate does not affect either of these measures [[17758]]
[+]	BGC20-0134	IM	Proinflammatory and anti-inflammatory cytokines [[473]]	Structured lipid [[791]]	Designed to restore the balance between proinflammatory and anti-inflammatory cytokines [[473]]
[+]	BIIB033	NP	LINGO-1 ("leucine-rich repeat and immunoglobulin-like domain–containing, Nogo receptor–interacting protein") [[377]] [[393]]	Human aglycosyl IgG1 monoclonal antibody [[377]] [[13242]] Crystal structure of a complex between the Fab fragment (region of the antibody that binds to antigens) and the extracellular region of human LINGO-1 has been determined [[10729]] Serum pharmacokinetics have been determined in both healthy individuals and individuals with MS and are similar in the two groups [[13242]] Serum half-life values range from 15 to 24 days after intravenous infusion [[13242]] Absorption is slow after subcutaneous injection, but the mean terminal half-life is similar to that after intravenous infusion, about 15 days [[13242]] Intravenous doses >3 mg per kg in humans lead to serum concentrations that are predicted to have pharmacological activity, based on remyelination studies in rats [[13242]] Cerebrospinal fluid (CSF) pharmacokinetics have been studied; the ratios of CSF to serum concentrations are quite variable between individuals [[13242]] Ratio of brain and spinal cord to plasma concentrations is likely to be about 0.1% in humans [[13242]] Concentrations in the central nervous system after systemic administration in rats are 0.1 to 0.4% of blood levels [[13426]]	Binds to a leucine-rich repeat domain of LINGO-1, as shown by structural studies [[10729]] Binding of the Fab (fragment antibody-binding) region of the antibody to LINGO-1 blocks contact points in LINGO-1 used in oligomerization [[10729]] Binding of the Fab (fragment antibody-binding) region of the antibody to LINGO-1 results in the formation of a stable complex comprised of 2 copies of LINGO-1 and 2 copies of Fab [[10729]] Binding of the Fab (fragment antibody-binding) region of the antibody to LINGO-1, and the resulting complex formation, blocks epitopes in the LINGO-1 IgG domain that function in oligodendrocyte differentiation [[10729]]	Promotes remyelination of the spinal cord in rodent experimental autoimmune encephalomyelitis model, because target molecule (LINGO-1) negatively regulates myelination [[377]] [[393]] Promotes differentiation of oligodendrocyte precursor cells and myelination in vitro [[364]] Accelerates remyelination in vivo in rodent models [[364]] Promotes functional recovery of demyelinated axons in rodent models [[364]] Monoclonal murine antibody mAb3B5, which recognizes mouse LINGO-1 and is a surrogate antibody for the human monoclonal Li81 (BIIB033) antibody, improves axon function in mice after experimental spinal cord demyelination [[17134]] Monoclonal murine antibody mAb3B5, which recognizes mouse LINGO-1 and is a surrogate antibody for the human monoclonal Li81 (BIIB033) antibody, reduces lesion areas and increases the number of remyelinated axons in lesions in mice after experimental spinal cord demyelination [[17134]]
[+]	Cladribine	IS IM	CD4+ T cells [[793]] DNA synthesis and repair [[793]] E-selectin [[556]]	Synthetic adenosine deaminase-resistant purine nucleoside analog [[552]] Phosphorylated by deoxycytidine kinase to active form [[552]] Oral bioavailability ranges between 37% and 51% [[793]] Terminal half-life ranges from 5.7 to 19.7 hours [[793]] Can cross the blood brain barrier [[793]]	Decreases the proportion of circulating CD4+ T cells relative to CD8+ T cells in MS patients [[793]] Increases the population of CD303+/CD123+ (plasmacytoid) circulating dendritic cells, which produce interferon-alpha, but does not affect the CD1c+/CD19- (myeloid) dendritic cell population, in SPMS patients [[6706]] Rapidly decreases B cell and CD4+ Th cell populations in SPMS patients [[6706]] Decreases the levels of the soluble adhesion molecules E-selectin and intracellular adhesion molecule-1 in treated MS patients [[556]] Decreases the levels of the pro-inflammatory cytokines interleukin 2 and interleukin 2R, based on observation of patients who had received 12 months of treatment for chronic progressive MS [[557]] Decreases the levels of pro-inflammatory cytokines interleukin 8 in and RANTES in RRMS patients [[558]] Depletes resting and proliferating lymphocytes in human cell culture [[554]] Impedes the migration of monocytes and lymphocytes in MS patient cell culture, suggesting that the drug could inhibit the migration of inflammatory cells into and within the central nervous system [[555]] Causes breaks in DNA strands in cultured lymphoblastic cells [[793]] Interferes with DNA synthesis and repair in cultured lymphoblastic cells [[793]] Reduces lymphocyte counts in culture [[793]] Inhibits cytokine secretion by peripheral blood T cells in vitro via mechanisms that are distinct from that that causes lymphocyte death [[3500]] Induces caspase-3 and caspase-9 (which play key roles in apoptosis) in monocytes but not in dendritic cells [[5743]] Induces apoptosis in monocytes (after 24 hours) and dendritic cells (in a caspase-independent manner, evident after 72 hours) [[5743]] Reduces antigen uptake by immature human peripheral blood mononuclear cell-derived dendritic cells, but not by immature bone marrow-derived mouse dendritic cells [[8886]] Does not hinder the differentiation of peripheral blood mononuclear cell-derived dendritic cells [[8886]] Alters surface markers on peripheral blood mononuclear cell-derived dendritic cells [[8886]] Does not affect the capacity of peripheral blood mononuclear cell-derived dendritic cells to stimulate T cells [[8886]] Reduces the production of inflammatory cytokines by mature peripheral blood mononuclear cell-derived dendritic cells [[8886]] Reduces the production of chemokines by mature peripheral blood mononuclear cell-derived dendritic cells, resulting in a reduction in monocyte attraction in vitro [[8886]] Brief exposure (72 hours) does not affect proliferation of those human peripheral blood mononuclear cells that survive [[19894]] Brief exposure (72 hours) changes cytokine production by human peripheral blood mononuclear cells toward a sustained anti-inflammatory profile, with increased release of interleukin-4 and -5 and an increased ratio of interleukin-4 to interferon-gamma [[19894]] Brief exposure (72 hours) does not affect the production of interferon-gamma, tumor necrosis factor-alpha, interleukin-6 (IL-6), IL-8, IL-17A, IL-23, or nerve growth factor beta by human peripheral blood mononuclear cells [[19894]]	Inhibits proliferation and induces apoptosis of cultured primary rat microglia, which are resident macrophages in the central nervous system; apoptosis involves components of the intrinsic mitochondrial-mediated apoptotic pathway but not the extrinsic death receptor-mediated apoptotic pathway [[2571]] Does not affect phagocytosis in cultured primary rat microglia, which are resident macrophages in the central nervous system [[2571]] Intracerebroventricular administration reduces clinical symptoms of experimental autoimmune encephalomyelitis [[7663]] Intracerebroventricular administration reverses the increased excitatory postsynaptic current frequency that occurs in experimental autoimmune encephalomyelitis [[7663]] Intracerebroventricular administration prevents synaptic alterations that occur in experimental autoimmune encephalomyelitis by inhibiting the effects of interleukin-1beta [[7663]] Intracerebroventricular administration does not affect the microglial and astroglial activation that occurs in experimental autoimmune encephalomyelitis [[7663]] Reduces antigen uptake by immature human peripheral blood mononuclear cell-derived dendritic cells, but not by immature bone marrow-derived mouse dendritic cells [[8886]] Does not hinder the differentiation of murine bone marrow-derived dendritic cells [[8886]] Alters surface markers on mature but not immature murine bone marrow-derived dendritic cells [[8886]] Alters the capacity of murine bone marrow-derived dendritic cells to polarize naïve T cells into effector T cells, such that induction of T cells that produce interferon-gamma and tumor necrosis factor-alpha is reduced and induction of T cells that produce interleukin 10 is increased [[8886]] Reduces the production of inflammatory cytokines and chemokines by mature murine bone marrow-derived dendritic cells [[8886]]
[+]	Cyclophosphamide	IS IM	T cells, particularly CD4+ helper T cells [[934]] [[935]] B cells [[934]]	Nitrogen mustard alkylating agent [[927]] Alkylates DNA, such that the alkyl group is attached to guanine bases [[927]] Leads to the formation of DNA interstrand crosslinks, DNA-protein cross-links, and single strand breaks in DNA [[948]] Cytotoxic [[948]] Antineoplastic drug [[927]] Prodrug that is converted to 4-hydroxycyclophosphamide and aldophosphamide by oxidase enzymes in the liver; these intermediates undergo intracellular decomposition into the active compound phosphoramide mustard [[927]] [[951]] Metabolite aldophosphamide is inactivated by aldehyde dehydrogenase [[951]] Pharmacokinetics have been determined in MS patients undergoing autologous stem cell transplantation [[949]]	Severely reduces the number of T and B lymphocytes in the peripheral blood in MS patients [[934]] Reduces the number of both CD4+ helper T cells and CD8+ suppressor T cells in MS patients, but the effect on CD4+ cells is more pronounced, so that the CD4:CD8 ratio declines [[935]] High dose (200 mg per kg) therapy preferentially eradicates naïve T cells (potentially the source of autoreactive lymphocytes) versus memory T cells in MS patients [[4570]] Reduces serum levels of immunoglobulins in MS patients [[934]] Activity in different cell types is inversely correlated with aldehyde dehydrogenase levels, such that cells that produce high levels of this enzyme (such as hematopoietic progenitor cells) are relatively resistant to cyclophosphamide and cells with low levels (such as lymphocytes) are quickly killed by cyclophosphamide [[931]] [[951]] Enters the central nervous system, based on the finding that it is present in cerebrospinal fluid [[928]] Reduces the level of myelin basic protein in the cerebrospinal fluid of MS patients [[945]] Increases interleukin-4, interleukin-5, and interleukin-10 levels in MS patients [[936]] [[937]] Reduces interleukin-12 levels, which are elevated in MS patients and correlate with MS disease activity, in MS patients [[937]] Reduces interferon-gamma levels in MS patients [[937]] Modulates CD4+ T cells, such that they display a T helper type 2 phenotype, in SPMS patients [[4495]] Increases the fraction of anti-inflammatory, interleukin-4-producing CCR4+ T cells in SPMS patients [[4495]] Normalizes the percentages of interferon gamma-producing CCR5+ and CXCR3+ CD8+ T cells in SPMS patients [[4495]] Has been effectively used to treat childhood-onset refractory MS [[5669]] Reduced the median annualized relapse rate (from 3.0 to 1.0) and the median Expanded Disability Status Scale score (from 3.5 to 2.0) in a group of 10 Chinese children with MS, as shown in a retrospective chart review [[19205]]	Suppresses experimental autoimmune encephalomyelitis, but paradoxically has also been shown to increase autoimmunity, in that it induces diabetes in non-obese diabetes-prone mice [[928]] Enhances new myelin synthesis in experimental autoimmune encephalomyelitis rodents [[928]]
[+]	Daclizumab	IS	Interleukin-2 receptor alpha (CD25) (high-affinity alpha subunit) [[432]] [[15077]] T cell expansion [[431]] Innate immune system [[2700]]	Recombinant humanized monoclonal antibody [[802]] IgG [[801]] Comprised of four subunits, two heavy chains and two light chains, with all four chains linked via disulfide bridges [[801]] Dimer [[801]] Molecular weight, ~150 kDa [[802]] DNA sequence is 90% human origin and 10% mouse origin [[801]] Contains approximately 2% carbohydrate by weight [[801]] Saturates activated T cells by 10 hours post-infusion; cells remain saturated for 64 days when the drug is given at 5 mg per kg [[802]] Pharmacokinetics have been evaluated in healthy volunteers in three double-blind, placebo-controlled trials after single- and multiple-dose subcutaneous and single-dose intravenous administration, and serum concentrations from these studies have been analyzed with nonlinear mixed-effects modeling [[13703]] Pharmacokinetics/pharmacodynamics have been studied in individuals with adult T-cell leukemia/lymphoma (ATL); whereas saturation of CD25 on the surface of circulating ATL cells occurred at all doses studied, a high dose of 8 mg per kg (which was well tolerated) was required for saturation on ATL cells in lymph nodes, suggesting that such higher doses would be more effective in MS as well [[14100]] Undergoes slow clearance, as shown by studies in healthy volunteers [[13703]] Undergoes slow clearance in individuals with RRMS, as shown by analysis of data from Phase II and Phase III trials [[26678]] At doses ≥100 mg, exhibits linear pharmacokinetics, as shown by studies in healthy volunteers [[13703]] At doses >100 mg, exhibits linear pharmacokinetics in individuals with RRMS, as shown by analysis of data from Phase II and Phase III trials [[26678]] Expected to saturate CD25 on target T cells within several hours at a dose of 150 mg once per month, and to then maintain this saturation until the next dose, based on nonlinear mixed-effects modeling of pharmacokinetic measurements from Phase I studies [[20688]] Expected to saturate CD25 on target T cells at a dose of 150 mg once per month; 4 to 6 months after the last dose, free CD25 levels are expected to return to baseline levels, based on nonlinear mixed-effects modeling of pharmacokinetic measurements from Phase I studies [[20688]] Bioavailability after subcutaneous administration is high (84%) in healthy volunteers [[13703]] Estimated effective half-life is 21 to 25 days and is thus suitable for monthly administration, as shown by studies in healthy volunteers [[13703]] Has a terminal half-life of 21 days in individuals with RRMS, as shown by analysis of data from Phase II and Phase III trials [[26678]] Exhibits high subcutaneous bioavailability in individuals with RRMS, as shown by analysis of data from Phase II and Phase III trials [[26678]] Pharmacokinetics have been determined in individuals with RRMS receiving a 150 mg subcutaneous dose every 4 weeks [[27302]] Exhibits slow absorption when administered as a 150 mg subcutaneous dose every 4 weeks, such that the median time to reach the maximum observed concentration is about 1 week, as shown in a study of 26 individuals with RRMS [[27302]] Reaches a steady state by the fourth injection when administered as a 150 mg subcutaneous dose every 4 weeks, as shown in a study of 26 individuals with RRMS [[27302]]	Exact mechanism is not well understood [[432]] Interrupts interleukin-2-mediated cell activation, thereby preventing expansion of autoreactive T lymphocytes [[432]] [[431]] Stimulates production and enhances function of CD56 (bright) natural killer cells in patients; in vitro, this inhibits survival of activated T cells [[433]] [[455]] Increases the number of CD56(bright) natural killer cells, as shown in the 52-week SELECT trial, and the numbers of such cells early in the course of treatment correlate with the number of new or newly enlarging T2-hyperintense lesions later during the first year of therapy [[16658]] May inhibit CD40L expression [[440]] Reduces regulatory T cell frequency and function, based on blood and cerebrospinal fluid samples in 15 patients [[444]] Reduces levels of regulatory T cells by ~50% over a 52-week period in individuals with RRMS; this decrease is not linked with daclizumab-associated clinical benefit [[15370]] Reduces levels of regulatory T cells (Tregs, which express FOXP3) by ~50% over a 52-week period in individuals with RRMS; FOXP3+ cells that remain exhibit a demethylated region specific for Tregs in the FOXP3 promoter, undergo cell cycling, and display little production of interleukin-2 (IL-2), interferon-gamma, and IL-17, showing that the Treg lineage is maintained during daclizumab therapy [[15370]] Increases serum concentrations of interleukin-2 (IL-2), and signaling through the intermediate-affinity receptor IL-2Rβγ causes STAT5 phosphorylation and FOXP3 expression, in individuals with RRMS [[15370]] Decreases the number of circulating innate lymphoid cells (which is elevated in untreated MS patients) [[2700]] Modifies the phenotype of innate lymphoid cells from inflammation-promoting lymphoid tissue inducer cells toward immunoregulatory natural killer cells via a mechanism that involves interleukin-2 signaling [[2700]] Inhibits intrathecal inflammation in MS patients, as determined by measuring cerebrospinal fluid levels of chemokine (C-X-C motif) ligand 13, which is associated with lymphoid neogenesis, and immunoglobulin G (IgG) index, a measure of intrathecal IgG production [[2700]] Reduces cell surface levels of CD25 on activated T cells in vitro through a mechanism involving trogocytosis mediated by monocytes [[6748]] Long-term treatment reverses the intrathecal enrichment of Epstein-Barr virus- and human herpes virus 6-specific T cell reactivities that occurs in individuals with RRMS [[13399]] Long-term therapy normalizes the abnormalities in immune cell subpopulations in the cerebrospinal fluid in individuals with RRMS, as shown by analysis of treated and untreated individuals with RRMS and healthy donors [[19026]] Long-term therapy reverses the strong enrichment of CD4+ and CD8+ T cells and B cells in the cerebrospinal fluid that occurs in untreated individuals with RRMS, as shown by analysis of treated and untreated individuals with RRMS and healthy donors [[19026]] Long-term therapy reverses increases in innate lymphoid cells and lymphoid tissue inducer cells in the cerebrospinal fluid and blood that occur in untreated individuals with RRMS, as shown by analysis of treated and untreated individuals with RRMS and healthy donors [[19026]] Long-term therapy increases the reduced proportion of monocytes in the cerebrospinal fluid that occurs in untreated individuals with RRMS, as shown by analysis of treated and untreated individuals with RRMS and healthy donors [[19026]] Long-term therapy leads to an expansion of CD56(bright) natural killer cells in individuals with RRMS, a marker that distinguishes them from healthy donors [[19026]] Does not affect influenza vaccine-induced antibody responses or expansion of memory B cells, as shown in a study of 23 daclizumab-treated individuals with MS after seasonal influenza vaccination (Afluria vaccine) [[26411]] Does not affect the activity of cytochrome P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A), as shown in a study in which individuals with MS being treated with daclizumab were given an oral cocktail of probe substrates of these enzymes [[28127]]
[+]	Dalfampridine	IM	Voltage-gated potassium channels [[348]] [[384]] Degenerin/epithelial sodium channels [[4942]] L-type calcium channels that contain subunit Cavbeta3 [[14096]]	Ampyra is a sustained-release oral form of fampridine [[502]] Undergoes only minor metabolic transformation [[356]] Eliminated via the kidney [[353]] A population pharmacokinetic model for extended release tablets has been developed using pooled data from several studies involving healthy volunteers and MS patients [[3966]] Population median estimated oral clearance of the extended release tablets has been determined to be 36 L/h for a 50-year-old woman (who exhibits creatinine clearance of 105 ml/min) and 42 L/h for a comparable man [[3966]] Approved dose for extended release tablets (10 mg twice daily) appears to be the optimum dosing regimen on the basis of a population pharmacokinetic model [[3966]] Pharmacokinetic profile indicates that the time to peak plasma concentration is 3.2 to 3.9 hours and the apparent terminal plasma half-life is 5.6 to 6.4 hours for the extended release (ER) tablets, approximately double that of immediate-release formulations, whereas the peak plasma concentration (21.6 ng/ml) of the ER form is about half that of the immediate-release form [[4010]] Single-dose and steady-state pharmacokinetics of extended release 7.5 mg tablets have been determined in healthy individuals and subjects with moderate or mild renal impairment; plasma concentrations of drug are higher in those with renal impairment and the pharmacokinetics of the 7.5 mg tablets in individuals with mild impairment are similar to results with 10 mg tablets in healthy subjects [[8178]]	Exact mechanism unknown [[340]] Hypothesized to relieve symptoms of MS by blocking voltage-dependent potassium channels and thus restoring conduction in demyelinated axons [[348]] Can potentially block voltage-gated potassium channels that are expressed on neurons and microglia in the central nervous system and on different types of immune cells, including T cells, macrophages, and dendritic cells, but exactly which potassium channels are affected clinically is unknown [[384]] Can act as a convulsant, probably because of blockage of varied voltage-gated potassium channels in the central nervous system; thus, has a narrow therapeutic window [[384]] [[340]] Improves walking speed in some individuals but not others, and a prolonged central motor conduction time at baseline may predict who has a better chance of responding, as shown by a prospective observational study of 20 individuals with MS [[9021]] Did not improve the walking speed of any individual with a normal baseline central motor conduction time (n=5) in a prospective observational study of 20 individuals with MS [[9021]] Improved upper limb tremor in one progressive MS patient [[3605]] Improved standing balance, but not the incidence of accidental falls, in individuals with MS who exhibited improved walking speed in response to dalfampridine, based on a 14-week post-marketing study involving 20 individuals [[10878]] Can improve gait function, and this effect can be enhanced by functional electrical stimulation to the fibular nerve, as shown in an unblinded case series study involving 20 participants with MS [[17553]] Associated with improvement of internuclear ophthalmoparesis in MS [[11501]]	4-Aminopyridine (the active ingredient in the sustained-release formulation Ampyra) blocks voltage-sensitive potassium channels, decreases potassium current, and increases the duration of action potentials, as shown by studies using nonmyelinated squid and cockroach axons [[340]] 4-Aminopyridine blocks fast internodal potassium current in rat spinal root myelinated axons [[415]] 4-Aminopyridine prolongs action potentials in demyelinated and unmyelinated sensory nerve fibers isolated from rat [[340]] 4-Aminopyridine can restore conduction in demyelinated sciatic nerves isolated from rat [[340]] 4-Aminopyridine can restore conduction in injured spinal cord axons from cat and guinea pig [[340]] 4-Aminopyridine has positive neurological effects that appear to be the result of blocking voltage-gated potassium channels that increase twitch tension in skeletal muscles and enhance synaptic transmission independent of demyelination, rather than by blocking voltage-gated potassium channels in demyelinated axons, as shown by studies in rats with experimental demyelination [[384]] 4-Aminopyridine inhibits degenerin/epithelial Na+ channels, including a specific acid-sensing ion channel (ASIC1a, which is expressed in central neurons) and brain, liver, intestine Na+ channel, in a dose- and voltage-dependent manner, as shown by experiments with rodent hippocampal neurons, Drosophila sensory neurons, and expression studies in Chinese hamster ovary cells [[4942]] Dalfampridine enhances sensorimotor function in a rat model of stroke [[6091]] 4-Aminopyridine (given either prophylactically or therapeutically) does not affect disease incidence or disease course in experimental autoimmune encephalomyelitis; demyelination, neuronal damage, and brain volume changes are not altered by treatment [[6363]] 4-Aminopyridine improves mobility in experimental autoimmune encephalomyelitis [[6363]] 4-Aminopyridine selectively potentiates L-type currents mediated by the calcium channel subunits Cav1.2, alpha2delta1, and Cavbeta3 at micromolar concentrations, potentiates N-type currents only at higher concentrations, and fails to potentiate P/Q-type currents, based on studies in which rat subuntis were expressed in human cells [[14096]] Potentiating effect of 4-aminopyridine on high voltage-activated calcium channels depends on the specific Cavalpha1 and Cavbeta channel subunits involved, such that Cavbeta3 (among 4 Cavbeta subunits studied) is most important for both L-type and N-type currents, based on studies in which rat subunits were expressed in human cells [[14096]] 4-Aminopyridine enhances the interaction of calcium channel subunits Cav1.2 and Cav2.2 with Cavbeta3, as well as the trafficking of these subunits to the plasma membrane, based on studies in which rat subunits were expressed in human cells [[14096]] Ability of low concentrations of 4-aminopyridine to potentiate end-plate potentials requires the activity of L-type calcium channels, based on experiments in rats [[14096]]
[+]	Dimethyl fumarate	IM NP	Cytokine secretion [[341]] CD62E [[341]] Inflammation [[341]]	After ingestion, is rapidly hydrolyzed to its primary metabolite, monomethyl fumarate, which is in turn further metabolized in the citric acid cycle [[341]] Reacts with the antioxidant glutathione to form fumarate-glutathione adducts (although monomethyl fumarate is the primary metabolite), as shown by studies in rats [[5375]] Half-life of dimethyl fumarate is 12 minutes [[341]] Half-life of metabolite monomethyl fumarate is 36 hours [[341]] Pharmacokinetics of delayed-release dimethyl fumarate have been determined in healthy individuals [[8138]]	Exact mechanism is unknown [[341]] Shifts T-helper response from Th1 to Th2 in cultured human cells [[341]] Reduces total counts of leukocytes and lymphocytes, such that after 12 months of therapy, CD3(+) T lymphocte counts decreased by 44% in a study of individuals with MS [[17366]] Reduces T lymphocyte counts, such that after 12 months of therapy, CD8(+) T lymphocyte counts decreased by 54.6% and CD4(+) T lymphocyte counts by 39.2%, resulting in a 35.5% increase in the CD4/CD8 ratio, in a study of individuals with MS [[17366]] Reduces eosinophil counts, such that levels decreased by 54.1% after 12 months of therapy in a study of individuals with MS [[17366]] Does not alter neutrophil, monocyte, basophil, or natural killer cell counts in individuals with MS [[17366]] Reduces absolute lymphocyte counts by 35%, CD3+ lymphocyte counts by 34%, CD4+ lymphocyte counts by 34%, CD8+ lymphocyte counts by 40%, and CD19+ lymphocyte counts by 48%, as shown by a retrospective chart review of 23 individuals with MS, with the a mean of 3.9 months between baseline and treatment counts [[20341]] Selectively decreases proportions of circulating central and effector memory T cells (and increases the proportion of naïve T cells) in individuals with MS, based on cross-sectional and longitudinal comparisons [[22951]] Reduces the frequencies of CD4+ and CD8+ memory T cells relative to naïve CD4+ and CD8+ T cells, as shown in a study of individuals with MS analyzed before and after 6 months of treatment [[25607]] Reduces the frequency of TH1 cells, increases the frequency of TH2 cells, and does not affect the frequency of TH17 cells in the CD4+ memory T cell population, as shown in a study of individuals with MS analyzed before and after 6 months of treatment [[25607]] Associated with reduced production of interferon gamma, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and interleukin 22 by CD4+ T cells, as shown in a study of individuals with MS analyzed before and after 6 months of treatment [[25607]] Does not change the frequency of CD4+ T cells that produce interleukin 4 (IL-4) and IL-17A, as shown in a study of individuals with MS analyzed before and after 6 months of treatment [[25607]] Increases the frequency of peripheral regulatory T cells, as shown in a study of individuals with MS analyzed before and after 6 months of treatment [[25607]] Reduces total numbers of peripheral blood B cells, and this reduction is a result of decreased numbers of CD27+ memory B cells and CD27- B cell subsets, in individuals with RRMS [[28330]] Increases the number of peripheral blood CD24(high) CD38(high) (transitional 2 marginal zone precursor) B cells, a type of B cell that produces interleukin 10, in individuals with RRMS; before treatment, this cell type is present at a reduced percentage in those with RRMS versus healthy controls [[28330]] Increases the number of peripheral blood CD27+ CD43+ B cells, a type of B cell that produces interleukin 10 and regulates immune responses, in individuals with RRMS; before treatment, this cell type is present at a reduced percentage in those with RRMS versus healthy controls [[28330]] Inhibits expression of tumor-necrosis-factor-induced CD62E, a protein that mediates cell adhesion to the vascular lining and is responsible for accumulation of leukocytes at sites of inflammation, in human endothelial cells [[341]] [[398]] Inhibits nuclear translocation of NF-κB in human endothelial cells stimulated with tumor necrosis factor-alpha, and this effect is enhanced by inhibition of NF-κB via a small-molecule inhibitor of IKKβ and by a proteasome inhibitor (bortezomib) [[23137]] Inhibits nuclear translocation of NF-κB in stimulated human endothelial cells, and this effect is is enhanced by NF-κB inhibitors, leading to reduction of the endothelial adhesion molecules E-selectin, VCAM-1, and ICAM-1 at the mRNA and protein level [[23137]] Inhibits nuclear translocation of NF-κB in stimulated human endothelial cells, and this effect is is enhanced by NF-κB inhibitors, resulting in a synergistic reduction in the rolling and adhesion of human lymphocytes on such endothelial cells [[23137]] Induces expression of the nuclear-factor (erythroid derived 2) related factor-2 (Nrf2)/NQO1 pathway in a human cerebral endothelial cell line [[9640]] Treatment leads to more nuclear translocation of NRF2 than does treatment with monoethyl fumarate, as shown by in vitro experiments involving primary human spinal cord astrocytes [[17704]] Dimethyl fumarate and monoethyl fumarate have different effects on expression of putative NRF2 target genes, as shown by in vitro experiments involving primary human spinal cord astrocytes [[17704]] Depletes intracellular and extracellular glutathione in a concentration-dependent manner, and the depletion, which is transient, is followed by glutathione accumulation, whereas monoethyl fumarate has more modest effects, as shown by in vitro experiments involving primary human spinal cord astrocytes [[17704]] Increases expression of the pancreatic antioxidant heme oxygenase-1 in human pancreatic tissue in vitro [[13682]] May promote increased myelin density in brain tissue, based on a study of a subset of participants in the DEFINE study in whom the brain magnetization transfer ratio, a possible indicator of myelin density, was evaluated over 2 years [[14126]] Does not consistently affect the expression of tight junction proteins in a human cerebral endothelial cell line, suggesting that the drug does not exert its functions by modulating the blood-brain barrier [[9640]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) reduces monocyte adhesion to and transendothelial migration across inflammed human brain endothelial cells [[24838]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) reduces expression of vascular cell adhesion molecule in human brain endothelial cells [[24838]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) promotes nuclear translocation of Nrf2 but does not influence nuclear translocation of NF-κB in human brain endothelial cells [[24838]] Induces apoptisis in human mast cells (derived from a cell line and from primary cord blood), a cell type involved in autoimmune diseases, and this apoptosis is linked with increased Bax and Bak expression and caspase-9 and caspase-6 activation [[7991]] Enhances the sensitivity of human mast cells derived from cord blood to apoptosis induced by TRAIL and dexamethasone [[7991]] Prevents NLRP3 inflammasome-mediated pyroptosis (a caspase-1-dependent type of programmed cell death) induced by ATP in macrophages derived from the human THP-1 monocyte line [[19739]] Inhibits the increased expression of matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 that is induced by tumor necrosis factor-alpha in primary human chondrocytes; MMPs degrade collagen and proteoglycans and lead to joint damage in osteoarthritis [[14392]] Reduces the loss of collagen type II induced by tumor necrosis factor-alpha in primary human chondrocytes [[14392]] Inhibits the activation of STAT3 (which is involved in loss of collagen type II in chondrocytes) induced by tumor necrosis factor-alpha in primary human chondrocytes [[14392]] Increases the abundance of Nrf2, as well as the expression of various Nrf2 target genes, in primary human umbilical vein endothelial cells [[17279]] Causes metabolic changes, including upregulation of citric acid cycle intermediates that could promote antioxidant responses, in a human oligodendrocyte cell line, as shown by global metabolomic analysis [[19149]] Increases the concentration of antioxidant molecules, including reduced glutathione, carnitine, and ascorbic acid, in a human oligodendrocyte cell line, as shown by global metabolomic analysis [[19149]] Prolonged treatment protects human oligodendrocyte cells against death induced by hydrogen peroxide [[19149]] Induces changes in membrane lipid metabolism, including an increase (after a transient decrease) in levels of phosphatidylcholines and sphingomyelin species, in a human oligodendrocyte cell line, as shown by shotgun lipidomics [[19149]] Both dimethyl fumarate and its metabolite monomethyl fumarate increase cell survival in a human neuroblastoma cell line exposed to oxygen-glucose deprivation [[25980]] Reduces both constitutive and tumor necrosis factor-alpha induced expression (at both the RNA and protein level) of inflammatory chemokine monocyte chemotactic protein 1 in human umbilical vascular endothelial cells [[20797]] Extends the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) induced by tumor necrosis factor-alpha in human umbilical vascular endothelial cells [[20797]] Reduces the nuclear translocation and phosphorylation of p65 induced by tumor necrosis factor-alpha in human umbilical vascular endothelial cells [[20797]] Reduces the expression of inflammatory cytokines granulocyte macrophage colony-stimulating factor, interleukin-6, chemokine (C-C motif) ligand 5, and platelet-derived growth factor subunit B induced by tumor necrosis factor-alpha in human umbilical vascular endothelial cells [[20797]] Like fingolimod and natalizumab, decreases expression of the proinflammatory micro-RNA miR-155, as shown by studies of monocytes isolated from treated versus untreated individuals with MS [[25798]] Like fingolimod and natalizumab, decreases expression of the antioxidant genes HMOX1 and OSGIN1, as shown by studies of monocytes isolated from treated versus untreated individuals with MS [[25798]] In vitro, inhibits production of inflammatory cytokines induced by lipopolysaccharide in monocyte-derived macrophages and microglia isolated from human fetal and adult brain tissue [[25798]] In vitro, promotes expression of the antioxidant gene HMOX1 in monocyte-derived macrophages and microglia isolated from human fetal and adult brain tissue [[25798]] Reduces activation of human neutrophils in vitro, as shown by monitoring production of reactive oxygen species, formation of neutrophil extracellular traps, migration, and surface marker expression [[22290]] Affects phosphorylation of p38 MAPK, ERK1/2, and Akt in human neutrophils in vitro in a stimulus-dependent manner [[22290]] Reduces phagocytosis by human neutrophils in vitro [[22290]] Reduces autoantibody-induced tissue injury, which is dependent on neutrophils, in an in vitro assay involving human skin cryosections [[22290]] Inhibits integrin α4 expression on activated human Jurkat T cells, whereas a Nrf2 activator increases integrin α4 expression [[22780]] Potential inhibitory effect on T cell invasion of the central nervous system is probably not directly mediated via an effect on brain endothelial cells [[20951]] Neither dimethyl fumarate nor its metabolite monomethyl fumarate blocks the nuclear translocation of NF-κB/p65 induced by interleukin 1beta in nonimmortalized single donor human brain microvascular endothelial cells; in contrast, dimethyl fumarate does inhibit such translocation in human umbilical vein endothelium [[20951]] Neither dimethyl fumarate nor its metabolite monomethyl fumarate blocks the activation of p38 MAPK induced by interleukin 1beta (IL-1beta), or basal or IL-1beta stimulated expression of intercellular adhesion molecule 1, in nonimmortalized single donor human brain microvascular endothelial cells [[20951]] Neither dimethyl fumarate nor its metabolite monomethyl fumarate blocks the adhesion of activated human T cells (Jurkat cells) to human brain microvascular endothelial cells [[20951]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) enhances human CD56+ (but not CD56-) natural killer (NK) cell lysis of human tumor cells, an effect mediated via the upregulation of NKp46 and CD107a expression on the NK cell surface [[15727]] Promotes apoptosis in human hematopoietic tumor cell lines but not in a normal B lymphocyte cell line [[15701]] Inhibits the nuclear translocation of nuclear factor-κB, as well as the expression of B-cell lymphoma extra-large and X-linked inhibitor of apoptosis, in human hematopoietic tumor cell lines [[15701]] Decreases proliferation and increases cell lysis in a human glioblastoma cell line [[9226]] Decreases the invasiveness of primary human glioblastoma cells [[15819]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) increases the toxicity associated with the proteasome inhibitors bortezomib and carfilzomib, which are anti-cancer drugs, in a variety of human cancer cells [[15819]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) increases the toxicity associated with the proteasome inhibitor bortezomib, an anti-cancer drug, in primary human glioblastoma cells; cells are protected from this toxicity by overproduction of c-FLIP-s or BCL-XL [[15819]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) increases the toxicity associated with the proteasome inhibitor bortezomib, an anti-cancer drug, in primary human glioblastoma cells; inhibition of AKT/ERK1/2/mTOR signaling increases this effect whereas activation of this signaling decreases it [[15819]] Inhibits breast cancer cell proliferation, as shown in studies of several human breast cancer cell lines, as well as xenograft tumor growth [[24874]] Inhibits NF-κB pathway activity, which promotes breast cancer, in several human breast cancer cell lines [[24874]] Inhibits the nuclear translocation and DNA binding of NF-κB in a human breast cancer cell line [[24874]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) acts synergistically with the myelofibrosis drug ruxolitinib, which inhibits Janus kinases 1/2, to kill a variety of human cancer cells [[28517]] Directly interacts with and covalently modifies recombinant human NF-κB p65 protein [[24874]] Did not prevent rebound after natalizumab discontinuation in one case of highly active RRMS [[24549]]	In experimental autoimmune encephalomyelitis models, activates the nuclear factor E2-related factor 2 (Nrf2) transcriptional pathway, which functions to modulate oxidative stress and has neuroprotective effects [[341]] Induces expression of NRF2 target genes in a tissue-specific manner, as shown in studies of wild-type and NRF2 knockout mice [[28069]] Regulates both NRF2-dependent and NRF2-independent gene expression, as shown in studies of wild-type and NRF2 knockout mice [[28069]] Affects the expression of histone deacetylase 1 and 2, such that levels initially increase (after 4 hours) but then decrease to control values or below (after 24 hours), in primary rat astrocytes [[7206]] In the presence of pro-inflammatory cytokines, reduces histone deacetylase (HDAC) levels in primary rat astrocytes, an activity that could promote activation of Nrf2 and suppression of the inflammatory response, as suggested by the finding that a selective HDAC inhibitor increases Nrf2 activity and decreases inflammatory astrocyte activation [[7206]] Increases lysine acetylation on histones H2a.1 and H3.3, as well as 6 other proteins, as shown by proteomic analysis of primary rat astrocytes [[7206]] Treatment leads to modifications of cysteine residues in KEAP1, a repressor protein that targets NRF2 for degradation, to a greater extent than does treatment with monoethyl fumarate, as shown by in vitro experiments in which rat KEAP1 was expressed in human embryonic kidney cells [[17704]] Inhibits maturation of dendritic cells and Th1 and Th17 cell differentiation by suppressing signaling by NF-kB and extracellular signal-regulated kinase 1 and 2, as shown by studies of mouse cells [[2252]] Appears to reduce oxidative stress without changing the activity of neuronal networks, as shown by examination of the effects of immunomodulatory concentrations of drug on mouse cells [[2411]] Increases the frequency of multipotent neurospheres in a culture of mouse neural stem/progenitor cells, as well as the self-renewal of these neurospheres [[19680]] Reduces apoptosis, and Increases the survival, of cultured rat neural stem/progenitor cells survival under oxidative stress [[19680]] Protects cultured rat motor neurons from oxidative stress, as measured by neurite outgrowth, number, and length, as well as cell body area [[19680]] Reduces the production of reactive oxygen species by cultured rat neural stem/progenitor cells in response to hydrogen peroxide treatment [[19680]] Increases the expression of Nrf2 at the RNA and protein level in response to oxidative stress in cultured rat neural stem/progenitor cells [[19680]] Neuroprotective effect against oxidative stress in cultured rat neural stem/progenitor cells may be mediated by the ERK1/2 MAPK pathway upstream of Nrf2, as shown by experiments involving various inhibitors [[19680]] Increases the expression of various anti-oxidative stress genes, including Gstp1, Nqo1, Sod2, Srxn1, and Fth1, in the presence of oxidative stress in cultured rat neural stem/progenitor cells [[19680]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) reduces neurodegeneration in a mouse model of retinal ischemia, such that it enhances expression of antioxidative genes regulated by Nrf2 and inhibits expression of inflammatory genes, Müller cell gliosis, and neuron loss in the ganglion cell layer, and these processes require Nrf2, as shown by studying Nrf2 knockout mice [[25164]] Both dimethyl fumarate and its metabolite monomethyl fumarate reduce cell death in mouse hippocampal slice cultures previously exposed to oxygen-glucose deprivation [[25980]] Both dimethyl fumarate and its metabolite monomethyl fumarate increase neuron survival in an immortalized mouse hippocampal cell line exposed to oxygen-glucose deprivation, but only dimethyl fumarate activates the anti-oxidative Nrf2 pathway [[25980]] Increases neuron survival in an immortalized mouse hippocampal cell line exposed to oxygen-glucose deprivation, and this effect requires Nrf2, as shown in Nrf2 knockdown experiments [[25980]] Both dimethyl fumarate and its metabolite monomethyl fumarate increase neuron survival in an immortalized mouse hippocampal cell line exposed to oxygen-glucose deprivation, but do not activate the hypoxia-inducible factor signaling pathway [[25980]] Direct administration to the central nervous system reduces, but does not eliminate, the upregulation in neuronal Ca2+ signaling and the excitotoxic morphological alterations caused by later direct administration of 100 mM glutamate, as shown by experiments in transgenic Ca2+ reporter mice [[24627]] Inhibits integrin α4 expression on circulating lymphocytes in mice with experimental autoimmune encephalomyelitis, but does not change total white blood cell counts [[22780]] Decreases proliferation and increases cell lysis in a mouse glioma cell line [[9226]] Inhibits hypoxia-induced expression of the transcription factor hypoxia-inducible factor-1α, as well as its target genes that encode interleukin-8 and vascular endothelial growth factor, in a mouse osteoblast precursor cell line [[9930]] Promotes degradation of the transcription factor hypoxia-inducible factor-1α in a proteasome-dependent manner, based on experiments using a mouse osteoblast precursor cell line [[9930]] Disrupts the interaction between the transcription factor hypoxia-inducible factor-1α (HIF-1α) and the chaperone heat shock protein 90, but enhances the interaction between HIF-1α and the receptor of activated protein kinase C, based on experiments using a mouse osteoblast precursor cell line [[9930]] Combination therapy consisting of murine interferon beta (which is immunomodulatory) and dimethyl fumarate (which is neuroprotective) is more effective in treating experimental autoimmune encephalomyelitis (providing better axon protection) than either therapy alone [[10600]] Reduces chronic pancreatitis induced by L-arginine in rats [[13682]] Reduces pancreatic levels of myeloperoxidase (a marker of inflammatory stress) and lipid peroxidation in rats with chronic pancreatitis induced by L-arginine [[13682]] Protects pancreatic islet cells, as well as non-endocrine tissue, in rats with chronic pancreatitis induced by L-arginine [[13682]] Reduces effects caused by 7-ketocholesterol, such as cell growth inhibition, overproduction of reactive oxygen species O2- and H2O2, apoptosis, and autophagy, in murine oligodendrocytes; lipid peroxidation processes associated with MS increase levels of this molecule [[27129]] Does not affect expression of the tight junction protein claudin-5 in an experimental autoimmune encephalomyelitis model, suggesting that the drug does not exert its functions by modulating the blood-brain barrier [[9640]] Does not decrease neurological problems, infiltration of inflammatory cells, or demyelination in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE) that are null for hydroxycarboxylic acid receptor 2 (HCA2), although it does have these effects in wild-type mice with EAE, showing that HCA2 is required for dimethyl fumarate's effect on this condition [[10837]] Does not reduce the infiltration of CD45+Ly-6G+ neutrophils into the spinal cords in mice with experimental autoimmune encephalomyelitis (EAE) that are null for hydroxycarboxylic acid receptor 2 (HCA2), although it does have this effect in wild-type mice with EAE; mouse neutrophils express HCA2 [[10837]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) does not reduce adherence of neutrophils that are null for hydroxycarboxylic acid receptor 2 to endothelial cells, although it does reduce adherence of wild-type neutrophils [[10837]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) does not reduce migration of neutrophils that are null for hydroxycarboxylic acid receptor 2 toward the chemokine CXCL2, although it does reduce migration of wild-type neutrophils [[10837]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) induces Nqo1 and Hmox1 expression relatively normally in cells that are null for hydroxycarboxylic acid receptor 2 [[10837]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) changes activated microglia from a pro-inflammatory to a neuroprotective phenotype via hydroxycarboxylic acid receptor 2 activation, as shown by experiments with a murine microglial cell line [[18700]] Monomethyl fumarate (the active metabolite of dimethyl fumarate) affects the phenotype of activated microglia via hydroxycarboxylic acid receptor 2-dependent effects on the AMPK-Sirt1 pathway, leading to deacetylation and inhibition of NF-kappaB and thus pro-inflammatory factor secretion, as shown by studies experiments with a murine microglial cell line [[18700]] Modulates glutatmate release at pre-synaptic terminals, resulting in neuroprotection, as shown by studies of corticostriatal slices from experimental autoimmune encephalomyelitis mice [[18700]] Reduces cerebral edema formation, as shown in a mouse ischemic stroke model [[17279]] Stabilizes the blood-brain barrier by inhibiting the disruption of interendothelial tight junctions, as shown in a mouse ischemic stroke model [[17279]] Decreases matrix metalloproteinase activity in ischemia-affected brain tissue, as shown in a mouse ischemic stroke model [[17279]] Inhibits the disruption of interendothelial tight junctions in murine cerebral microvascular endothelial cells under ischemic conditions, and this effect is dependent on Nrf2 [[17279]] Inhibits ischemia-induced expression of inflammatory cytokines and chemokines in murine astrocytes in vitro [[17279]] Increases the abundance of nuclear Nrf2, as well as the expression of various Nrf2 target genes, in murine cerebral endothelial cells and astrocytes in vitro [[17279]] Promotes neurological recovery (with a 24 hour window of therapeutic opportunity) in rodent models of intracerebral hemorrhage in a Nrf2-dependent manner [[18919]] Inhibits Theiler's murine encephalomyelitis virus-induced demyelinating disease in mice [[17266]] Increases the Nrf2 antioxidant response in mice with Theiler's murine encephalomyelitis virus-induced demyelinating disease [[17266]] Decreases levels of interleukin 17A mRNA in mice with Theiler's murine encephalomyelitis virus-induced demyelinating disease [[17266]] Reduces blistering in a mouse model of epidermolysis bullosa acquisita (a neutrophil-dependent autoimmune disease that involves subepidermal blistering) [[22290]] Dimethyl fumarate (but not its metabolite monomethyl fumarate) promotes necroptosis in a mouse colon cancer cell line via depletion of glutathione, increased reactive oxygen species, and activation of mitogen-activated protein kinases [[18763]] Improves the disease course of experimental autoimmune neuritis in Lewis rats [[24304]] Improves proximal and distal conduction in the sciatic nerve in experimental autoimmune neuritis in Lewis rats [[24304]] Increases Nrf2 levels in peripheral axons in experimental autoimmune neuritis in Lewis rats [[24304]] Reduces infiltration of macrophages and T cells into peripheral nerves in experimental autoimmune neuritis in Lewis rats [[24304]] Has not been shown to affect fertility or exhibit teratogenicity in animal studies [[24626]]
[+]	Dronabinol	NP	Cannabinoid receptor CB1 [[9525]] [[9527]] Cannabinoid receptor CB2 [[9528]]	Tetrahydrocannabinol is a naturally-occurring, terpenophenolic, psychoactive compound that is produced by plants of the Cannabis genus [[9471]] [[9501]] delta-9-Tetrahydrocannabinol is the most active form of tetrahydrocannabinol [[9501]] delta-9-Tetrahydrocannabinol was initially isolated, characterized, and partially synthesized in 1964 [[9471]] Dronabinol is a synthetic version of delta-9-tetrahydrocannabinol [[9501]] Molecular weight, 314.46 [[9501]] Antioxidant [[9503]] Very lipophilic [[9501]] Onset of action occurs 0.5 to 1 hours after administration, with the peak effect occurring 2 to 4 hours after administration [[9501]] Absorbed almost completely after a single oral dose, but only 10 to 20% reaches systemic circulation because of high solubility in lipids and hepatic metabolism [[9534]] Pharmacokinetics after both single and multiple doses have been examined in healthy individuals [[9501]] Hydroxylated by CYP enzymes in the liver; the resulting metabolites, some of which retain activity, are then converted to glucuronides, which are excreted into the intestine [[9526]] Excreted, along with its metabolites, in both urine and feces [[9501]] Steady-state levels are reached during the first two weeks of treatment, based on a study of the urinary cannabinoid/creatinine ratio [[9534]]	delta-9-Tetrahydrocannabinol is largely responsible for the psychotropic properties of cannabis [[9526]] Acts as an agonist of the cannabinoid receptor CB1, a G protein-coupled receptor, and inhibits cyclic AMP accumulation, as shown by experiments in which the receptor was expressed in a Chinese hamster ovary cell line [[9527]] Acts as an agonist for the CB1 and CB2 receptors, inhibiting foreskolin-stimulated accumulation of cyclic AMP, as shown by experiments involving Chinese hamster ovary cells transfected with CB1 or CB2 cDNAs [[10084]] Binds the cannabinoid receptor CB2, a G protein-coupled receptor, as shown by experiments in which the receptor was expressed in monkey kidney COS cells [[9528]] Displays neuroprotective, antioxidant, and anti-apoptotic effects against three toxins relevant to Parkinson's disease (1-methyl-4-phenylpyridinium, lactacystin, and paraquat) in cultures of differentiated neuroblastoma cells, and these effects might be mediated by the peroxisome proliferator-activated receptor-gamma [[9507]]	Binds the cannabinoid receptor CB1 from rat brain [[9525]] Inhibits the development of experimental autoimmune encephalomyelitis [[9506]] Strongly reduces signs of inflammation in the central nervous system in an experimental autoimmune encephalomyelitis model [[9506]] Reduces tremor and spasticity in a chronic relapsing experimental allergic encephalomyelitis mouse model [[9478]] Non-sedating doses reduce disability accumulation during relapsing experimental autoimmune encephalomyelitis in mice in a dose-dependent manner [[16157]] Non-sedating doses do not reduce relapsing autoimmunity during relapsing experimental autoimmune encephalomyelitis in mice [[16157]] Reduces the inflammatory Th17 phenotype (which is enhanced in MS), as shown by experiments with mouse T cells that induce experimental autoimmune encephalitis upon injection [[13129]] Suppresses, in a dose-dependent manner, the production and secretion of interleukin-17 by reactivated mouse T cells that induce experimental autoimmune encephalitis upon injection [[13129]] Reduces the expression of interleukin-6 (an important factor in Th17 induction) at the RNA and protein level by reactivated mouse T cells that induce experimental autoimmune encephalitis upon injection [[13129]] Does not affect the level of tumor necrosis factor-alpha or interferon-gamma produced by reactivated mouse T cells that induce experimental autoimmune encephalitis upon injection [[13129]] Provides neuroprotection in a rat model of Parkinson's disease [[9509]] Displays neuroprotective properties in rat cortical neuron cultures, a function that is independent of cannabinoid receptor activity [[9503]] Protects cultured rat cortical neurons from glutamate toxicity [[9503]] Prevents oxidative damage induced by hydroperoxide in rat cortical neuron cultures [[9503]] Displays anti-inflammatory effects toward a mouse macrophage cell line [[9504]] Reduces lipopolysaccharide (LPS)-induced release of inflammatory mediators nitric oxide, interleukin 6, and prostaglandin E2, as well as LPS-induced induction of cyclooxygenase 2, by a mouse macrophage cell line [[9504]] Competitively inhibits acetylcholinesterase from the electric eel [[9508]]
[+]	Estriol	IM NP	Estrogen receptor beta [[443]] T cells [[461]] Dendritic cells [[423]]	Safest of the three forms of estrogen [[460]] [[443]] Largely absent in the non-pregnant state [[460]] [[443]] Levels increase progressively during pregnancy [[460]] [[443]]	Induces cultured T cells to shift from a Th1 to a Th2 state [[461]] Increases levels of interleukin-5 (IL-5) and IL-10 and decreases levels of tumor necrosis factor-alpha in stimulated peripheral blood mononuclear cells isolated from treated individuals [[460]] Might reduce the relapse rate in MS, as suggested by the observation that pregnancy, when estriol-1 levels increase substantially, is associated with strongly reduced relapse rates [[443]] [[464]] Estrogens have been shown to protect neurons from excitotoxicity and oxidative stress in vitro [[443]]	Reduces the severity of experimental autoimmune encephalomyelitis in mice [[443]] Generates tolerogenic dendritic cells, which protect against experimental autoimmune encephalomyelitis In mice [[423]] Estrogens affect anti-inflammatory processes by acting on cytokines, chemokines, matrix-metalloproteinase-9, antigen presentation, and dendritic cell function [[443]] Estrogens induce CD4+CD25+ regulatory T cells in mice with experimental autoimmune encephalomyelitis [[443]] Prevents changes in hippocampal synaptic transmission in mice with experimental autoimmune encephalomyelitis [[1565]] A pregnancy level of estrogen promotes regulatory T cell and Th2 differentiation in both ovariectomized and pregnant experimental autoimmune encephalomyelitis mice [[15700]] A pregnancy level of estrogen reduces clinical symptoms of experimental autoimmune encephalomyelitis in both ovariectomized and pregnant mice [[15700]] A pregnancy level of estrogen decreases demyelination and cell infiltration in the central nervous system and T cell proliferation in the spleen in experimental autoimmune encephalomyelitis mice [[15700]] A pregnancy level of estrogen increases anti-inflammatory cytokine production in splenocytes in experimental autoimmune encephalomyelitis mice [[15700]] A pregnancy level of estrogen increases the frequency of Th2 and T regulatory cells in experimental autoimmune encephalomyelitis mice [[15700]] A pregnancy level of estrogen reduces expression of Th1 and Th17 transcription factors (such as T-bet and ROR-γt) and Th17 cytokines [such as interferon gamma, tumor necrosis factor α, interleukin 17 (IL-17) and IL-23] at the mRNA level in the central nervous system in experimental autoimmune encephalomyelitis mice [[15700]]
[+]	Fingolimod	IM NP	Sphingosine 1-phosphate receptors [[301]] Immune cell migration [[301]] Histone deacetylases [[11236]]	Structural sphingosine analog [[307]] [[299]] Phosphorylated to fingolimod phosphate by sphingosine kinase-2 [[301]]; phosphorylated form binds to 4/5 of sphingosine 1-phosphate (S1P) receptor subtypes (S1P1, S1P3, S1P4, S1P5) [[301]] [[334]] Crosses blood-brain barrier [[301]] Lipophilic [[301]] Derived from myriocin, a metabolite from the fungus Isaria sinclairii (used in traditional Chinese medicine) [[301]] Can be measured in human plasma and mouse subcellular compartments by an analytical method involving liquid chromatography-tandem mass spectrometry [[1767]] Unphosphorylated and phosphorylated forms accumulate in immune cells at micromolar concentrations, based on experiments using spleen cells from mice [[17212]] Pharmacokinetics are not altered by a combined oral contraceptive (ethinylestradiol/levonorgestrel) [[2271]] Does not affect the pharmacokinetics of a combined oral contraceptive (ethinylestradiol/levonorgestrel) [[2271]] Potency against the sphingosine-1-phosphate (S1P) receptor subtype S1P1, selectivity against other S1P receptors, and species cross-reactivity have been compared for multiple S1P1 receptor agonists (including fingolimod, siponimod, and CS-0777) [[7461]] Multiple sphingosine-1-phosphate (S1P) receptor subtype S1P1 agonists (including fingolimod, siponimod, and CS-0777) all signal identically through the S1P1 receptor, causing receptor degradation [[7461]] Nonproprietary fingolimod varients display different properties (such as particle size and the presence of impurities) than does proprietary fingolimod, according to a company-sponsored study [[12368]] Single-crystal structures have been determined [[17555]] Three different crystalline forms have been identified and characterized [[17555]]	Exact mechanism unknown [[307]] Phosphorylated version is a strong agonist of four sphingosine 1-phosphate (S1P) receptor subtypes, as shown in experiments using recombinant human receptors [[334]], but unlike the natural ligand S1P, ultimately induces degradation of the S1P1 receptor in cell culture, showing that the drug is a functional antagonist of this receptor [[329]] Reduces the number of naive T cells and central memory T cells, but not effector memory T cells, in the blood of MS patients, presumably because the first two cell types recirculate through lymph nodes regularly and are retained there [[328]] Depletes T cells with a lymph node-homing phenotype (naïve and central memory cells) from the peripheral blood of MS patients with varying kinetics, such that naïve CD4+ T cell counts decrease 2 hours after the first dose, naïve CD8+ T cell counts after 3 hours, and central memory CD4+ T cell counts after 5 hours, whereas CD8+ central memory cell counts do not decrease significantly after the first dose [[6792]] Reduces the number of Th17 central memory T cells in the blood of MS patients, probably because the cells are retained in secondary lymphoid organs [[327]] Decreases the proportion of central memory T cells and naïve T cells in the peripheral blood, but increases the proportion of effectory memory T cells and suppressor precursor T cells, and an increased percentage of CD4+ central memory T cells is associated with an increased risk of relapse, as shown in a study of 23 individuals with RRMS [[18505]] Reduces levels of the pro-inflammatory lipid ceramide and mRNA levels of the ceramide-producing enzyme acid sphingomyelinase (which are enhanced in MS lesions) to control levels, based on studies of astrocytes from control white matter from postmortem brain tissue of MS patients (after treatment with tumor necrosis factor alpha increased these levels) [[2544]] Reduces transendothelial monocyte migration (a marker of blood-brain barrier dysfunction), as shown by experiments with supernatants derived from reactive astrocytes from postmortem brain tissue of MS patients [[2544]] May help prevent disruption of the blood-brain barrier, based on experiments with immortalized human brain microvascular endothelial cells [[17603]] Phosphorylated form increases the level of the tight junction protein claudin-5 in immortalized human brain microvascular endothelial cells [[17603]] Does not affect levels of occludin (a tight junction protein), intercellular adhesion molecule-1, or melanoma cell-adhesion molecule in immortalized human brain microvascular endothelial cells [[17603]] Phosphorylated form increases transendothelial electrical resistance in immortalized human brain microvascular endothelial cells [[17603]] Pretreatment with the phosphorylated form reverses the decrease in levels of the tight junction protein claudin-5 in immortalized human brain microvascular endothelial cells caused by exposure to sera from individuals with RRMS or SPMS [[17603]] Pretreatment with the phosphorylated form reverses the decrease in transendothelial electrical resistance in immortalized human brain microvascular endothelial cells caused by exposure to sera from individuals with RRMS or SPMS [[17603]] Pretreatment with the phosphorylated form reverses the increase in levels of vascular cell adhesion molecule 1 in immortalized human brain microvascular endothelial cells caused by exposure to sera from individuals with RRMS or SPMS [[17603]] Decreases inflammatory cytokine-induced death of cultured human brain microvascular endothelial cells, an effect that is mediated by the sphingosine-1 phosphate receptor 1 [[20319]] Induces the release of granulocyte macrophage colony-stimulating factor from human astrocytes, which in turn decreases inflammatory cytokine-induced death of human brain microvascular endothelial cells in vitro [[20319]] Reduces transmigration of human peripheral blood mononuclear cells in an in vitro co-culture model of the blood-brain barrier involving cytokine-activated human brain microvascular endothelial cells and human astrocytes under conditions of shear stress [[20319]] Decreases the percentage of circulating CD56(bright)CD62L+ (immature) natural killer (NK) cells (the predominant NK cell phenotype within lymph nodes), suggesting that fingolimod blocks egress of such NK cells from lymph nodes, as it does with T cells [[5263]] One month of treatment does not change the frequency of CCR6+ and CD161+ T cells (CCR6 and CD161 are indicative of Th17 cells) in the pool of circulating CD4+ and CD8+ cells in MS patients [[5943]] One month of treatment reduces the frequencies of CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ cells that express pro-inflammatory cytokines (interferon gamma with or without interleukin-17) [[5943]] One month of treatment increases the frequency of CD4+ CD24(high)CD127(low) regulatory T cells, which is reduced in MS patients versus healthy controls [[5943]] Treatment is associated with different amounts of fluctuation in total lymphocyte counts in different individuals, such that higher counts in "fluctuating" individuals reflect higher levels of CCR7-CD8+ effector cells, which are controlled less by fingolimod than other subsets [[8085]] Two weeks of treatment reduces the frequency of activated memory B cells [CD38(int-high)], especially those that express a marker of cell proliferation, Ki-67, in individuals with MS [[9772]] Two weeks of treatment increases the frequency of activated plasmablasts (CD138+) within the plasmablast population in individuals with MS, indicating that these activated plasmablasts are relatively resistant to the drug [[9772]] Affects T cell activation, such that the resulting phenotype is less inflammatory (with diminished expression of interferon gamma and granzyme B, two pathogenic cytokines), and this effect requires T cell factor 1 upregulation, as shown in in vitro studies of T cells from individuals with MS and healthy controls [[25176]] Upregulates T cell factor 1 (which downregulates interferon gamma and granzyme B, two pathogenic cytokines), as shown in in vitro studies of T cells from individuals with MS and healthy controls [[25176]] Upregulates expression of T cell factor 1 (which is expressed at lower levels by T cells from individuals with MS versus healthy controls) in individuals with MS [[25176]] Decreases expression of the proinflammatory micro-RNA miR-155, as shown by studies of monocytes isolated from treated versus untreated individuals with MS [[25798]] Decreases expression of the antioxidant genes HMOX1 and OSGIN1, as shown by studies of monocytes isolated from treated versus untreated individuals with MS [[25798]] Reduces the number of B cells in circulation in individuals with MS [[10175]] Reduces the proportion of memory B cells, and increases the proportion of naïve B cells (and transitional B cells in the naïve B cell population), in circulation in individuals with MS [[10175]] Reduces levels of the costimulatory molecule CD80 on B cells from individuals with MS to levels seen in healthy individuals [[10175]] Reduces the production of the pro-inflammatory cytokine tumor necrosis factor alpha, and increases the production of the anti-inflammatory cytokine interleukin-10, by B cells from individuals with MS, findings that may be related to the fingolimod-related decrease in circulating memory B cells and increase in circulating transitional B cells [[10175]] Reduces the proportion of non class-switched and class-switched memory B cells (both of which are linked with MS pathogenesis), but increases the proportion of naïve B cells, in peripheral blood of individuals with MS, as shown in a 12 month followup study [[14907]] Increases the proportion of memory conventional and regulatory T cells, and decreases the proportion of naïve conventional and regulatory T cells (which drive MS pathogenesis) in peripheral blood of individuals with MS, as shown in a 12 month followup study [[14907]] Associated with increased expression of CD80 and CD86 on B cells and of programmed death-1 on circulating follicular helper T cells in individuals with MS, as shown in a 12 month followup study [[14907]] Increases mRNA levels of CD39 (an ectoenzyme expressed by T regulatory cells that decreases extracellular concentrations of ATP, a molecule with proinflammatory effects), aryl hydrocarbon receptor (AHR, a transcription factor that can regulate CD39 expression), and CYP1B1 (the expression of which is induced by AHR), as shown by an analysis of peripheral blood mononuclear cells from individuals with RRMS [[15279]] Decreases mRNA levels of interleukin-17 (IL-17), IL-22, and FOXP3 (expressed by T regulatory cells and recently activated T cells), as shown by an analysis of peripheral blood mononuclear cells from individuals with RRMS [[15279]] Reduces circulating CD4+ T cells, CD19+ B cells, and T regulatory cells (Tregs); cells in the remaining CD4+ T cell population were enriched for FOXP3+ cells and Tregs expressing CD39, as shown by an analysis of peripheral blood mononuclear cells from individuals with RRMS [[15279]] Decreases the level of newly-produced T and B lymphocytes in the peripheral blood of individuals with MS, based on studies of blood samples taken before treatment began and after 6 and 12 months [[15380]] Reduces T cell receptor repertoire diversity in the peripheral blood of individuals with MS, based on studies of blood samples taken before treatment began and after 6 and 12 months [[15380]] Does not interfere with T cell release from the thymus, as shown in a study of individuals with MS treated with fingolimod and healthy controls [[16377]] Reduces the number of conventional CD4+ T cells that express CCR7, and thereby increases the relative proportion of regulatory T cells, as shown in a study of individuals with MS treated with fingolimod and healthy controls [[16377]] Does not have a negative effect on the phenotypes of naïve T cells or on surrogate markers of thymic T cell development (which include T cell receptor diversity in regulatory T cells, as well as the frequency of cells that express T cell receptors with dual specificity), as shown in a study of individuals with MS treated with fingolimod and healthy controls [[16377]] Decreases leukocyte counts in the cerebrospinal fluid (CSF), but does not affect oligoclonal bands in the CSF or intrathecal IgG synthesis [[17016]] Has little effect on B cells in the cerebrospinal fluid, but strongly reduces B cells in the peripheral blood [[17016]] Decreases the proportion of CS4+ T cells in the cerebrospinal fluid, but this effect is less extreme than that in peripheral blood [[17016]] Reduces levels of neurofilament light chain subunit (a marker of axonal injury) in the cerebrospinal fluid, as shown by an analysis of a subset of participants in the FREEDOMS trial [[17840]] Increases the proportion of regulatory B cells (CD38+ CD27- CD24+ CD5+) relative to all B cells in the peripheral blood as compared with that in treatment-naïve individuals with MS and healthy controls [[17460]] Increases the production of interleukin-10 by regulatory B cells [[17460]] Increases the movement of regulatory B cells across a monolayer of primary human brain microvascular endothelial cells [[17460]] Increases the frequency of regulatory B cells in the cerebrospinal fluid [[17460]] Increases the ratio of B cells (and naïve B cell, memory B cell, and regulatory B cell subsets) in the cerebrospinal fluid versus the blood, in agreement with the observation that fingolimod increases transendothelial migration of B cells in vitro [[17460]] Increases the proportion of regulatory B cells relative to all B cells in the peripheral blood, and individuals who exhibit higher fractions of such cells in the blood tend to display stable clinical and radiological measures of disease, whereas those with lower fractions tend to exhibit active disease [[17460]] Reduces levels of markers of inflammatory activity (CXCL13, CHI3L1, and CHIT1) and axonal damage (neurofilament light protein) in cerebrospinal fluid when administered to individuals switching from first-line disease-modifying therapies, but does not affect levels of these markers in individuals switching from natalizumab, as shown in a study of 43 individuals with RRMS [[28354]] Changes the distribution of lymphocyte subsets in peripheral blood, such that the mean percentage of natural killer cells increased from 11.2 to 53.9, the mean percentage of CD4+ cells decreased from 58.7 to 8.3, and the CD4+:CD8+ ratio decreased from 3.6 to 0.35 in a 6-month study involving 25 previously untreated individuals with MS [[24570]] Reduces plasma levels of endothelial cell-derived microparticles to levels similar to those in healthy individuals, as shown by studies of treated and untreated individuals with MS and healthy individuals [[27892]] Increases plasma levels of B cell-derived microparticles to levels similar to those in healthy individuals, as shown by studies of treated and untreated individuals with MS and healthy individuals [[27892]] Elevates the ratio of naïve to memory B cells in the blood of individuals with MS [[28958]] Increases the percentage of plasma cells in the blood of individuals with MS [[28958]] Increases the proportion of transitional B cells in the blood of individuals with MS [[28958]] Increases the proportion of regulatory B cell subsets (interleukin 10+, CD25+, and CD5+ B cells) in the blood of individuals with MS [[28958]] Increases the percentage of activated CD69+ B cells among circulating B cells that remain in the blood of individuals with MS [[28958]] Decreases ICAM-1+ cells in the blood of individuals with MS, which might imply reduced capacity for antigen presentation [[28958]] Elevates the ratio of transforming growth factor beta to pro-inflammatory cytokines in the blood of individuals with MS [[28958]] Phosphorylated form activates Bcl2 (an anti-apoptotic protein) in transformed B cells from individuals with MS [[28958]] Slightly reduces the T-cell response to varicella-zoster virus and Epstein-Barr virus [[6137]] Reduces vaccination-induced immune responses against influenza antigens and tetanus toxoid antigens in some individuals with MS, as shown by a randomized, placebo-controlled trial [[16697]] Associated with an increased T-cell response specific for varicella-zoster virus and varicella zoster virion component IE63 (relative to the number of CD3+ T cells) that peaks after 6 months of treatment and then reverts to baseline after 12 and 24 months, as shown in a study of 31 fingolimod-treated individuals; two individuals who lacked such a response developed herpes zoster [[27025]] Enhances the ability of human natural killer cells (activated by interleukin 2) to lyse several cell types (cells from tumor cell lines and immature and mature dendritic cells) [[8284]] Enhances the ability of human NK17/NK1 cells (which express CD56 and CCR4) to lyse cells from a tumor cell line [[8284]] Increases the expression of NKp30 and NKp44 (natural killer cytotoxicity receptors) and NKG2D on the surface of human natural killer cells [[8284]] Decreases the expression of CD158 (a killer inhibitory receptor) on the surface of human natural killer cells [[8284]] Decreases the expression of CCR6 on the surface of immature human dendritic cells [[8284]] Does not reduce the number of CD1c+ dendritic cells or monocytes in peripheral blood in individuals with MS [[17354]] Does not impair activation of CD1c+ dendritic cells (based on upregulation of CD86 on these cells) [[17354]] Reduces lipopolysaccharide-induced secretion of tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-6 by ex vivo CD1c+ dendritic cells and monocytes, based on experiments using cells from fingolimod-treated and untreated individuals with MS and healthy individuals [[17354]] Reduces platelet counts, as shown in a study of 80 individuals with MS, with samples taken one month before and one month after fingolimod treatment began [[26988]] Inhibits myeloid cell activation [[23983]] In vitro exposure inhibits lipopolysaccharide-induced expression of the activation markers CD25 and CD150 and secretion of tumor necrosis factor alpha in human monocytes, but does not affect their survival [[23983]] Impairs the ability of monocytes to be activated by low or intermediate concentrations of lipopolysaccharide, but not by saturating concentrations, thus raising the activation threshold of the monocytes, as shown in experiments with cells from healthy individuals, individuals with untreated MS, and individuals with MS treated with fingolimod [[23983]] Inhibits subsequent sphingosine 1-phosphate-induced signaling of extracellular-signal-regulated kinase (pERK1/2) in cultured human fetal astrocytes [[5314]] Does not inhibit serum- or interleukin-1beta-induced signaling of extracellular-signal-regulated kinase (pERK1/2) in cultured human fetal astrocytes [[5314]] Might desensitize astrocytes to sphingosine 1-phosphate receptor stimulation, but sustain reactions that are independent of such stimulation, thus modulating specific neuroinflammatory responses [[5314]] Phosphorylated form increases levels of mRNAs encoding the neurotrophic mediators leukemia inhibitory factor, interleukin 11, and heparin-binding EGF-like growth factor in human astrocytes, an effect mediated by sphingosine-1-phosphate receptors 1 and 3 [[22115]] Phosphorylated form increases secretion of the neurotrophic mediators leukemia inhibitory factor and interleukin 11 from human astrocytes [[22115]] Phosphorylated form blocks the tumor necrosis factor-induced expression of inflammatory mediators (CXCL10, BAFF, MX1, and OAS2) by human astrocytes [[22115]] Phosphorylated version promotes differentiation of fetal oligodendrocyte progenitor cells in culture [[10930]] Reduces relapses and decreases brain volume loss in RRMS, and these two effects independently predict the effect of therapy on disability, as shown by analysis of data from the FREEDOMS clinical trial [[17014]] Associated with a consistent reduction in the annualized rate of brain atrophy, as shown by analysis of data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials and their extensions; furthermore, participants who switched to fingolimod from the comparator were found to then display atrophy rates similar to those who were randomized to fingolimod initially [[18401]] Associated with a trend toward reduction of the conversion of acute gadolinium-enhancing lesions to chronic T1 hypointensities (or "chronic black holes"), as shown in a retrospective, nonrandomized comparison of 26 individuals with MS treated with fingolimod with 30 individuals with MS on no therapy [[22446]] Suppressed paroxysmal dysarthria–ataxia syndrome (which involves transient alterations in speech and limb or gait ataxia) in an individual with RRMS [[17133]] Comparison of a Markov transition model approach and survival analysis methods for quantifying the effects of fingolimod on disability progression has been published [[4975]] Associated with an increase in macular volume within 5 months in a longitudinal observational study [[4171]] Fingolimod directly inhibits the human ether-a-go-go-related gene (hERG) current, whereas siponimod does not, in a model in which hERG channels are expressed in human embryonic kidney 293 cells [[13837]] Stimulates protein phosphatase 2A (PP2A) or PP2A-like activity in the Jurkat human T cell line; PP2A is a tumor suppressor that is inactive in some cancers [[7207]] [[7133]] Decreases the viability of human tumor cells (melanoma, cervix carcinoma, and breast carcinoma) in vitro [[10719]] Induces apoptosis in acute myeloid leukemia cells, M2 subtype, by rapidly increasing levels of pro-apoptotic ceramide [[12646]] In combination with monomethyl fumarate (MMF, the active metabolite of dimethyl fumarate), reduces the viability of primary human glioblastoma cells and activated microglia more than MMF alone [[15819]] Sensitizes human hepatocellular carcinoma cells to the cytotoxic effects of the kinase inhibitor drug sorafenib [[23211]] Potently inhibits transient receptor potential melastatin 7 (TRPM7), a channel kinase, based on studies involving stable expression of TRPM7 in human embryonic kidney 293 cells [[3912]] Has been used to treat two individuals with natalizumab-associated progressive multifocal leukoencephalopathy (PML) who displayed severe MS relapses after natalizumab discontinuation; the MS symptoms improved and the PML did not worsen [[9063]] May not confer benefit in individuals who are positive for aquaporin-4 antibodies, based on results from 4 individuals; 3 of these individuals exhibited disease exacerbations soon after beginning treatment [[9549]] Ability to affect sphingosine 1-phosphate receptor 1 (S1P1R) appears to be affected by genetic variations in S1P1R identified by exon sequencing of >12,000 individuals [[14323]] Phosphorylated form induces endocytosis and degradation of wild-type sphingosine 1-phosphate receptor 1 (S1P1R), but only weakly affects the endocytosis and degradation of two mutant forms of S1P1R (I45T and G305C), which are encoded by natural variants of the S1P1R gene, as shown by experiments involving expression of these proteins in cultured cells [[14323]] Phosphorylated form accumulates in the nucleus of human neuroblastoma cells [[11236]] Increases acetylation of specific lysine residues in histone H3 (Lys9), histone H4 (Lys5), and histone H2B (Lys12) in human neuroblastoma cells [[11236]] Phosphorylated form (but not the unphosphorylated form) strongly inhibits the activity of recombinant human class I histone deacetylases (HDAC1, HDAC2, HDAC3, and HDAC8) [[11236]] Binds to histone deacetylase I, as shown by experiments with recombinant enzyme and immunoprecipitation from HeLa cells [[11236]] Phosphorylated form protects neuronal cells from damage caused by synthetic human prion protein peptide [[11434]] May shield neurons from degenerating in the presence of human immunodeficiency virus (HIV), as shown in experiments monitoring gene expression in differentiated human neuronal progenitor cells exposed to HIV (meeting report) [[22562]] Reduces intracortical excitability, which is primarily mediated by glutamate, in individuals with RRMS [[12566]] Dramatically reduced gadolinium-enhancing lesions in an individual with highly active RRMS, who had previously discontinued natalizumab because of side effects [[13121]] May increase the probability of conception in woman with RRMS linked with secondary infertility [[18411]] Associated with a reduction in heart rate as compared with baseline when therapy is initiated; the lowest heart rate occurs 5 hours after the first dose, as shown in a prospective study of 27 individuals with RRMS [[19711]] Associated with a reduced nighttime heart rate as compared with baseline, but a normal daytime heart rate, after three months of therapy, as shown in a prospective study of 24 individuals with RRMS [[19711]] Did not cause significant changes in the cerebral blood flow, platelet function, or macular thickness in a double-blind, placebo-controlled study of healthy volunteers [[12060]]	In mice, affects lymphocyte movement into circulation from the thymus and secondary lymphoid organs (a process mediated by sphingosine 1-phosphate 1 receptors on lymphocytes), reducing the number of lymphocytes in circulation and increasing the number in secondary lymphoid organs [[301]] May have beneficial effects in the central nervous system beyond effects on immune cell trafficking [[307]]; role in neuroprotection might result from interactions with neuron and glia sphingosine 1-phosphate receptors [[301]] Affects expression of some myelin proteins and inflammatory mediators at the mRNA level and improves clinical status of mice with relapsing-remitting experimental autoimmune encephalomyelitis [[305]] Active phosphorylated form reduces Schwann cell-mediated myelination in cultured rat cells [[2328]] Reduces breakdown of the blood-brain barrier during delayed-type hypersensitivity lesion formation in a Lewis rat model of MS [[9368]] Reduces recruitment of lymphocytes and macrophages/activated microglia to delayed-type hypersensitivity lesions during lesion formation in a Lewis rat model of MS [[9368]] Reduces the area of demyelination, but does not affect recruitment of lymphocytes within lesions, during the chronic disease phase (when the blood-brain barrier has resealed) in a focal delayed-type hypersensitivity model of MS in Lewis rats [[9368]] Reduces levels of circulating γδ T cells, as well as levels of conventional αβ T cells, in mice [[20159]] Results in the accumulation of interleukin-17 (IL-17)+Vγ4+, IL-17+Vγ4-, and IL-17-Vγ4- T cells in the lymph nodes in mice [[20159]] Results in the sequestration of interleukin-17-producing Vγ4+ γδ T cells in the draining lymph nodes under inflammatory conditions at the skin; these cells would normally infiltrate the inflammed skin [[20159]] Results in the sequestration of interleukin-17-producing Vγ4+ γδ T cells in the draining lymph nodes in experimental autoimmune encephalomyelitis, inhibiting the infiltration of these cells into the central nervous system [[20159]] Downregulates sphingosine 1-phosphate receptor 1 expression, and the ability to respond to sphingosine 1-phosphate, in Vγ4+ γδ T cells in mice [[20159]] Phosphorylated form reduces levels of the tight junction protein occludin in rat brain microvascular endothelial cell culture under inflammatory conditions [[24997]] Phosphorylated form does not reduce endothelial barrier permeability in rat brain microvascular endothelial cell culture under inflammatory conditions [[24997]] Phosphorylated form does not affect levels of endothelial matrix metalloproteinases MMP-9 and MMP-2 in rat brain microvascular endothelial cell culture under inflammatory conditions [[24997]] Systemic treatment causes dendritic cells to accumulate in the central nervous system in normal mice [[9928]] Reduces the egress of dendritic cells (DCs) from the central nervous system to the cervical lymph nodes (a site where CNS-specific T cells are activated) as the DCs travel via the rostral migratory stream [[9928]] Although systemic delivery inhibits experimental autoimmune encephalomyelitis (EAE), delivery to the rostral migratory stream, through which dendritic cells normally migrate to the cervical lymph nodes and modulate regulatory T cell function, increases the severity of EAE [[9928]] Delivery to the rostral migratory stream induces experimental autoimmune encephalomyelitis in a disease-resistant mouse strain by reducing dendritic cell (DC) egress from the central nervous system (CNS) to the cervical lymph nodes, where DCs normally enhance regulatory T cell function and downregulate CNS autoimmunity [[9928]] Does not change the inflammatory activity of dendritic cells from the central nervous system [[9928]] Inhibits experimental autoimmune encephalomyelitis in Cbl-b-deficient mice, indicating that fingolimod may still be useful in individuals with MS with Cbl-b abnormalities [[17926]] (CBLB polymorphisms in humans have been linked to MS risk; one has been shown to affect T cell response to type I interferons [[14046]]) Ameliorates experimental autoimmune encephalomyelitis (EAE), even when administered after pathology onset, in EAE mice [[24416]] Inhibits the Akt-mTOR signaling pathway, which is activated in experimental autoimmune encephalomyelitis (EAE), in EAE mice [[24416]] Increases the frequency of Treg cells [which is reduced in experimental autoimmune encephalomyelitis (EAE)] and reduces the frequency of Th1 cells (which is increased in EAE) in the spleen in EAE mice [[24416]] Late-therapeutic treatment improves sociability deficits and prophylactic treatment improves gait in one experimental autoimmune encephalomyelitis mouse model, but neither form of treatment reduces clinical scores in this model [[24979]] Causes subtle changes in behavior (longer ultrasonic vocalizations and more motor activity as compared with vehicle treatment) in experimental autoimmune encephalomyelitis mice in the period before clinical symptoms (weight loss and limb paralysis) become apparent [[11214]] Active phosphorylated form induces apoptosis in cultured rat Schwann cells [[2328]] Inhibits demyelination induced by lysolecithin in rat cerebellar slice cultures [[8355]] With the sphingosine-1-phosphate receptor 1 (S1P1R) agonist SEW2871, increases S1P1R expression in astrocytes in rat cerebellar slice cultures [[8355]] Inhibits the release of chemokines LIX, MIP-1alpha, and MIP-3alpha in rat cerebellar slice cultures in which demyelination was induced by lysolecithin [[8355]] May inhibit demyelination, in part, by reducing chemokine-mediated communication between immune and central nervous system cells [[8355]] Inhibits events mediated by sphingosine-1-phosphate (S1P) and inflammatory cytokines (translocation of NFkappaB and nitric oxide production) in astrocytes, and thus astrocyte-mediated neurodegeneration, as shown by experiments with an in vitro model; S1P and cytokines are upregulated in astrocytes in MS and experimental autoimmune encephalomyelitis lesions [[12647]] Inhibits activation of astrocytes and production of nitric oxide in experimental autoimmune encephalomyelitis mice [[12647]] When used In vitro to treat myelin oligodendrocyte glycoprotein-reactive splenocytes from mice, reduces demyelination caused by these cells in mouse cerebellar slices [[11539]] When used In vitro to treat mouse splenocytes that have been engineered to be stimulated by myelin oligodendrocyte glycoprotein (MOG), reduces the release of pro-inflammatory cytokines (interferon gamma and interleukin-6) by these cells during MOG stimulation [[11539]] Phosphorylated form, but not nonphosphorylated form, inhibits interleukin-2 (IL-2) production stimulated by IL-33 in a mouse lymphoma cell line overexpressing the IL-33 receptor [[24873]] Increases oligodendrocyte progenitor cell number and proliferation in the brain and spinal cord white matter, concurrent with its associated reduction in disease score, in mice with experimental autoimmune encephalomyelitis [[17001]] Increases oligodendrocytes, myelination, and oligodendrocyte progenitor cell differentiation in mice with experimental autoimmune encephalomyelitis [[17001]] Increases levels of Sonic hedgehog (Shh), as well as levels of the Shh receptor Smoothened and effector Gli1, in the central nervous system white matter of mice with experimental autoimmune encephalomyelitis [[17001]] Improves symptoms and increases oligodendrocyte progenitor proliferation and differentiation, but this effect is abolished by the Sonic hedgehog pathway inhibitor cyclopamine, in mice with experimental autoimmune encephalomyelitis [[17001]] Modestly accelerates remyelination in the central nervous system after acute but not chronic exposure to the toxin cuprizone, which induces demyelination [[13782]] Appears to reduce ongoing axonal damage (assessed by the axonal buildup of amyloid precursor protein-positive spheroids) after cuprizone-induced central nervous system demyelination [[13782]] Enhances remyelination in a mouse model of local demyelination [[22757]] Does not increase remyelination in the mouse cerebellum when given after demyelination is induced by cuprizone [[20500]] Does not change the number of microglia, astrocytes, or mature oligodendrocytes in the mouse cerebellum when given after demyelination is induced by cuprizone [[20500]] Protects rats immunized with myelin basic protein against experimental autoimmune encephalomyelitis and this effect is associated with a strong reduction in the number of T cells in the spinal cord [[306]] Reduces microglial activation in chronic delayed type hypersensitivity-like lesions in experimental autoimmune encephalitis, an effect that can be monitored in vivo by positron emission tomography and a radioligand [[16410]] Inhibits intracellular vesicle mobility and secretion, thereby affecting regulated exocytosis, in cultured rat astrocytes [[1915]] Does not affect T and B cell memory activation or expansion upon viral infection in animal models [[402]] Reduces anti-viral immune responses (by reducing the accumulation of virus-specific T cells in the central nervous system) in mice infected with a neurotropic strain of mouse hepatitis virus, increasing disease severity and mortality [[13125]] Reduces neuroinflammation and demyelination in mice infected with a neurotropic strain of mouse hepatitis virus [[13125]] Increases levels of brain-derived neurotrophic factor (at the mRNA and protein level) in cultured cortical neurons from mice, an effect that requires mitogen-activated protein kinase signaling and synaptic activity [[2796]] Increases brain-derived neurotrophic factor levels in the cortex, hippocampus, and striatum of mice [[2796]] Protects cultured mouse neurons from death induced by NMDA (a synthetic compound that kills neurons by overstimulating them) in a manner dependent on brain-derived neurotrophic factor [[2796]] Increases the frequency and amplitude of excitatory postsynaptic currents, but reduces the amplitude and frequency of inhibitory postsynaptic currents, in cultured mouse neurons [[2796]] Protects cultured mouse cortical neurons against excitotoxic death, in an experiment in which fingolimod-treated cells were challenged with toxic concentrations of N-methyl-d-aspartate; neuroprotective effects were reduced by inhibitors of mitogen associated protein kinase and phosphatidylinositol-3-kinase pathways [[3625]] Reduces excitotoxic cell death (induced by N-methyl-D-aspartic acid) of primary rat neuronal cells and in cerebrocortical cultures from rat pups [[18766]] Chronic treatment reduces hippocampal neurodegeneration and microglial activation induced by intracerebroventricular administration of kainic acid in rats [[18766]] Reduces lipopolysaccharide (LPS)-induced phosphorylation of the mitogen-activated protein kinase (MAPK) p38, but not JNK, in primary rat microglial cells; MAPK signaling is involved in inflammatory responses to brain injury that are mediated by microglia [[18766]] Direct administration to the central nervous system reduces, but does not eliminate, the upregulation in neuronal Ca2+ signaling and the excitotoxic morphological alterations caused by later direct administration of 100 mM glutamate, as shown by experiments in transgenic Ca2+ reporter mice [[24627]] Prevents destabliization of dendrites and dendrite loss induced by denervation in enterohino-hippocampal slice cultures from mice [[28766]] Inhibits myeloid cell activation [[23983]] Reduces production of tumor necrosis factor alpha by myeloid cells in the central nervous system and spleen in an experimental autoimmune encephalomyelitis mouse model [[23983]] Protects against damage (white matter abnormalities and long-term cognitive defects) in a neonatal model of oxygen toxicity [[22542]] Reduces oxidative stress, activation of microglia, and expression of proinflammatory cytokines in a neonatal model of oxygen toxicity [[22542]] Reduces hypomyelination and oligodendrocyge degeneration and increases oligodendrocyte maturation in a neonatal model of oxygen toxicity [[22542]] Rapidly reduces the activity of P-glycoprotein, a drug efflux pump, in rat brain capillaries and in in vivo experiments in rat brains [[3022]] Increases the uptake of several small-molecule drugs to the brain via an inhibitory effect on P-glycoprotein (a drug efflux pump that impedes delivery of such drugs across the blood-brain barrier), as shown by experiments in rats [[3022]] Induces cell cycle arrest in G(0)/G(1) phase in mouse lymphocytes [[3064]] Blocks concanavalin A-induced mitogenesis in mouse lymphocytes [[3064]] Inhibits production of proinflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta, and interleukin-6) by activated microglia from mice via interactions with S1P1 receptors [[4456]] Enhances production of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor by activated microglia from mice [[4456]] Reduces interferon gamma and Granzyme B production (a measure of effector function) by splenic CD8+ T cells from experimental autoimmune encephalomyelitis mice; the unphosphorylated form (and not the phosphorylated form) has this effect in vitro, indicating that it is independent of the effect on sphingosine-1-phosphate receptors [[10361]] Reduces the cytotoxic function of murine CD8+ T cells in vitro; the unphosphorylated form (and not the phosphorylated form) has this effect, indicating that it is independent of the effect on sphingosine-1-phosphate receptors [[10361]] Ability to suppress murine CD8+ T cell function is reversed by arachidonic acid (AA), suggesting that the effect is due to inhibition of cytosolic phospholipase A2 (which functions in AA production) [[10361]] Nearly doubles the mortality rate during murine influenza virus infection [[10361]] Decreases the infiltration of both CD4+ and CD8+ T cells into the lungs during murine influenza virus infection [[10361]] Reduces production of Granzyme B (a protease that mediates apoptosis in target cells) by CD8+ T cells during murine influenza virus infection [[10361]] Both fingolimod and siponimod induce atrioventricular conduction block at high dose, whereas fingolimod but not siponimod prolongs the QT interval at high dose and siponimod but not fingolimod prolongs the PR interval at low dose, in a guinea-pig model [[13837]] Prolongs the cycle length when applied directly to rat atrioventricular nodal tissue in vitro, as measured using extracellular potentials recordings [[18256]] Reduces disturbances in atrioventricular nodal pacemaker activity induced by both ischaemia and reperfusion when applied directly to rat atrioventricular nodal tissue in vitro [[18256]] Phosphorylated version activates ERK1/2, CREB, and p38MAPK in cultured rat neurons and astrocytes [[10930]] When administered in eye drop form, reduces symptoms of dry eye disease (specifically, reduces signs of inflammation, restores goblet cells, and reduces ocular surface lesions), as shown in experiments in non-obese diabetic mice [[24769]] Attenuates learning and memory impairment induced by intrahippocampus injection of beta-amyloid peptide in rats [[5052]] Reduces production of amyloid-beta in cultured mouse neurons [[6021]] Decreases brain levels of amyloid-beta 40, but increases levels of amyloid-beta 42, in APP transgenic mice, a model of Alzheimer's disease [[6021]] Restores memory, and concurrently alters the expression of certain genes, in a rat model of Alzheimer's disease [[6465]] Enhances motor function, increases survival, strengthens neuronal activity, and decreases brain atrophy in a mouse model of Huntington's disease [[8824]] Reduces long-term memory problems and loss of dendritic spines in CA1 hippocampal neurons in a mouse model of Huntington's disease [[20469]] Inhibits astrogliosis in the hippocampus in a mouse model of Huntington's disease [[20469]] Reduces levels of tumor necrosis factor alpha and induced nitric oxide synthase, and normalizes levels of p75NTR, in the hippocampus in a mouse model of Huntington's disease [[20469]] Treatment either before or after intracerebral lipopolysaccharide (LPS) injection (which causes neuroinflammation) in rats reduces memory impairment induced by LPS [[13029]] Alters a gene expression profile (involving mitogen-activated protein kinase and inflammatory genes) that is associated with memory impairment induced by intracerebral lipopolysaccharide injection in rats [[13029]] Improves memory and learning in mice injected with the neurotoxic protein amyloid beta, an effect that is linked with the re-establishment of normal levels of brain-derived neurotrophic factor in the hippocampus and cerebral cortices [[10514]] Inhibits apoptosis of islet beta-cells and prevents the development of diabetes in db/db mice, a model of diabetes [[2981]] Reduces the growth of metastatic melanoma in mice [[10719]] Modulates the immune system in mice with metastatic melanoma, decreasing the frequency of Foxp3+ cells (T regulatory cells) but not affecting CD8+ T cells or the production of interferon gamma by lymphocytes [[10719]] In vitro, decreases the viability of murine melamona cells by inducing apoptosis [[10719]] Systemic administration reduces chemotherapy-induced neuropathic pain, and associated activation of neuroinflammatory processes (dependent on sphingosine 1-phosphate receptor subtype 1), in a rat model [[11313]] Reduces inflammation in obstructed kidneys in mice [[10488]] Reduces urinary protein, inflammatory cell infiltration into the tubulointerstitial tissue of the kidney, and tubulointerstitial injury in a rat model of nephropathy [[21191]] Reduces the expression of inflammatory cytokines monocyte chemoattractant protein-1, tumor necrosis factor-alpha, interleukin-6 (IL-6), and IL-10, as well as arginase-1, in the kidney cortex in a rat model of nephropathy [[21191]] Reduces levels of Sphk1 [an enzyme that synthesizes sphingosine 1-phosphate (S1P)], S1P receptors 1 and 3, and S1P in the kidney in a rat model of nephropathy (in which levels of these proteins, and that of S1P, are increased) [[21191]] Stimulates purified bovine protein phosphatase 2A [[7207]] Stimulates Ca2+ influx and calcineurin activity in fission yeast [[8853]] Phosphorylated form accumulates in the nucleus of primary hippocampal neurons from mice [[11236]] Increases acetylation of a lysine 9 in histone H3 in primary hippocampal neurons from mice [[11236]] Phosphorylated form accumulates in mouse brain [[11236]] Inhibits histone deacetylase activity, and increases acetylation of lysine 9 in histone 3, in the hippocampus in mice [[11236]] Enhances fear extinction, but does not alter the acquisition of fear memories, as shown by experiments in severe combined immune deficient mice, which lack functional B and T cells (thus, these effects appear to be independent of fingolimod's effects on lymphocyte trafficking) [[11236]] Exhibits an antidepressant-like activity in mice under chronic unpredictable stress or chronically treated with corticosterone [[20155]] Chronic treatment reverses the stress-induced decrease in brain-derived neurotrophic factor and increase in histone deacetylase 2 levels in the hippocampus in "responder" mice (those who exhibit less immobility in a forced swim test in response to fingolimod) [[20155]] Does not affect the abundance of brain-derived neurotrophic factor or histone deacetylase 2 at the protein level in the hippocampus of unstressed mice [[20155]] Increases neural progenitor proliferation and survival in the dentate gyrus of the hippocampus in adult mice [[25895]] Increases proliferation and survival of cultured mouse hippocampal neural stem and precursor cells that express the sphingosine-1 phosphate receptor type 1 [[25895]] Improves the ability of mice to discriminate between a hostile and a similar non-hostile environment after fear conditioning [[25895]] Does not affect survival of mice infected with the neuroinvasive parasite Toxoplasma gondii, but does affect leukocyte numbers and parasite load in the brain [[13835]] Decreases histone deacetylase activity and reverses the loss of estrogen and progesterone receptor expression induced by a high-fat diet in breast carcinomas in a line of transgenic mice that spontaneously develop such tumors [[19842]] Suppresses breast tumors in a line of transgenic mice that spontaneously develop such tumors, an effect that is more dramatic in mice fed a high-fat diet, which promotes such cancer [[19842]]
[+]	Firategrast	IM	Alpha4beta1 integrin [[1338]] [[1339]]	Molecular weight: 499.5 [[1376]] Pharmacological half-life is 2.5 – 4.5 hours, compared to 11 days for natalizumab, a drug in the same class [[1339]] Orally bioavailable small molecule α4-integrin antagonist [[1338]] [[1339]]	Similar mechanism of action to natalizumab (α4-integrin blocker), but its faster elimination could improve safety profile [[1338]] [[1339]]
[+]	Flupirtine	NP	Neuronal potassium channels [[1342]] Membrane resting potential [[1341]] NMDA receptor channels (indirectly) [[1347]]	Molecular weight: 304 [[1498]] Weakly lipophilic base with a pKa of around 5.3 [[1340]] Derivative of triaminopyridine [[1340]] Non-opioid analgesic [[1342]] Pharmacokinetic properties have been determined [[1340]] [[1342]] Excellent tolerability profile [[1342]]	Stabilizes membrane resting potential by activating neuronal Kv7 potassium channels [[1340]] Indirectly antagonizes NMDA receptors [[1347]] Reduces muscle spasticity in humans[[1348]] Prevents apoptosis and reduced formation of reactive oxygen species by in cultured human retinal pigment epithelial cells [[1342]]	Increases the survival of retinal ganglion cells and, when combined with interferon beta, significantly improved visual function in a rats with experimental autoimmune encephalitis /optic neuritis [[1341]] May exert neuroprotective effect in rats with experimental autoimmune encephalitis /optic neuritis via activation of inwardly rectifying potassium channels [[1341]] Improves cognitive function in a 28-patient clinical trial of patients with Creutzfeldt-Jakob disease, suggesting neuroprotective effects [[1343]] Acts as a muscle relaxant in rats without inducing sedation or reducing spontaneous movement [[1342]] [[1344]] Reduces axonal hyperexcitabilty in rat nerve fibers with induced neuropathy via slow potassium channel activation [[1345]] Displays antioxidant properties in rat cell cultures [[1346]]
[+]	Glatiramer acetate	IM NP	Immune cells [[343]] 26S proteasome-mediated degradation of myelin basic protein [[14142]]	Designed to mimic myelin basic protein [[343]] Random polymer of four residues found in myelin basic protein (L-glutamic acid, L-alanine, L-lysine, L-tyrosine) [[408]] Average molecular weight, 6.4 kDa [[343]] Polar [[343]] Not likely to cross the blood-brain barrier [[343]] Binds to class II major histocompatibility complex molecules on antigen-presenting cells [[343]]	Exact mechanism unknown [[343]] Is an immunomodulator that appears to normalize dysregulated immune system circuits in MS [[343]] May act as a universal antigen (induces in vitro proliferation of naive T cell populations from both healthy controls and MS patients) [[403]] Affects the function of many types of immune cells, including several types of T cells, dendritic cells, and natural killer cells [[343]] Shifts CD4+ T cell response from Th1 (pro-inflammatory cytokine secreting T helper type 1) to Th2 (anti-inflammatory cytokine secreting T helper type 2) [[343]] Upregulates cytotoxic CD8+ T cells to healthy levels [[343]] Increases the capability of T regulatory cells (which suppress autoimmunity) [[343]] Induces CD8+ T cell proliferative responses that are lower in individuals with untreated MS than in healthy individuals; over months, glatiramer acetate therapy upregulates the CD8+ T cell responses to levels seen in healthy people [[25099]] Induces CD4+ T cell proliferative responses that are similar in healthy individuals and individuals with untreated MS [[25099]] Induces cytotoxic CD8+ T cells that can kill CD4+ T cells [[25100]] Increases the frequency of naïve T cells, decreases the frequency of central memory T cells (which is increased in MS patients), and increases the frequency of T-suppressor cells in RRMS patients [[2099]] Induces expression of interferon gamma and interleukin 4 mRNAs ex vivo in mononuclear cells from MS patients; expression above a certain threshold predicts a better response to glatiramer acetate in patients (a better chance of being relapse free and a better relapse-free survival rate) [[1684]] Increases the killing ability of natural killer cells from humans against dendritic cells [[343]] Often increases the cytotoxic activity of natural killer (NK) cells (isolated from RRMS patients treated with glatiramer acetate) toward immortalized leukemia cells (an increased activity that correlates with increased expression of NK cell activating cytotoxicity receptors and reduced expression of CD158, an inhibitor molecule, on the NK cell surface); these NK cells can also lyse both autologous immature and mature dendritic cells [[5746]] Reduces the percentage of dendritic cells expressing CD40 in MS patients; a higher percentage of such cells is associated with an increased risk of relapse [[1993]] Downregulates the expression of the P2X7 purinergic receptor in peripheral blood monocytes from MS patients, as shown by PCR analysis [[2100]] Increases the phagocytic activity of monocytes, based on a comparison of cells from treated versus non-treated MS patients or healthy controls and on in vitro experiments, an activity that appears to come from a CD14++CD16+ subset of monocytes [[4407]] Decreases microglial activation, as determined by measuring uptake of [(11)C]-R-PK11195, a radiopharmaceutical for positron emission tomography, in MS patients before and after 1 year of treatment [[5776]] Rapidly (within 4 to 12 hours after the first exposure) changes immune cell levels and function, such that the CD4/CD8 T cell ratio decreases, CD8+ T cell homeostasis alters, suppression by CD8+ T cells increases, and interleukin 10 and tumor necrosis factor-α production increases [[5605]] Restores the production of interleukin-10 (IL-10) and decreases the production of IL-6 by peripheral B cells, as shown by a comparison of B cells isolated from healthy individuals and individuals with MS with or without treatment with glatiramer acetate [[14074]] Treatment alters the proliferation of and increases immunoglobulin production by in vitro-activated B cells, as shown by a comparison of B cells isolated from healthy individuals and individuals with MS with or without treatment with glatiramer acetate [[14074]] Attenuates the pro-migratory pattern of immune cell adhesion molecules [which includes upregulated LFA-1 (on certain T cells and B cells), VLA-4 (on certain T cells and natural killer cells), ICAM-1 (on B cells), and ICAM-3 (on natural killer cells)] in RRMS patients, but the effects are relatively slow and unselective [[5764]] Does not affect the frequency of CD27+CD43+ B1 cells, which is reduced in RRMS [[10963]] Reduces the absolute number of circulating CD19+ B cells (which is reduced in naïve-to-treatment individuals with RRMS relative to healthy controls), as shown in a longitudinal study [[19122]] Does not affect the absolute number of peripheral CD4+CD45RO+ cells (CD4+ T cells with a memory phenotype), which is increased in naïve-to-treatment individuals with RRMS, as shown in a longitudinal study [[19122]] Reduces circulating concentrations of soluble CD40 ligand and soluble tumor necrosis factor-receptor, as shown in a longitudinal study of individuals with RRMS [[19122]] Benefits a subset of individuals with RRMS (such that the time since last relapse and the duration of treatment is positively correlated), and only these responders exhibit brain antigen-specific B cells in their blood, based on a study of 34 individuals; the correlation between B cells and treatment response was not seen in 23 individuals treated with interferon beta [[21801]] In contrast to interferon beta, does not increase blood levels of B-cell activating factor (BAFF, the primary survival factor for B cells); BAFF levels are higher in individuals with MS than in healthy controls, but those with MS who do not relapse have higher BAFF levels than those who do, as shown in a prospective longitudinal study of 170 individuals with MS over 2.3 years [[24059]] Displays neuroprotective functions [[343]] [[5629]] Associated with increased levels of soluble thrombomodulin, which is released from the cell surface of cerebrovascular endothelial cells when they are damaged and promotes a protective response, in RRMS patients [[3108]] Promotes production of brain-derived neurotrophic factor by T cells, which promotes nerve regeneration and remyelination [[343]] Response induced in patients appears to be influenced by allelic combinations of immune-response genes [[2195]] Affects the expression of certain genes in monocytes, as shown in an mRNA microarray study involving 8 individuals with RRMS [[8111]] Upregulates expression of genes encoding anti-inflammatory markers, and affects expression of genes involved in multiple pathways related to the immune system, in a manner different than that of Probioglat, a different glatiramoid, as shown by genome-wide expression studies in a human monocyte cell line [[19244]] Affects the expression of hundreds of genes, and many of these are differentially affected by Copaxone (Teva) and a generic version, Polimunol (Synthon), as shown by studies in a human monocyte cell line [[25147]] Probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients [[4420]] Does not affect the fraction of CD8+ T cells that produce interleukin-17 (IL-17) or IL-10, cell subsets that are elevated in RRMS patients in remission as compared with healthy people [[6515]] Appears to have a stabilizing effect on erythrocyte membranes in individuals with RRMS [[5760]] Reduces increased levels of phospholipase A2 in erythrocyte membranes in individuals with RRMS [[5760]] Reduces levels of lipid peroxidation products in erythrocyte membranes in individuals with RRMS [[5760]] Associated with increased levels of advanced glycation end products in blood serum proteins relative to levels in untreated individuals with RRMS, which are in turn higher than in healthy individuals [[7611]] Reduces plasma levels of osteopontin (a protein with roles in inflammation and immunity), which are increased in RRMS and SPMS [[7469]] Reduces expression of the transcription factor interferon regulatory factor-1 (IRF-1) in chondrocytes from individuals with osteoarthritis, in which IRF-1 levels are increased, and this role involves inhibition of transcription factor STAT1 activation [[10276]] Reduces the tumor necrosis factor-α–induced upregulation of interferon regulatory factor-1 expression at both the RNA and protein level in human chondrocytes [[10276]] Suppresses the tumor necrosis factor-α–induced upregulation of matrix metalloproteinase 13 (an enzyme that degrades collagen and that is encoded by a gene that is a target of the transcription factor interferon regulatory factor-1) at both the RNA and protein level in human chondrocytes [[10276]] Suppresses the tumor necrosis factor-α–induced degradation of collagen II in human chondrocytes [[10276]] Suppresses the tumor necrosis factor-α–induced production of nitric oxide and expression of inducible nitric oxide synthase in human chondrocytes [[10276]] Inhibits binding (induced by tumor necrosis factor-α) of monocytes (from a human monocytic cell line) to primary human umbilical vein endothelial cells [[15980]] Inhibits the expression of the the proinflammatory chemokine monocyte chemotactic protein-1 and the adnesion molecules vascular adhesion molecule-1 and E-selectin induced by tumor necrosis factor-α in human umbilical vein endothelial cells [[15980]] Inhibits the nuclear translocation of NF-κB p65 induced by tumor necrosis factor-α in human umbilical vein endothelial cells [[15980]] Inhibits the phosphorylation and subsequent degradation of IκBα (which inhibits NF-κB nuclear translocation) induced by tumor necrosis factor-α in human umbilical vein endothelial cells [[15980]] Increases serum levels of endogenous secretory receptor for advanced glycation end-products (esRAGE); serum esRAGE levels are reduced during clinical relapse [[15134]] Inhibits production of proinflammatory cytokines by human monocytes by inhibiting signaling mediated by Toll-IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF), as shown by experiments involving specific Toll-like receptor agonists [[24050]] Inhibits the proteasome-mediated degradation of human myelin basic protein expressed in human embryonic kidney 293 cells [[14142]] Might influence the intracellular processing of myelin basic protein by antigen-presenting cells in regions outside of the central nervous system [[14142]] Inhibits human platelet activation in vitro [[19869]] Reduces thrombin-induced calcium influx into human platelets, as well as thrombin-induced expression of activation markers and platelet aggregation [[19869]] During treatment, new inflammatory events are more likely in individuals with MS who display a distinct RNA profile, with increased expression of RNAs involved in lymphocyte signaling pathways [[3277]] Effectiveness (measured in terms of a lack of relapses and disease progression) correlates with a decrease in the titer of IgG antibodies against human herpes virus 6A/B, whereas an increase predicts relapse, as shown in a 2-year longitudinal study [[12927]] Associated with reduced expression of microRNA-146a (miR-146a) and miR-142-3p, which is increased in peripheral blood mononuclear cells from individuals with RRMS versus healthy controls, indicating that glatiramer acetate may normalize abnormal miRNA expression [[11847]] Associated with decreased macular volume in individuals with RRMS [[8189]] Mean adherence rates have been determined (through the analysis of 24 studies reporting on this topic) for intramuscular interferon beta-1a, given once a week (69.4%); subcutaneous interferon beta-1b, given every other day (63.8%); subcutaneous interferon beta-1a, given 3 times a week (58.4%); and glatiramer acetate, given daily (56.8%), with better outcomes in adherent versus nonadherent individuals shown in a smaller number of studies [[10840]] Associated with a relative reduction of 21.6% in the risk of ≥1 relapses during 2 years of treatment and is less cost effective than natalizumab, according to a pharmacoeconomic analysis that used pre-existing data [[6325]] and costs of treatment in the Russian healthcare system [[12332]] Treatment is associated with a distinct gut microbiome (with genus-level differences) in individuals with MS [[14440]] Use is associated with differences in the composition of the gut microbiome; differences between treated and untreated individuals with MS were found for Bacteroidaceae, Faecalibacterium, Ruminococcus, Lactobacillaceae, and Clostridium in an exploratory study [[17602]] Responders to glatiramer acetate (who are clinically stable) exhibit higher expression of response gene to complement 32 and Fas ligand and lower expression of interleukin 21 as compared with nonresponders (who experience acute relapses), as shown in a study that monitored a cohort of 15 individuals with RRMS for 2 years [[22020]] Because specific disease-modifying therapies (DMTs) are effective in some individuals and not others, genetic biomarkers of treatment sensitivity could be useful in DMT selection; discriminative genetic markers (variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes) have been identified, with the CCR5d+ IFNAR1G combination indicating interferon beta rather than glatiramer acetate treatment, based on a study of responders and nonresponders among >500 individuals treated with interferon beta or glatiramer acetate [[10888]] Unlike natalizumab, was not observed to decrease the extent and severity of damage to white matter, as shown in a diffusion tensor imaging study [[27835]] Not an immunosuppressor [[343]] Does not affect the percentage of circulating 6-sulfo LacNAc(+) dendritic cells, proinflammatory cells that are present in demyelinated brain lesions and are often present in cerebrospinal fluid in individuals with MS [[14709]] Does not increase plasma levels of brain-derived neurotrophic factor (BDNF) in individuals with RRMS; BDNF levels are reduced in these individuals [[11760]] Does not affect levels of phosphorylated receptor tyrosine kinase B in blood cells from individuals with RRMS [[11760]] Does not affect markers of neuroprotection that include serum levels of brain-derived neurotrophic factor (BDNF), BDNF expression in peripheral immune cells, nerve conduction, and neuropsychological parameters, as shown in a 24-month observational study of 21 individuals with RRMS [[22344]] Does not affect an MS-associated pattern of peripheral oxidative stress markers (reduced blood levels of Coenzyme Q10 and increased blood levels of anti-oxidized-low-density lipoprotein antibodies) [[10629]] Resumption of treatment within two weeks after delivery (versus later in the postpartum year) does not decrease the risk of relapse in the first six months postpartum, but might decrease the risk later in the first year postpartum [[10154]]	Augments B cell activity in mice, suppressing experimental autoimmune encephalomyelitis (EAE), as shown by the finding that B cells from glatiramer acetate-treated mice suppress EAE in recipient mice [[343]] Induces production of antibodies against glatiramer acetate that might enhance remyelination in experimental autoimmune encephalomyelitis mice [[343]] Developed to induce experimental autoimmune encephalomyelitis, but surprisingly inhibited it [[343]] Induces the secretion of CXCL13 (a chemoattractant for B cells) after administration to mice [[3011]] Induces the secretion of CCL22 (a chemoattractant for Th2 cells) after administration to mice, and this effect is independent of the class II major histocompatibility complex, indicating involvement of an innate immune receptor [[3011]] Induces the secretion of CCL22 (a chemoattractant for Th2 cells) in bone marrow-derived macrophages from mice [[3011]] Reduces the expression of Toll-like receptor (TLR) 9, which plays a role in the activation of innate immunity and subsequent adaptive immunity, and Myd88, a universal adapter protein for TLRs, in experimental autoimmune encephalomyelitis mice [[3892]] Shifts dendritic cells toward an anti-inflammatory phenotype, reducing expression of the cytokine osteopontin, interleukin 17, and its mediator the nuclear receptor RORgamma, in dendritic cells of experimental autoimmune encephalomyelitis mice [[3892]] Enhances production of interleukin 10 by dendritic cells in experimental autoimmune encephalomyelitis mice [[3892]] Reduces the expression of pro-inflammatory, brain-specific chemokines that might attract antigen promoting cells to the central nervous system in experimental autoimmune encephalomyelitis mice [[3892]] Induces a strong neuroprotective response in mice who received a crush injury to the optic nerve after glatiramer acetate treatment, but this response is absent if the mice are exposed to chronic mild stress before receiving glatiramer acetate (and the response is regained if glatiramer acetate is combined with Prozac) [[4478]] Has a neuroprotective role against glutamate toxicity in experimental autoimmune encephalomyelitis mice [[4802]] Reverses the changes in striatal glutamate-mediated excitatory postsynaptic currents (which are induced by tumor necrosis factor-α) that occur in experimental autoimmune encephalomyelitis mice [[4802]] Reduces microglial activation and expression of tumor necrosis factor-α in experimental autoimmune encephalomyelitis mice [[4802]] Partially prevents the rapid decline in memory that occurs in relapsing-remitting experimental autoimmune encephalomyelitis mice [[15699]] Does not decrease damage when administered after cerebral ischemia in mice, despite an increase in neurogenesis (with induced permanent middle cerebral artery occlusion) and a decrease in microglial proinflammatory cytokines (with induced transient occlusion) [[3325]] Significantly upregulates or downregulates 1,474 genes in mouse splenocytes [which were harvested after mice were treated with glatiramer acetate (GA), and then reactivated ex vivo with GA], as shown by gene expression profiling [[5198]] Induces pathways involved with T and B lymphocyte proliferation and activation, antigen presenting cell stimulation, and effector T lymphocyte differentiation in mouse splenocytes, as shown by gene expression profiling and functional pathway analysis [[5198]] Affects the expression of hundreds of genes, and many of these are differentially affected by Copaxone (Teva) and a generic version, Polimunol (Synthon), as shown by studies in mouse splenocytes [[25147]] Modulates the expression of several microRNAs (miR-155-5p, miR-27a-3p, miR-9-5p, and miR-350-5p, as detected in urine), indicating that they are potential biomarkers of glatiramer acetate response, at the peak of disease in a mouse model of experimental autoimmune encephalomyelitis [[20905]] Promotes maturation of oligodendrocytes in an animal model (involving cuprizone-induced demyelination) [[5788]] Reduces expression of brain-derived neurotrophic factor and neuregulin (a soluble gliotrophic factor) in experimental autoimmune encephalomyelitis (EAE) mice (both factors that are increased in EAE), but does not affect either in the absence of EAE [[6423]] Inhibits experimental autoimmune encephalomyelitis (EAE), and this therapeutic effect requires CD8+ T cells; furthermore, adoptive transfer of glatiramer acetate-induced CD8+ T cells suppresses signs of EAE, a process that requires non-classical MHC I, interferon gamma, and perforin, but not interleukin 10 [[6571]] Attenuates demyelination, sciatic nerve axonal injury, and neurological deficits in experimental autoimmune neuritis rats, which serve as a model for Guillain-Barré syndrome, a demyelinating disease of the peripheral nervous system [[8820]] Inhibits autoreactive T-cell proliferation stimulated by the peripheral nervous system antigen P0 or by the central nervous system antigen myelin basic protein, as shown with lymphocytes isolated from experimental autoimmune neuritis rats [[8820]] Suppresses behavioral changes that occur at an early phase of a model of MS in mice, concomitant with an increase in circulating T cells in the blood, but before T cell infiltration into the central nervous system [[8857]] Protects the myelin sheath from demyelination in rats treated with pentylenetetrazol to induce epilepsy, reducing epileptiform discharges (seen on an electroencephalogram) and the frequency of seizures [[9266]] Reduces myelin damage in the spinal cord of mice with relapsing-remitting or chronic experimental autoimmune encephalomyelitis; this reduction occurs even when treatment is given late in the disease course, indicating that glatiramer acetate may mediate myelin repair [[16790]] Increases the number of myelinated axons, and the thickness of the myelin sheath, in the spinal cords of mice treated on postnatal days 7 to 21 [[9559]] Increases axon diameter in mice treated on postnatal days 7 to 21 [[9559]] Increases the number of proliferating progenitor and mature oligodendrocytes in mice treated on postnatal days 7 to 21 [[9559]] Therapeutic treatment has beneficial effects on both myelinated and non-myelinated axons in a chronic experimental autoimmune encephalomyelitis mouse model [[12361]] Therapeutic treatment restores axon conduction and improves motor performance in a chronic experimental autoimmune encephalomyelitis mouse model [[12361]] Therapeutic treatment reduces infiltrataion of microglia/macrophages and T cells in the spinal cord and corpus callosum in a chronic experimental autoimmune encephalomyelitis mouse model [[12361]] Therapeutic treatment increases the number of oligodendrocytes in the spinal cord and corpus callosum in a chronic experimental autoimmune encephalomyelitis mouse model [[12361]] Therapeutic treatment improves nodal protein organization in a chronic experimental autoimmune encephalomyelitis mouse model [[12361]] Prophylactic treatment normalizes the expression of experimental autoimmune encephalomyelitis-induced genetic markers in the spinal cord in mice [[10350]] Increases levels of insulin-like growth factor and brain-derived neurotrophic factor in white matter in mice treated on postnatal days 7 to 21 [[9559]] Improves function in a performance test (given on postnatal day 21) in mice treated on postnatal days 7 to 21 [[9559]] Increases levels of brain-derived neurotrophic factor (deficiencies in which may play a role in Huntington's disease) in both wild-type and Huntington's disease model striatal cells, as well as in striatal tissue from a transgenic mouse model of Huntington's disease [[14643]] Reduces an early hyperactivity phenotype that is displayed by a transgenic mouse model of Huntington's disease [[14643]] Inhibits the degradation of myelin basic protein (purified from bovine brain) by the 26S proteasome (purified from mouse brain) in a ubiquitin-free in vitro system [[14142]] Binds the 26S proteasome (purified from mouse brain) but does not bind myelin basic protein (purified from bovine brain) [[14142]] Does not undergo 26S proteasome-mediated hydrolysis in an in vitro system, despite binding to the proteasome (purified from mouse brain) [[14142]] Inhibits type I interferon signaling, as shown in experiments involving mice lacking various proteins involved in innate immune signaling pathways [[24050]] Induces phosphorylation of Akt on serine 473, a marker of phosphoinositide 3-kinase activation, but does not increase intracellular concentrations of cAMP, in mouse monocytes [[24050]] Inhibits production of proinflammatory cytokines by monocytes in response to Toll-like receptor ligands in a manner that does not require myeloid differentiation primary response gene 88 (MyD88) but does require Toll-IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF), as shown in experiments involving cells derived from mice deficient for these genes [[24050]] Inhibits production of proinflammatory cytokines in a manner that does not appear to require nuclear factor-κB signaling, as shown in lipopolysaccharide-stimulated mouse monocytes [[24050]] Inhibits production of proinflammatory cytokines by lipopolysaccharide-stimulated monocytes in a manner that requires interferon-α/β receptor subunit 1 (IFNAR1), as shown in experiments involving cells derived from IFNAR1-deficient mice [[24050]] Inhibits production of interferon-beta, a cytokine induced by the Toll-IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF) pathway, by lipopolysaccharide-stimulated mouse monocytes [[24050]] Inhibits activation of p38 mitogen-activated protein kinase, which regulates activating transcription factor-2, an interferon-beta enhanceosome component, by lipopolysaccharide-stimulated mouse monocytes [[24050]] Inhibits nuclear translocation of components of the interferon-beta enhanceosome in lipopolysaccharide-stimulated mouse monocytes [[24050]] Does not provide clinical benefit in mice deficient for Toll-IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF) upon induction of experimental autoimmune encephalomyelitis [[24050]] Inhibits mouse platelet activation in vitro [[19869]] Reduces thrombin-induced calcium influx into mouse platelets, as well as thrombin-induced expression of activation markers and platelet aggregation [[19869]] Inhibits platelet-mediated macrophage activation, in an experiment involving co-culture of mouse cells [[19869]] Prolongs bleeding time (which occurs if platelet activation is reduced) by 2.7-fold in a tail bleeding test in mice [[19869]] In mouse splenocytes, the biological effect of the branded version is more constant across batches than that of a generic version, as assessed by transcriptional profiling and computational methods, according to a study from Teva [[9533]] In mouse splenocytes, the branded version induces distinct changes in regulatory T cells and cells of myeloid lineage as compared to a generic version, as assessed by transcriptional profiling and computational methods, according to a study from Teva [[9533]] In mouse Th2-polarized T cells, which are responsive to glatiramer acetate, Glatopa and Copaxone induced equivalent changes in gene expression in a microarray analysis involving 39,429 probes across the entire genome, according to a study from Momenta [[22684]] Does not affect survival of mice infected with the neuroinvasive parasite Toxoplasma gondii, but does affect leukocyte numbers and parasite load in the brain [[13835]] Reduces neurological deficit in a rat model of acute ischemic stroke [[18034]] Increases production of neurotrophin-3 and thus neurogenesis in the subventricular zone, subgranular zone, and cerebral cortex in a rat model of acute ischemic stroke [[18034]] Reduces infarct volume in a rat model of transient middle cerebral artery occlusion, even when given during the chronic phase [[18034]] Does not protect mice against acute ischemic stroke [[9991]]
[+]	GNbAC1		MSRV-Env (envelope protein of the MS–associated retrovirus) [[8947]]	Humanized monoclonal antibody derived using recombinant DNA techniques [[8947]] Binds selectively and with high affinity to the MSRV-Env extracellular domain [[8947]] Antibody of the IgG4/κ subclass [[8947]] Contains 2 heavy and 2 light chains; disulfide linkage in the core region has been enhanced [[8947]] Molecular weight, ∼147 kDa [[8947]] Produced in Chinese hamster ovary cells [[8947]] Exhibits a dose-linear pharmacokinetic profile [[8947]] Mean elimination half-life ranged from 19 to 26 days in a Phase I dose-escalation study [[8947]] Mean elimination half-life ranged from 27 to 37 days in a Phase II study [[15278]]	Designed to neutralize the expression of MSRV-Env, the envelope protein from an endogenous human retrovirus that has been linked with MS [[8947]] Does not affect the frequency of various lymphocyte subsets (CD4+ and CD8+ T cells, CD19+ B cells, or CD33+ monocytes), based on a study of 10 individuals with MS and 5 healthy controls [[21641]] Does not affect the response to varicella-zoster virus or tetanus vaccine, based on a study of 10 individuals with MS and 5 healthy controls [[21641]]	Displays effectiveness against MSRV-Env–induced experimental allergic encephalitis [[8947]] Preincubation of the human endogenous retrovirus type W envelope protein (ENV) with GNbAC1 reduces the ability of ENV to induce stress reactions in primary rat oligodendroglial precursor cells [[15680]] Preincubation of the human endogenous retrovirus type W envelope protein (ENV) with GNbAC1 blocks the strong induction of inducible nitric oxide synthase gene expression by ENV in primary rat oligodendroglial precursor cells [[15680]] Preincubation of the human endogenous retrovirus type W envelope protein (ENV) with GNbAC1 blocks ENV-induced formation of nitrotyrosine protein residues in primary rat oligodendroglial precursor cells [[15680]] Preincubation of the human endogenous retrovirus type W envelope protein (ENV) with GNbAC1 reduces the upregulation of proinflammatory cytokine [tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6] gene expression caused by ENV in primary rat oligodendroglial precursor cells [[15680]] Preincubation of the human endogenous retrovirus type W envelope protein (ENV) with GNbAC1 restores the ability of primary rat oligodendroglial precursor cells to differentiate in the presence of ENV (as assayed by the expression of myelin basic protein), an ability that is inhibited ENV alone [[15680]]
[+]	Idebenone	NP	Reactive oxygen species [[8697]] [[8757]]	Structural analog of coenzyme Q10, a molecule that transfers electrons between complexes in the electron transport chain in the inner mitochondrial membrane [[8696]] Synthetic compound [[8759]] Can act as an electron carrier in the mitochondrial electron transport chain [[8697]] Exists in reduced and oxidized forms [[8759]] Antioxidant [[8697]] Almost insoluble in water; soluble in organic solvents [[8759]] MW, 338.441 [[465]] Has a reduced molecular weight and an increased solubility in water as compared with coenzyme Q10, suggesting that idebenone should be the more bioavailable of the two compounds [[8696]] Only a small percentage is absorbed from the gastrointestinal tract in humans [[8759]] Absorbed rapidly in humans, such that a peak concentration is reached 1 to 2 hours after a 10 to 100 mg dose [[8759]] Serum levels are rapidly reduced by excretion in humans [[8759]] Displays linear pharmacokinetics after both single and repeat doses in Phase I studies of healthy men [[8766]] Plasma concentrations increase about five-fold in fed versus fasting men [[8766]] Pharmacokinetics in plasma have been determined in rat and dog studies [[8759]] Eliminated as metabolites within 48 hours after oral administration in rats and dogs [[8759]] Can enter the brain, as shown by rat and dog studies [[8759]] Some portion that enters the brain is recoverable in the mitochondrial fraction, as shown by rat and dog studies [[8759]]	Undergoes reduction by nicotinamide adenine dinucleotide (phosphate) (NAD(P)H):quinone oxidoreductase enzymes, allowing electron transfer to the mitochondrial respiratory chain from cytosolic NAD(P)H in hepatoma cells [[8755]] Partially restores ATP levels in hepatocytes in which mitochondrial complex I is repressed [[8755]] Reduces levels of nicotinamide adenine dinucleotide (NADH) in lymphoblastoid cells in a dose-dependent manner [[8755]] Reduces lactate production from cybrid cells derived from individuals with MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) [[8755]] Improves cognitive and psychoneurological problems associated with cerebrovascular disease in some clinical studies [[8759]] Has shown positive effects on memory and cognition in some but not all clinical studies of Alzheimer's disease [[8772]]	Can act as an electron carrier in the mitochondrial electron chain in isolated mitochondria from dogs [[8697]] Action site is likely nicotinamide adenine dinucleotide (NADH)-linked complex I from the mitochondrial electron transport chain, as shown by experiments on isolated mitochondria from dogs and rats [[8697]] Is an efficient substrate for succinate:Q reductase and ubiquinol:cytochrome c reductase, complex II and III of the electron transport chain, respectively, as shown by experiments with beef heart mitochondria [[8753]] Is a relatively poor substrate (as an electron acceptor) for nicotinamide adenine dinucleotide (NADH):Q reductase (complex I of the electron transport chain), as compared with other coenzyme Q analogs, as shown by experiments with beef heart mitochondria [[8753]] Strongly inhibits both redox and proton pumping activities of complex I from the mitochondrial electron transport chain, as shown by experiments with beef heart mitochondria [[8753]] Inhibits lipid peroxidation reactions in isolated mitochondria from dogs [[8697]] Inhibits both glycerophosphate- and succinate-dependent production of reactive oxygen species, as shown by experiments with mitochondria from brown adipose tissue from hamsters [[8757]] Promotes superoxide radical formation, probably by mediating electron transfer from an Fe-S cluster in complex I of the electron transport chain to oxygen, as shown by experiments with submitochondrial particles from bovine heart [[8760]] Protects HT22 (mouse hippocampal neuronal cell line) cells from cell death induced by glutamate in vitro [[6863]] Improves cerebral energy metabolism (probably by enhancing glucose use, the formation of cyclic AMP, and serotonin turnover) and thus protects against neurological problems caused by cerebral ischemia in rat models [[8759]] Stimulates the release of serotonin and norepinephrine, but does not affect the release of dopamine, in rat models [[8759]] Has positive effects on memory impairment in rat models [[8759]] Partly restores nerve growth factor (NGF) levels in the frontal and parietal cortices in rats that display age-associated decreases in NGF levels [[8771]] Improves performance in different tasks in rats with bilateral forebrain lesions [[8771]] Provides protection against amyloid beta peptide-induced defects in energy metabolism (which include an accumulation of reactive oxygen species, a reduction in cellular redox activity, and reduced ATP levels) in rat PC12 cells [[8775]] Is cardioprotective in a mouse model of Friedreich ataxia, a neurodegenerative condition that is linked with cardiomyopathy and is caused by reductions in the mitochondrial protein frataxin [[8761]] When applied preventively, does not affect the incidence or onset of experimental autoimmune encephalomyelitis in mice [[6863]] When applied therapeutically, does not decrease the severity of experimental autoimmune encephalomyelitis in mice [[6863]] Does not reduce inflammation, axonal damage, or demyelination in the central nervous system in mice with experimental autoimmune encephalomyelitis [[6863]]
[+]	Imilecleucel-T	IM	Myelin-specific, autoreactive T cells [[7692]] [[7693]]	Patient-specific T cell immunotherapy [[7692]] Production and use involves the following steps: [[7692]] (i) Collecting blood from an individual with MS [[7692]] (ii) Isolating peripheral blood mononuclear cells [[7692]] (iii) Generating an autologous pool of myelin-reactive T cells; peptides that represent three myelin proteins (myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein) are used to identify and expand specific myelin-reactive T cells [[7706]]; 109 peptides are evaluated to determine the dominant epitopes to which that patient's cells respond [[7692]] (iv) Expanding and irradiating the cells [[7692]] (v) Reintroducing these attenuated T cells to the individual with MS to induce a therapeutic immune response [[7692]] (vi) Repeating this procedure annually, so that a new personalized treatment is created on the basis of a patient's immunity to myelin at that time [[7692]]	Exact mechanism is unclear [[7693]] Vaccination with autologous, irradiated myelin basic protein-reactive T cells induces a complicated cellular immune response that is directed at the vaccine cells [[7693]] Vaccination with autologous, irradiated myelin basic protein (MBP)-reactive T cells depletes circulating MBP-reactive T cells in individuals with MS [[7694]] Vaccination with autologous, irradiated myelin basic protein-reactive T cells induces T cell responses in individuals with MS; regulatory T cells lines derived from these individuals inhibit the cells used for vaccination, and the cytolytic activity of the CD8+ T cell lines is major histocompatibility complex class I-restricted [[7694]] Vaccination with autologous, attenuated myelin basic protein-reactive T cells induces a response that is dominated by T cell receptor (TCR)-alpha-beta+ cells, which are primarily CD4+ and CD8+, but TCR-gamma-delta+ cells and natural killer cells are present as well, as shown in vaccine-stimulated cultures of cells from vaccinated individuals [[7695]] Vaccination with autologous, irradiated myelin basic protein-reactive T cells does not induce an antibody response in individuals with MS [[7695]] Vaccination with autologous, irradiated myelin basic protein (MBP)-reactive T cells clonally depletes circulating MBP-reactive T cells; after time, MBP-reactive T cells sometimes reappear, but they have different clonal origins than those that persisted before vaccination [[7696]] Vaccination with autologous, irradiated myelin basic protein-reactive T cells induces CD8+ regulatory T cells that lyse immunizing cells in a clonotype-specific (or "idiotypic") fashion, a mechanism that might involve different hypervariable regions of the T cell receptor [[7696]] Irradiated proteolipid protein peptide-specific CD4+ T cell clones, used to stimulate purified autologous CD8+ T cells from the peripheral blood of individuals with MS, result in two different groups of cells after expansion: (i) CD8+ T cell clones that recognize CD4+ T cells on the basis of their T cell receptor variable beta structures (an anti-idiotypic response) and (ii) CD8+ T cell clones that recognize activated CD4+ T cells independent of such structures or antigen specificity (an anti-ergotypic response) [[7697]]	Exact mechanism is unclear [[7693]] Rat T lymphocytes that are reactive against myelin basic protein (MBP) induce experimental autoimmune encephalomyelitis (EAE) when inoculated into rats, but establish resistance against EAE if the cells are first attenuated by irradiation or other treatment [[7699]] Vaccination with an appropriate (low) dose of T lymphocytes that are reactive against myelin basic protein (MBP) protects against experimental autoimmune encephalomyelitis in rats through a mechanism that involves induction of two types of T lymphotes [CD4+ CD8- helper cells (which stimulate the MBP-specific vaccinating cells) and CD4- CD8+ suppressor cells (which suppress the response of the vaccinating cells to MBP)] [[7700]] In rats, vaccination with T cells specific for myelin basic protein induces anti-vaccine T cell responses, such that these T cells recognize a clonotype-specific determinant (referred to as "the idiotype") on the immunizing cells that is probably the T cell receptor [[7693]] [[7700]] In rats, T cell vaccination induces anti-vaccine T cell responses, such that these T cells recognize uncharacterized activation markers (referred to as "the ergotype") on the vaccine cells [[7693]] [[7754]] T cell vaccination may cause autoreactive T cells to undergo a Th1 to Th2 shift [[7693]] T cell vaccination induces anti-T cell antibodies in an experimental autoimmune encephalomyelitis (EAE) rat model, which are associated with recovery from EAE [[7698]]
[+]	Interferon beta-1a	IM	Interferon beta receptor [[1071]] T cell differentiation pathways [[1071]] Pathways regulating transfer of Inflammatory cells across the blood brain barrier [[1071]]	Molecular weight: ~22,500 daltons [[1063]] [[1064]] Produced in genetically engineered Chinese Hamster Ovary cells expressing a human beta interferon gene [[1063]] [[1064]] Glycoprotein [[1063]] [[1064]] Distinct glycoforms (all derived from Chinese Hamster Ovary cell culture), with different glycan antennarity (branching), have been characterized relative to biological activity in vitro; forms with higher antennarity appear to sustain bioactivity better [[13173]] Cytokine [[1063]] [[1064]] Avonex exhibits specific activity of 200 million international units of antiviral activity per mg [[1063]] Rebif exhibits specific activity of 270 million international units of antiviral activity per mg [[1064]] Pharmacokinetic and pharmacodynamic properties have been described in healthy volunteers [[1066]] [[1067]] [[1068]] Pharmacokinetics and pharmacodynamics of peginterferon beta-1a have been compared in individuals with normal versus impaired renal function; the results do not indicate that the dose should be adjusted in those with impaired renal function [[13498]] Betaseron (interferon beta-1b) and Rebif (interferon beta-1a), which are formulated with human serum albumin, contain more aggregated protein and particles than does Avonex (interferon beta-1a), and the higher aggregate levels correlate with higher reported rates of neutralizing-antibody formation for Betaseron and Rebif [[4176]] Pharmacokinetics and pharmacodynamics of peginterferon beta-1a have been evaluated in participants in the ADVANCE trial [[14064]] Accumulation of peginterferon beta-1a was not observed in participants in the ADVANCE trial [[14064]] Peak serum concentrations of peginterferon beta-1a occur 1 to 1.5 days post-dosing, based on analysis of data from the ADVANCE trial [[14064]] Peginterferon beta-1a exhibits a median half-life of about 2 to 3 days, based on analysis of data from the ADVANCE trial [[14064]] Each dose of peginterferon beta-1a is associated with increased levels of neopterin (a biomarker of pharmacological activity that is induced by the drug) for 10 to 14 days, based on analysis of data from the ADVANCE trial [[14064]] A single dose of peginterferon beta-1a is associated with 60% greater drug exposure than six subcutaneous interferon beta-1a (Rebif) doses given over two weeks, as shown in a crossover study involving 30 healthy individuals [[29067]]	Specific mechanism unknown [[1063]] [[1064]] Enhances CD4+ regulatory T cell function and boosts CD4+ regulatory T cell number [[1069]] Reduces levels of activated T cells [[1070]] Increases the proportion of CD56(bright) (immature) natural killer cells and decreases the proportion of cytotoxic CD56(dim) (mature) natural killer cells in the periphery [[5263]] Interferon beta (either -1a or -1b) treatment increases the frequncy of naïve T cells and decreases the frequency of central memory T cells (which is increased in MS) in RRMS patients [[2099]] Interferon beta reduces expression of natural killer cell receptor 1 in peripheral blood mononuclear cells; such expression is increased in individuals with MS relative to healthy controls [[13172]] Affects the expression of proteins regulating antigen presentation and cell recognition between T cells and antigen presenting cells [[1070]] Promotes cell death by downregulating anti-apoptosis protein FLIP [[1070]] Shifts T cell differentiation toward the Th2 (anti-inflammatory) response [[1070]] [[1071]] Inhibits CD4+ T cell expression of genes encoding Th22 and Th17 cytokines, including the Th22 cell transcription factor aryl hydrocarbon receptor, the Th1 cell transcription factor T-bet, and the Th17 cell transcription factor retinoic acid–related orphan nuclear hormone receptor C, as seen in a 6-month study involving 23 individuals with RRMS [[24131]] Enhances CD4+ T cell expression of the gene encoding the Th2 transcription factor GATA3, as seen in a 6-month study involving 23 individuals with RRMS [[24131]] Inhibits CD4+ T cell expression of genes encoding interleukin 17F (IL-17F), IL-21, and IL-27Rα, and enhances expression of the IL-21R gene, as seen in a 6-month study involving 23 individuals with RRMS [[24131]] Reduces the fraction of CD4+ T cells expressing interleukin 22 (IL-22) and IL-17F and of CD8+ T cells expressing IL-17A and IL-17F, as seen in a 6-month study involving 23 individuals with RRMS [[24131]] Reduces the fraction of CD4+ T cells expressing interleukin 17F, a change that correlates with decreased demyelination, as seen in a 6-month study involving 23 individuals with RRMS [[24131]] Increases the fraction of CD4+ and CD8+ T cells expressing interleukin 10, a change that correlates with increased remyelination in normal-appearing brain tissue, as seen in a 6-month study involving 23 individuals with RRMS [[24131]] Reduces serum levels of interleukin 17A (IL-17A) in individuals with RRMS who are treated early in the course of the disease (≤1 year from onset), and this reduction is greater than in those treated later; IL-17A levels are increased in treatment naïve individuals with RRMS versus healthy controls [[28518]] Interferon beta does not affect the frequency of CD27+CD43+ B1 cells, which is reduced in RRMS [[10963]] Reduces serum nitrite levels (by 77%) and the annual relapse rate (by 70%), but does not affect cytokine levels or ratios in a manner that reflects effects on disease course, based on a 3-year longitudinal study of 20 RRMS patients receiving intramuscular interferon beta-1a as monotherapy [[6199]] Causes upregulation of Toll-like receptor 7 when applied to cultured dendritic cells [[1071]] [[1072]] Long-term treatment with Rebif reduces the percentage of circulating 6-sulfo LacNAc(+) dendritic cells, proinflammatory cells that are present in demyelinated brain lesions and are often present in cerebrospinal fluid in individuals with MS [[14709]] Reduces the secretion of tumor necrosis factor-alpha, interleukin 1beta (IL-1beta), IL-6, and IL-12p70 by isolated, stimulated sulfo LacNAc(+) dendritic cells, proinflammatory cells that are present in demyelinated brain lesions and are often present in cerebrospinal fluid in individuals with MS [[14709]] Inhibits the ability of isolated, stimulated sulfo LacNAc(+) dendritic cells, proinflammatory cells that are present in demyelinated brain lesions and are often present in cerebrospinal fluid in individuals with MS, to promote differentiation and proliferation of T cells [[14709]] Interferon beta increases serum levels of endogenous secretory receptor for advanced glycation end-products (esRAGE); serum esRAGE levels are reduced during clinical relapse [[15134]] Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS as compared with the number in treatment-naïve individuals or those treated with glatiramer acetate [[16751]] Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS; such cells are a significant source of interleukin 10 in these individuals and in healthy controls [[16751]] Interferon beta does not induce the secretion of interleukin 10 from unstimulated peripheral blood mononuclear cells from healthy individuals, but does enhance secretion when the cells are stimulated [[16751]] Interferon beta increases blood levels of B-cell activating factor (BAFF, the primary survival factor for B cells); BAFF levels are higher in individuals with MS than in healthy controls, but those with MS who do not relapse have higher BAFF levels than those who do, as shown in a prospective longitudinal study of 170 individuals with MS over 2.3 years [[24059]] May decrease the ability of T cells to cross the blood brain barrier by lowering levels of trophic chemokines that draw Th1 cells to the blood vessel wall [[1070]] Downregulates the expression of matrix metalloproteinases by activated T cells, which limits their ability to cross the blood brain barrier [[1070]] Stabilizes the blood brain barrier in human cell lines as well as cow, pig, and mouse cell lines [[1071]] [[1073]] Might block cytotoxic molecules involved in demyelination [[1070]] Causes the formation of neutralizing antibodies, which may decrease treatment efficacy [[1074]] Interferon beta treatment can cause the production of antibodies that bind the drug, and their prevalence varies depending on the drug preparation; in one study of 124 individuals, 38.1% of those receiving Betaferon, 21.9% receiving Rebif, and 26.8% receiving CinnoVex produced binding antibodies [[8978]] Interferon beta is associated with the formation of neutralizing antibodies; in a cross-sectional study in which serum samples from 2711 individuals with MS were submitted to the same independent laboratory, such antibodies occurred at a frequency of 35% for Rebif 44 microg (subcutaneous interferon beta-1a), 22% for Betaseron (interferon beta-1b) and Rebif 22 microg, and 7.5% for Avonex (intramuscular interferon beta-1a) [[20093]] Interferon beta is associated with the formation of neutralizing antibodies; in one study of 2711 individuals with MS, in those with detectable neutralizing antibodies, the titer was very high in 42% to 47% of individuals treated with interferon beta-1a but in only 22% of those treated with beta interferon-1b [[20093]] Interferon beta is associated with the formation of neutralizing antibodies; a systematic review and meta-analysis of controlled trial data indicated that interferon beta-1a (Avonex) is least likely to lead to the formation of such antibodies (in 2.0 to 18.9% of individuals, as compared with 16.5 to 35.4% of individuals for interferon beta-1a (Rebif) and 27.3% to 53.3% for interferon beta-1b (Betaferon/Betaseron) [[20964]] Interferon beta is associated with the formation of neutralizing antibodies; a systematic review and meta-analysis of controlled trial data indicated the risk of such antibodies is dose-dependent, such that the risk at the 30 microg dose of interferon beta-1a (Avonex) is 64% less that at the 60 microg dose [[20964]] Reverts the mature forms of the lysosomal proteases, cathepsin S and D, to the precursor forms in CD34+ hematopoietic stem cells from RRMS patients, the state seen in healthy individuals [[5073]] During interferon beta treatment, new inflammatory events are more likely in individuals with MS who display a distinct RNA profile, with increased expression of RNAs involved in lymphocyte signaling pathways [[3277]] Reduces serum levels of interleukin 16, which are elevated in individuals with MS, and this reduction begins after 2 months of therapy [[9968]] Interferon beta increases serum levels of interleukin 7, a cytokine that has been associated with MS, but decreases IL-7 receptor alpha chain expression and IL-7 consumption in peripheral blood leukocytes, indicating that interferon beta impairs IL-7 responsiveness [[10971]] Increases expression of interleukin 10, decreases expression of inducible nitric oxide synthase, and does not affect expression of matrix metallopeptidase 9 or the metallopeptidase inhibitor TIMP-1 at the RNA level in human astrocytoma cells [[24816]] Natalizumab or interferon beta treatment is associated with significantly reduced serum levels of a "cytokine signature" [a summed value of levels of tumor necrosis factor-alpha, interferon gamma, S100B, interleukin 1beta (IL-1beta), IL-6, IL-8, IL-17, and IL-23] in individuals with MS as compared with levels in drug naïve individuals with MS [[12197]] Interferon beta treatment is associated with higher serum levels of pro-inflammatory cytokines as compared with natalizumab treatment in individuals with MS [[12197]] Three major forms of interferon beta therapy (Avonex, Betaseron, and Rebif) are associated with a robust gene expression signature from blood that involves 25 upregulated genes; all of the drugs induce a similar maximum interferon beta activation state, although the average effect of Avonex is less than that of the other drugs [[17269]] Induces a transcriptional response in blood in 60% of individuals with SPMS, which is similar to a gene expression signature in individuals with RRMS who respond to interferon beta-1a treatment, as shown in a study of 50 individuals with SPMS, 20 of whom were treated with interferon beta-1a [[24023]] Treatment may reconstitute inadequate endogenous interferon beta control of pathogenic Th17 cytokine production by CD4+ T cells in RRMS [[11163]] Mean adherence rates have been determined (through the analysis of 24 studies reporting on this topic) for intramuscular interferon beta-1a, given once a week (69.4%); subcutaneous interferon beta-1b, given every other day (63.8%); subcutaneous interferon beta-1a, given 3 times a week (58.4%); and glatiramer acetate, given daily (56.8%), with better outcomes in adherent versus nonadherent individuals shown in a smaller number of studies [[10840]] Associated with a relative reduction of 3.6% (Avonex) or 15.2% (Rebif) in the risk of ≥1 relapses during 2 years of treatment and is less cost effective than natalizumab, according to a pharmacoeconomic analysis that used pre-existing data [[6325]] and costs of treatment in the Russian healthcare system [[12332]] Effectiveness of interferon beta (measured in terms of a lack of relapses and disease progression), in individuals lacking neutralizing antibodies against the drug, correlates with a decrease in the titer of IgG antibodies against human herpes virus 6A/B, whereas an increase predicts relapse, as shown in a 2-year longitudinal study [[12927]] Response to interferon beta treatment correlates with levels of IgM antibodies against Epstein-Barr viral capsid antigen, as shown in a study of 87 individuals with MS [[11130]] Among individuals with clinically isolated syndrome treated with intramuscular interferon beta-1a, several MRI outcomes, measured at baseline and 6 months, were associated with increased risk for clinical disease progression over 48 months in a prospective observational study of 210 individuals [[18436]] Intramuscular version reduces gray matter atrophy (which is associated with sustained disability progression) but not white matter atrophy, as shown by retrospective analysis of placebo-controlled clinical trial data from 140 individuals with RRMS; the reduction in gray matter atrophy was seen during year 2 of treatment [[20693]] Unlike natalizumab, interferon beta was not observed to decrease the extent and severity of damage to white matter, as shown in a diffusion tensor imaging study [[27835]] Interferon beta probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients [[4420]] Interferon beta does not affect the fraction of CD8+ T cells that produce interleukin 17 (IL-17) or IL-10, cell subsets that are elevated in RRMS patients in remission as compared with healthy people [[6515]] Interferon beta does not affect an MS-associated pattern of peripheral oxidative stress markers (reduced blood levels of Coenzyme Q10 and increased blood levels of anti-oxidized-low-density lipoprotein antibodies) [[10629]] Because specific disease-modifying therapies (DMTs) are effective in some individuals and not others, genetic biomarkers of treatment sensitivity could be useful in DMT selection; discriminative genetic markers (variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes) have been identified, with the CCR5d+ IFNAR1G combination indicating interferon beta rather than glatiramer acetate treatment, based on a study of responders and nonresponders among >500 individuals treated with interferon beta or glatiramer acetate [[10888]] Resumption of interferon beta treatment within two weeks after delivery (versus later in the postpartum year) does not decrease the risk of relapse in the first six months postpartum, but might decrease the risk later in the first year postpartum [[10154]] Effects on MRI activity and systemic markers of inflammation do not appear to be influenced by serum vitamin D levels, as shown by a study of 88 individuals with RRMS [[18891]] Potential interferon beta treatment response genetic markers have been identified in a genome-wide association study involving 151 individuals with MS and validated in an independent group of 479 individuals [[28384]] Nonresponse to interferon beta therapy is associated with an intronic variant in the gene SLC9A9, which encodes an Na+ -H+ exchanger, as shown in a genome-wide association study and validated in 3 independent cohorts [[18999]]	Promotes neuronal growth and survival in cultured mouse cells [[1070]] [[1075]] Promotes the release of nerve growth factor in cultured astrocyte cells [[1070]] [[1091]] Protects neurons against injury induced by a mitochondrial complex I toxin, but not injury induced by a complex II toxin, as determined by studying rat brain striatal slices using electrophysiological techniques [[8110]] Neuroprotective effect against mitochondrial complex I inhibition requires STAT1 signaling, as shown by studies of rat brain striatal slices [[8110]] Neuroprotective effect against mitochondrial complex I inhibition occurs in striatal brain slices from experimental autoimmune encephalomyelitis (EAE) mice as well as in slices from control mice, even though the toxicity of such inhibition is more extreme in EAE [[8110]] Combination therapy consisting of murine interferon beta (which is immunomodulatory) and dimethyl fumarate (which is neuroprotective) is more effective in treating experimental autoimmune encephalomyelitis (providing better axon protection) than either therapy alone [[10600]] Treatment with a combination of interferon beta-secreting mesenchymal stem cells and minocycline reduces the severity of experimental autoimmune encephalomyelitis, primarily by promoting blood-spinal cord barrier integrity [[12224]] (Recombinant mouse) interferon beta expands the population of transitional and regulatory B cells, and increases secretion of interleukin 10 in the spleen, in experimental autoimmune encephalomyelitis mice [[16751]] (Recombinant mouse) interferon beta reduces the severity of experimental autoimmune encephalomyelitis in mice [[16751]] (Recombinant mouse) interferon beta increases the production of anti-myelin oligodendrocyte glycoprotein IgG, but not IgM, in experimental autoimmune encephalomyelitis mice; disease severity does not correlate with the increased IgG levels [[16751]] (Recombinant mouse) interferon beta does not provide a clinical or histopathological benefit in experimental autoimmune encephalomyelitis (EAE) mice that are deficient for B cells (muMT mice), although it does in wild-type EAE mice [[16751]]
[+]	Interferon beta-1b	IM	T lymphocytes [[1145]] Blood-brain barrier (?) [[1135]] [[1145]] [[1147]] T cell trafficking (?) [[1145]] [[1164]]	Interferons are naturally-occurring cytokines that are secreted in response to pathogens [[1131]] [[1179]] Betaseron is a recombinant protein that is produced by fermentation of a strain of Escherichia coli containing a plasmid for expression of human interferon beta(ser17) (in which serine is substituted for cysteine at position 17) [[1170]] Extavia is identical to Betaseron [[1160]] Unlike the natural protein, is not glycosylated [[1170]] Lyophilized, 165-residue protein [[1179]] Molecular weight, 18,500 daltons [[1170]] Serum concentrations are very low or undetectable after subcutaneous administration at the recommended dose [[1131]] Pharmacokinetic properties have been determined in healthy volunteers [[1131]] Controlled release, PEGylated version has been studied in mice [[2483]] Analysis has been performed to determine residues where covalent modification with polyethylene glycol does not inhibit (or improves) bioactivities in vitro (in contrast, random modification decreases the bioactivity) [[7305]] Betaseron (interferon beta-1b) and Rebif (interferon beta-1a), which are formulated with human serum albumin, contain more aggregated protein and particles than does Avonex (interferon beta-1a), and the high levels of aggregates correlate with higher reported rates of neutralizing-antibody formation for Betaseron and Rebif [[4176]] A single injection can induce anti-drug antibodies in immune tolerant transgenic mice, and the titer increases with increasing frequency of treatment and dose [[4751]] Induces anti-drug antibodies in immune tolerant transgenic mice, such that intravenous delivery is the most immunogenic route; intramuscular, subcutaneous, and intraperitoneal delivery are similar to each other in their immunogenic effects [[4751]]	Mechanism in MS is unknown [[1179]] Suppresses the development of inflammatory brain lesions in MS patients [[1136]] [[1142]] Decreases the expected number of contrast enhancing lesions (CELs) seen in MRI, such that new CEL formation is inhibited, but the resolution of previously-formed CELs is not enhanced, as shown by a population analysis using datasets from two different studies involving 24 individuals [[20692]] Stabilizes the blood-brain barrier (BBB), based on experiments in which serum from RRMS patients treated with interferon beta-1b reduced the permeability of an in vitro BBB model (human endothelial cells co-cultured with rat astrocytes) as compared with serum from untreated patients [[1132]] Downregulates expression of the integrin VLA-4/CD49d (which is implicated in MS pathology) on CD8+ T cells and on primed but not naïve CD4+ cells in MS patients, in agreement with the idea that the drug influences the interaction of immune cells and the blood-brain barrier [[1145]] Increases the plasma concentration of soluble vascular cell adhesion molecule-1 (the soluble form of the VLA-4 integrin ligand) in MS patients [[1146]] Inhibits MS-induced apoptosis of endothelial cells (potentially indicating a role in preserving the blood-brain barrier), as shown by experiments in which apoptosis of human umbilical endothelial cells was induced by sera from exacerbating MS patients and blocked by interferon beta-1b [[1147]] Inhibits interleukin-2–induced secretion of gelatinases (matrix metalloproteinases that digest subendothelial basement membrane components) and migration across an artificial basement membrane by human T cells, suggesting that the drug might interfere with the migration of activated T cells to the central nervous system [[1164]] Inhibits chemokine-induced expression of matrix metalloproteinase-9 and migration of human peripheral blood mononuclear cells across a fibronectin matrix [[1165]] Decreases serum matrix metalloproteinase-9 activity in MS patients [[1166]] Increases serum levels of intercellular adhesion molecule-1 in MS patients [[1166]] Reduces the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 (a ratio that is a predictor of new gadolinium-enhancing lesions) in SPMS patients [[1167]] Reduces serum levels of inflammatory cytokines that are associated with MS pathogenesis (interleukin-12 p40 and interleukin-23) in RRMS patients [[1168]] Affects cytokine release differently in cultured CD4+ and CD8+ T cells from RRMS and PPMS patients, such that the drug inhibits interferon-gamma and induces interleukin (IL)-4 selectively in CD4+ T cells from RRMS patients; induces IL-10 in all RRMS cell populations but only slightly in PPMS cells; always inhibits IL-5; and does not affect IL-17A [[3010]] Reduces serum levels of interferon-gamma (a sign of the intensity of an immune reaction) during relapses, based on a study of 35 women with RRMS [[13128]] Interferon beta increases serum levels of interleukin-7, a cytokine that has been associated with MS, but decreases IL-7 receptor alpha chain expression and IL-7 consumption in peripheral blood leukocytes, indicating that interferon beta impairs IL-7 responsiveness [[10971]] Natalizumab or interferon beta treatment is associated with significantly reduced serum levels of a "cytokine signature" [a summed value of levels of tumor necrosis factor-alpha, interferon gamma, S100B, interleukin-1beta (IL-1beta), IL-6, IL-8, IL-17, and IL-23] in individuals with MS as compared with levels in drug naïve individuals with MS [[12197]] Interferon beta treatment is associated with higher serum levels of pro-inflammatory cytokines as compared with natalizumab treatment in individuals with MS [[12197]] Associated with increased serum levels of brain-derived neurotrophic factor, which are inversely correlated with the degree of disability (measured by the Expanded Disability Status Scale score), as shown in a study of 82 individuals with MS [[22589]] In vitro treatment decreases CXCR4-dependent chemotaxis of T cells from individuals with RRMS or healthy individuals [[20495]] Reduces expression of CXCR4 mRNA, as well as surface expression of CXCR4, by primary human T cells [[20495]] Three major forms of interferon beta therapy (Avonex, Betaseron, and Rebif) are associated with a robust gene expression signature from blood that involves 25 upregulated genes; all of the drugs induce a similar maximum interferon beta activation state, although the average effect of Avonex is less than that of the other drugs [[17269]] Interferon beta does not affect the frequency of CD27+CD43+ B1 cells, which is reduced in RRMS [[10963]] Decreases plasma concentrations of nitrogen dioxide + nitrate radical, 3-nitrotyrosine, and S-nitrosothiol, increases plasma concentrations of asymmetric and symmetric dimethyl-L-arginine, and increases plasma arginase activity in patients with RRMS [[3323]] Reduces serum nitrite levels (by 71%) and the annual relapse rate (by 71%), but does not affect cytokine levels or ratios in a manner that reflects effects on disease course, based on a 3-year longitudinal study of 18 RRMS patients receiving subcutaneous interferon beta-1b as monotherapy [[6199]] Affects the expression of multiple genes (including CD20, a target of B cell depletion therapy), as shown by DNA microarray experiments to examine genome-wide RNA expression profiles of peripheral mononuclear blood cells from RRMS patients [[1169]] Affects the expression of a variety of genes, including genes with roles in antioxidant activity, mitochondrial fatty acid metabolism, and immune regulation, as shown by analysis of patient gene expression profiles; greater changes were seen in long-term versus acute dosing [[2176]] Increases the expression of mRNAs encoding Toll-like receptors TLR3 and TLR7 and MyD88 (a TLR adaptor molecule) in vitro in peripheral blood mononuclear cells from healthy volunteers and in vivo in individuals with RRMS [[7531]] Increases the expression of Toll-like receptor 7 (TLR7) and MyD88 (a TLR adaptor molecule) proteins in plasmacytoid dendritic cells (DCs), but not in monocytes, myeloid DCs, B cells, CD4+ T cells, or CD8+ T cells [[7531]] Treatment is associated with an increase in the expression of Toll-like receptor 7 in plasmacytoid dendritic cells of individuals with CIS or RRMS [[7531]] Increases the expression Toll-like receptor 7 (TLR7) in plasmacytoid dendritic cells from healthy volunteers; subsequent stimulation of these cells with a TLR7-specific ligand then strongly increases production of interferon-alpha as compared to production in cells not pretreated with interferon beta-1b [[7531]] Decreases the expression of mRNAs encoding Toll-like receptors TLR6 and TLR9 in vitro in peripheral blood mononuclear cells from healthy volunteers and decreases TLR9 (but not TLR6) mRNA expression in vivo in individuals with RRMS [[7531]] Does not significantly affect the expression of mRNAs encoding Toll-like receptors TLR1, TLR2, TLR4, TLR8, and TLR10 in peripheral blood mononuclear cells from healthy volunteers [[7531]] Increases intracellular levels of Cu Zn superoxide dismutase (SOD1) in peripheral blood mononuclear cells (PBMCs); levels of SOD1 are reduced in cerebrospinal fluid and PBMCs in individuals with RRMS versus healthy controls [[21426]] Increases intracellular and extracellular levels of Cu Zn superoxide dismutase (SOD1) in SK-N-BE neuroblastoma cell culture; levels of SOD1 are reduced in cerebrospinal fluid and PBMCs in individuals with RRMS versus healthy controls [[21426]] Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start), in peripheral blood mononuclear cells from both healthy individuals and individuals with MS, as well as fetal brain cells and tumor cells; this transcript contains a unique first exon and the last 5 exons of full-length NCOA7 [[14618]] Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start); the encoded protein displays oxidation resistance activity [[14618]] Induces the transcription of an alternate form of nuclear receptor coactivator 7 (NCOA7), termed NCOA7-AS (alternate start); this induction requires activation of the interferon receptor as well as the JAK-STAT pathway [[14618]] Increases the relative proportion of CD4+ T cells and decreases the proportion of CD8+ T cells in MS patients [[1145]] Increases CD8+ regulatory T cell function in MS patients to levels similar to those in patients without MS [[1135]] Increases the proportion of CD56(bright) (immature) natural killer cells and decreases the proportion of cytotoxic CD56(dim) (mature) natural killer cells in the periphery [[5263]] Interferon beta reduces expression of natural killer cell receptor 1 in peripheral blood mononuclear cells; such expression is increased in individuals with MS relative to healthy controls [[13172]] Interferon beta (either -1a or -1b) treatment increases the frequncy of naïve T cells and decreases the frequency of central memory T cells (which is increased in MS) in RRMS patients [[2099]] Interferon beta increases serum levels of endogenous secretory receptor for advanced glycation end-products (esRAGE); serum esRAGE levels are reduced during clinical relapse [[15134]] Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS as compared with the number in treatment-naïve individuals or those treated with glatiramer acetate [[16751]] Interferon beta expands the number of peripheral regulatory CD19+CD24++CD38++ transitional B cells in individuals with RRMS; such cells are a significant source of interleukin-10 in these individuals and in healthy controls [[16751]] Interferon beta does not induce the secretion of interleukin-10 from unstimulated peripheral blood mononuclear cells from healthy individuals, but does enhance secretion when the cells are stimulated [[16751]] Interferon beta increases blood levels of B-cell activating factor (BAFF, the primary survival factor for B cells); BAFF levels are higher in individuals with MS than in healthy controls, but those with MS who do not relapse have higher BAFF levels than those who do, as shown in a prospective longitudinal study of 170 individuals with MS over 2.3 years [[24059]] Induces the proliferation and differentiation of human neural stem/progenitor cells in vitro [[1144]] Induces the development of anti-interferon antibodies in about one-third of MS patients, which usually disappear over time, but the effect of these antibodies on the response to treatment is unclear [[1135]] Interferon beta treatment can cause the production of antibodies that bind the drug, and their prevalence varies depending on the drug preparation; in one study of 124 individuals, 38.1% of those receiving Betaferon, 21.9% receiving Rebif, and 26.8% receiving CinnoVex produced binding antibodies [[8978]] Interferon beta is associated with the formation of neutralizing antibodies; in a cross-sectional study in which serum samples from 2711 individuals with MS were submitted to the same independent laboratory, such antibodies occurred at a frequency of 35% for Rebif 44 microg (subcutaneous interferon beta-1a), 22% for Betaseron (interferon beta-1b) and Rebif 22 microg, and 7.5% for Avonex (intramuscular interferon beta-1a) [[20093]] Interferon beta is associated with the formation of neutralizing antibodies; in one study of 2711 individuals with MS, in those with detectable neutralizing antibodies, the titer was very high in 42% to 47% of individuals treated with interferon beta-1a but in only 22% of those treated with beta interferon-1b [[20093]] Interferon beta is associated with the formation of neutralizing antibodies; a systematic review and meta-analysis of randomized and non-randomized controlled trial data indicated that interferon beta-1a (Avonex) is least likely to lead to the formation of such antibodies (2.0 to 18.9% of individuals, as compared with 16.5 to 35.4% of individuals for interferon beta-1a (Rebif) and 27.3% to 53.3% for interferon beta-1b (Betaferon/Betaseron) [[20964]] Inhibits the activity of the ubiquitin/proteasome system (which is elevated in MS patients), as shown by analysis of plasma from MS patients; the level of inhibition correlates with the reduction in the number of T1-weighted enhancing lesions [[2185]] During interferon beta treatment, new inflammatory events are more likely in individuals with MS who display a distinct RNA profile, with increased expression of RNAs involved in lymphocyte signaling pathways [[3277]] Additively enhances the effects of 25-hydroxyvitamin D [25(OH)D] on MS activity, as shown in a study that measured serum levels of 25(OH)D and global gene expression profiles in individuals who began interferon beta-1b treatment after a CIS, who were monitored for ≤2 years [[14265]] Effectiveness of interferon beta (measured in terms of a lack of relapses and disease progression), in individuals lacking neutralizing antibodies against the drug, correlates with a decrease in the titer of IgG antibodies against human herpes virus 6A/B, whereas an increase predicts relapse, as shown in a 2-year longitudinal study [[12927]] Response to interferon beta treatment correlates with levels of IgM antibodies against Epstein-Barr viral capsid antigen, as shown in a study of 87 individuals with MS [[11130]] Together with the anticoagulant agent warfarin, was used successfully to treat an individual with Baló's concentric sclerosis (a rare form of MS) and antiphospholipid syndrome [[16467]] Mean adherence rates have been determined (through the analysis of 24 studies reporting on this topic) for intramuscular interferon beta-1a, given once a week (69.4%); subcutaneous interferon beta-1b, given every other day (63.8%); subcutaneous interferon beta-1a, given 3 times a week (58.4%); and glatiramer acetate, given daily (56.8%), with better outcomes in adherent versus nonadherent individuals shown in a smaller number of studies [[10840]] Associated with a relative reduction of 10.5% (Betaferon) in the risk of ≥1 relapses during 2 years of treatment and is less cost effective than natalizumab, according to a pharmacoeconomic analysis that used pre-existing data [[6325]] and costs of treatment in the Russian healthcare system [[12332]] Unlike natalizumab, interferon beta was not observed to decrease the extent and severity of damage to white matter, as shown in a diffusion tensor imaging study [[27835]] Interferon beta probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients [[4420]] Lack of response to interferon beta-1b treatment for 2 years is not correlated with an increase in serum levels of interleukin 17F (IL-17F), although levels of IL-17F above 200 pg/ml might forecast nonresponsiveness, based on analysis of samples from 239 RRMS patients [[6271]] Interferon beta does not affect the fraction of CD8+ T cells that produce interleukin-17 (IL-17) or IL-10, cell subsets that are elevated in RRMS patients in remission as compared with healthy people [[6515]] Interferon beta does not affect an MS-associated pattern of peripheral oxidative stress markers (reduced blood levels of Coenzyme Q10 and increased blood levels of anti-oxidized-low-density lipoprotein antibodies) [[10629]] Because specific disease-modifying therapies (DMTs) are effective in some individuals and not others, genetic biomarkers of treatment sensitivity could be useful in DMT selection; discriminative genetic markers (variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes) have been identified, with the CCR5d+ IFNAR1G combination indicating interferon beta rather than glatiramer acetate treatment, based on a study of responders and nonresponders among >500 individuals treated with interferon beta or glatiramer acetate [[10888]] Resumption of interferon beta treatment within two weeks after delivery (versus later in the postpartum year) does not decrease the risk of relapse in the first six months postpartum, but might decrease the risk later in the first year postpartum [[10154]] Potential interferon beta treatment response genetic markers have been identified in a genome-wide association study involving 151 individuals with MS and validated in an independent group of 479 individuals [[28384]] Nonresponse to interferon beta therapy is associated with an intronic variant in the gene SLC9A9, which encodes an Na+ -H+ exchanger, as shown in a genome-wide association study and validated in 3 independent cohorts [[18999]]	Interferon beta (used experimentally rather than interferon beta-1b) affects myeloid antigen-presenting cells, which may be responsible for immune modulation mediated by interferon beta, as shown by experiments in mice [[1139]] Appears to suppress the Nod-like receptor, pyrin domain-containing 3 inflammasome and thereby ameliorate experimental autoimmune encephalomyelitis in a mouse model [[1877]] Supresses Nod-like receptor, pyrin domain-containing 3 inflammasome activity in a mechanism that is mediated by suppressor of cytokine signaling 1, Vav1, Rac1-GTP, and mitochondrial reactive oxygen species generation [[1877]] Attenuates experimental autoimmune encephalomyelitis (EAE) pathogenicity, but only in Nod-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome-dependent, and not in NLRP3 inflammasome-independent, EAE [[1877]] Combination therapy consisting of murine interferon beta (which is immunomodulatory) and dimethyl fumarate (which is neuroprotective) is more effective in treating experimental autoimmune encephalomyelitis (providing better axon protection) than either therapy alone [[10600]] Treatment with a combination of interferon beta-secreting mesenchymal stem cells and minocycline reduces the severity of experimental autoimmune encephalomyelitis, primarily by promoting blood-spinal cord barrier integrity [[12224]] (Recombinant mouse) interferon beta expands the population of transitional and regulatory B cells, and increases secretion of interleukin-10 in the spleen, in experimental autoimmune encephalomyelitis mice [[16751]] (Recombinant mouse) interferon beta reduces the severity of experimental autoimmune encephalomyelitis in mice [[16751]] (Recombinant mouse) interferon beta increases the production of anti-myelin oligodendrocyte glycoprotein IgG, but not IgM, in experimental autoimmune encephalomyelitis mice; disease severity does not correlate with the increased IgG levels [[16751]] (Recombinant mouse) interferon beta does not provide a clinical or histopathological benefit in experimental autoimmune encephalomyelitis (EAE) mice that are deficient for B cells (muMT mice), although it does in wild-type EAE mice [[16751]]
[+]	Laquinimod	IM NP	NFkB-mediated inflammatory pathways [[567]] T helper cell response [[567]] B cells [[2675]]	Quinoline 3-carboxamide derivative; the N-carboxyamide substitution appears to make the drug safer than other quioline 3-carboxamide derivatives tested [[822]] Derived from linomide (roquinimex), a compound tested for treating RRMS that failed Phase III trials because it caused serious cardiopulmonary toxicity [[561]] Has higher potency and a better toxicological profile than roquinimex, the compound from which laquinimod was derived [[824]] Absorbed rapidly after oral administration [[822]] Half life is 80 hours after oral administration [[822]] Bioavailability is 82% to 95% [[822]] Does not accumulate in tissues [[822]] Metabolized in the liver by the cytochrome P-450 enzyme system (specifically, the enzyme CYP3A4), suggesting that interactions with other drugs that are metabolized by CYP3A4 are possible [[570]] [[822]]	Suppresses gene expression related to antigen presentation and inflammation, mostly through the NFkB pathway, as determined by microarray analysis of peripheral blood mononuclear cells from MS patients [[567]] Downregulates signaling via transforming growth factor beta, pro-inflammatory cytokine expression, and genes involved with leukocyte extravasation, as shown by microarray analysis of gene expression changes in the blood of individuals involved in the ALLEGRO trial [[19092]] Increases serum levels of brain-derived neurotrophic factor, which might contribute to neuroprotection, in MS patients [[568]] Increases levels of brain-derived neurotrophic factor and insulin-like growth factor in cells in vitro [[816]] Decreases levels of inflammatory cytokines and matrix metalloproteinase-9 in cells in vitro [[816]] Reduces the percentage of CD5+ B cells (which is often increased in MS) in populations of purified B cells from healthy individuals and MS patients [[816]] Increases regulatory B cell markers [CD25, interleukin-10 (IL10), and CD86] and decreases IL4 in human B cells from MS patients or healthy volunteers [[2675]] Increases interleukin-10 and transforming growth factor beta produced by B and T cells in a B cell-mediated manner [[2675]] Appears to decrease the immunogenicity of dendritic cell responses [[5351]] Reduces the ability of human dendritic cells (derived from monocytes), which have been matured with lipopolysaccharide, to stimulate CD4+ T cell proliferation and pro-inflammatory cytokine secretion [[5351]] Reduces chemokine production by mature dendritic cells [[5351]] Reduces secretion of chemokines and cytokines by stimulated dendritic cells, which were derived from MS patients treated with laquinimod [[5351]] Decreases levels of CD1c+ and plasmacytoid CD303+ dendritic cells, and modifies dendritic cell maturation, in MS patients [[5351]] Pretreatment reduces activation of human microglia (induced by lipopolysaccharide), and associated production of pro- and anti-inflammatory cytokines and matrix metalloproteinase-9, in culture [[14871]] Reduces activation of human microglia and associated production of tumor necrosis factor-alpha mediated by stimulation of Toll-like receptor 2 (TLR2) and TLR4, but not TLR3, in culture [[14871]] Reduces activation of human microglia (induced by lipopolysaccharide) and associated activation of Jun-N-terminal kinase, ribosomal S6 kinase, and AKT/protein kinase B pathways, in culture [[14871]] Reduces activation of human microglia [induced by lipopolysaccharide (LPS)] and prevents the associated LPS-mediated downregulation of the microRNA miR124a (which is involved in the maintenance of microglia quiescence), in culture [[14871]] Reduces neuronal death induced by activation of microglia, and reduces elevated nitric oxide, in cocultures of human neurons and microglia [[14871]] Does not negatively affect the viability, proliferation, migration, or differentiation of human neural stem cells or oligodendrocyte progenitor cells in vitro over the short-term [[13023]] Two years of continuous therapy for MS does not change the relative proportion of circulating T cells, FoxP3+ CD25(hi) regulatory T cells, B cells, monocytes, macrophages, natural killer cells, or dendritic cells, as shown by a prospective longitudinal analysis of cohorts receiving placebo or laquinimod [[7119]] Two years of continuous therapy for MS does not affect the ability to respond to immunological stimuli such as tetanus antigen, as shown by a prospective longitudinal analysis of cohorts receiving placebo or laquinimod [[7119]] Does not cause significant changes in a variety of immune cell populations, including monocytes, B cells, CD4+ T cells, CD8+ T cells, regulatory T cells, natural killer cells, natural killer T cells, and mature dendritic cells, as shown by analysis of peripheral blood samples from participants in the ALLEGRO trial over two years [[19253]] Does not cause significant changes in antigen-specific or mitogen-induced proliferative responses of peripheral blood mononuclear cells, as shown by analysis of samples from participants in the ALLEGRO trial over two years [[19253]] Does not affect the expression of major histocompatibility complex class II molecules by stimulated monocytes, as shown by analysis of peripheral blood samples from participants in the ALLEGRO trial over two years [[19253]] Reduces the expression of CD86 (a costimulatory molecule) by monocytes stimulated by lipopolysaccharide but not interferon-gamma, as shown by analysis of peripheral blood samples from participants in the ALLEGRO trial over two years [[19253]] Does not affect the expression of CD80 (a costimulatory molecule) by stimulated monocytes, as shown by analysis of peripheral blood samples from participants in the ALLEGRO trial over two years [[19253]] Reduces the secretion of proinflammatory chemokines CCL2 and CCL5 by stimulated monocytes, as shown by analysis of peripheral blood samples from participants in the ALLEGRO trial over two years [[19253]] Most of what is known comes from experiments in rodents, because studies in patients are lacking [[560]]	Inhibits the development of experimental autoimmune encephalomyelitis [[562]] [[563]] [[566]] Reduces mean clinical disease scores, Th1 cytokine production, and inflammatory responses in the central nervous system when given either prophylactically or therapeutically to an experimental autoimmune encephalomyelitis mouse model [[9043]] Associated with improved motor performance, which correlates with reduced demyelination and axon damage and increased numbers of myelinated axons, in an experimental autoimmune encephalomyelitis mouse model [[9043]] Inhibits the infiltration of CD4+ T cells and macrophages into the spinal cord, preventing relapse after experimental autoimmune encephalomyelitis initiates [[566]] Reduces demyelination, inflammation, and axonal damage in experimental autoimmune encephalomyelitis rodents [[571]] Reduces astrogliosis, demyelination, and axonal damage in experimental autoimmune encephalomyelitis mice [[2341]] Protects against neurotoxicant-induced demyelination in mice via a mechanism that involves downregulation of astrocytic NF-kB activation [[2387]] Interferes with T cell migration in experimental autoimmune encephalomyelitis [[566]] Reduces proinflammatory cytokines, such as interleukin 17, in experimental autoimmune encephalomyelitis rodents [[566]] Shifts the cytokine balance toward TH2/TH3 cytokines by promoting transforming growth factor beta, interleukin 10, and interleukin 4 and inhibiting interleukin 12 and tumor necrosis factor-alpha in experimental autoimmune encephalomyelitis rodents [[562]] Restores brain-derived neurotrophic factor expression to healthy levels in experimental autoimmune encephalomyelitis mice [[2341]] May reduce anxiety and depression, possibly by increasing brain-derived neurotrophic factor in the hippocampus, as shown by studies of rodent behavioral models [[12801]] Prevents inflammation-induced GABAergic synaptic alterations (when administered in either preventative or therapeutic form) and limits glutamatergic synaptic alterations (when administered in preventative form) in experimental autoimmune encephalomyelitis mice [[4179]] Preserves the sensitivity of cannabinoid CB1 receptors, which is normally lost during experimental autoimmune encephalomyelitis (EAE), in EAE mice [[4179]] Increases inhibitory post-synpatic currents and reduces excitatory post-synaptic currents in experimental autoimmune encephalomyelitis mice [[4179]] Pretreatment reduces activation of murine microglia (induced by lipopolysaccharide), and associated production of tumor necrosis factor-alpha, in culture [[14871]] Preventative treatment reduces the density of microglia and macrophages, normalizes levels of transcripts associated with microglia and macrophage activation, and reduces axonal injury in the spinal cord of experimental autoimmune encephalomyelitis mice [[14871]] Restores levels of the microRNA miR124a (which is involved in the maintenance of microglia quiescence) in the spinal cord of experimental autoimmune encephalomyelitis mice [[14871]] When given during the disease course, halts progressive demyelination and axonal loss in experimental autoimmune encephalomyelitis mice [[14871]] Reduces neuronal death induced by activation of microglia, and reduces elevated nitric oxide, in cocultures of murine neurons and microglia [[14871]] Reduces levels of inducible nitric oxide synthase, which can produce free radical toxicity, in the spinal cord of experimental autoimmune encephalomyelitis mice [[14871]] Suppresses or delays nephritis in a mouse model of systemic lupus erythematosus [[9957]] Reduces the number of monocyte/macrophages, dendritic cells, and lymphocytes in the spleen and kidney in a mouse model of systemic lupus erythematosus [[9957]] Induces myeloid-derived suppressor cells in the spleen and kidney in a mouse model of systemic lupus erythematosus [[9957]] Reduces secretion of tumor necrosis factor-alpha by macrophages and interferon-gamma and interleukin-17 by lymphocytes, based on a study of a mouse model of systemic lupus erythematosus [[9957]]
[+]	Masitinib	IM	KIT (a stem cell factor, also called c-KIT) receptor as well as select other tyrosine kinases [[1334]] Mast cells [[1334]]	Toxicity and pharmacokinetics have been studied in dogs [[1379]] [[1380]] Specificity compared to other tyrosine kinase inhibitors (such as imatinib) may improve safety profile [[1334]]	Blocks the stem cell factor receptor KIT (also called the c-KIT receptor) in cultured cells [[1334]] Blocks platelet derived growth factor receptor in cultured cells [[1334]] Does not target kinases thought to be involved in cardiotoxicity such as ABL, based on experiments in cultured cells [[1334]] Inhibits human mast cell degranulation, cytokine production, and migration of bone marrow cells in cultured cells [[1334]] Slowed cognitive decline in Alzheimer disease in a Phase II study, presumably by acting on mast cells in the brain [[1335]] Likely regulates inflammation indirectly, via mast cells’ release of proinflammatory mediators and control of blood-brain barrier permeability [[1335]] Improved symptoms of rheumatoid arthritis in a Phase II study [[1336]]	Inhibits tumor growth in vivo in mice [[1334]] Reduces brain ischemia caused by experimental stroke in rats [[14923]] Does not damage chromosomes or affect mitosis in mouse cells [[1334]]
[+]	MEDI-551	IS	CD19, a B cell-specific antigen that is part of the B cell receptor complex and that functions in determining the threshold for B cell activation [[11914]] B cells [[11914]] Plasmablasts, B cells that express CD19 (but not CD20) and that secrete large quantities of antibodies; depletion of plasmablasts may be useful in autoimmune diseases involving pathogenic autoantibodies [[11914]]	An afucosylated version of a humanized and affinity-optimized anti-CD19 monoclonal antibody [[11914]] Produced by expressing a humanized and affinity-optimized anti-CD19 monoclonal antibody in a fucosyltransferease-deficient Chinese hamster ovary cell line [[11914]] Produced without the fucose carbohydrate modification on the Fc region to increase affinity to FcγRIIIA, the low affinity immunoglobulin gamma Fc region receptor III-A [[11914]]	Binds to human FcγRI (an Fc receptor that binds antibodies with high affinity) and FcγRIIa (an Fc receptor that binds antibodies with low affinity) with similar affinity as the fucosylated version of the antibody [[11914]] Binds to human FcγRIIIA (an Fc receptor that binds antibodies with low affinity) with 9-fold greater affinity than the fucosylated version of the antibody [[11914]] Displays enhanced antibody-dependent cellular cytotoxicity against a B cell lymphoma line as compared with (i) the fucosylated version of the antibody or (ii) rituximab (an anti-CD20 monoclonal antibody) in assays using human natural killer cells as effector cells [[11914]] Much lower concentrations are required for antibody-dependent cellular cytotoxicity against a B cell lymphoma line in vitro for MED-551 versus (i) the fucosylated version of the antibody or (ii) rituximab, an anti-CD20 monoclonal antibody [[11914]] Depletes B cells from peripheral blood mononuclear cells (the source of both target and effector cells in this assay) from normal donors at lower concentrations than does rituximab, an anti-CD20 monoclonal antibody [[11914]] Displays effective antibody-dependent cellular cytotoxicity against many different B cell leukemia and lymphoma cell lines in assays using natural killer cells as effector cells [[11915]] Displays effective antibody-dependent cellular cytotoxicity against patient-derived primary chronic lymphocytic leukemia and acute lymphoblastic leukemia cells in assays using natural killer cells as effector cells [[11915]] Inhibits growth of human CD19+ lymphoma xenografts in severe combined immunodeficient mice; MEDI-551 and rituximab (an anti-CD20 monoclonal antibody) in combination have a greater effect than either antibody alone [[11915]] Forms a complex with CD19 at the surface of pre-B cells (from acute lymphoblastic leukemia cell lines) and patient-derived blast cells that persists for >5 hours; this prolonged period may be important for therapeutic effectiveness [[11916]] Binds pre-B cells from acute lymphoblastic leukemia cell (ALL) lines, resulting in the formation of immune synapses between these target cells and primary natural killer cells and, ultimately, swelling, lysis, and death of the target cells, as shown by fluorescent imaging studies [[11916]]	Binds to mouse FcγRIV (the ortholog of human FcγRIIIA) with 10-fold greater affinity than the fucosylated version of the antibody [[11914]] Depletes B cells in vivo from both blood and spleen in transgenic mice (which express human CD19 and CD20) at lower doses than does rituximab, an anti-CD20 monoclonal antibody [[11914]] Depletion of B cells from blood and spleen in transgenic mice (which express human CD19 and CD20) requires monocytes/macrophages but not natural killer cells, neutrophils, or complement [[11914]] Promotes macrophage-mediated phagocytosis of mouse B cells ex vivo [[11914]] Reduces B cells from the bone marrow by ~90% (versus <50% for rituximab, an anti-CD20 monoclonal antibody) in transgenic mice expressing human CD19 and CD20; this difference may be responsible for the longer time to B cell recovery in mice treated with MED-551 [[11914]]
[+]	Minocycline	IM NP	T cells [[6953]] Microglia [[6953]] Leukocyte migration [[6953]]	Semisynthetic tetracycline derivative [[6938]] Antibacterial agent that is active against many gram-positive and gram-negative organisms [[6938]] Bacteriostatic [[6938]] Bacterial protein synthesis inhibitor [[6938]] Molecular weight, 457.48 Da [[6953]] Lipophilic [[6953]] Can cross the blood-brain barrier [[6953]] Antioxidant [[6955]] Calcium and iron chelator [[6956]] [[6973]] In fasting adults given two 100 mg Minocin capsules, the maximum serum concentrations occur in 1 to 4 hours [[6938]] In fasting adults given two 100 mg Minocin capsules, the serum half-life ranges from 11.1 to 22.1 hours [[6938]] Undergoes almost complete absorption [[6938]]	Exact mechanism unknown [[6953]] Inhibits the transmigration of T cells (from healthy individuals) across a fibronectin barrier in vitro (suggesting that the drug might inhibit leukocyte transmigration across such matrix barriers in vivo, which is required for infiltration into the central nervous system) [[6954]] Inhibits the activity of matrix metalloproteinases MMP-9 (which is elevated in MS) and MMP-2 in vitro; MMPs have been implicated in fibronectin degradation, a process required for leukocyte transmigration [[6954]] Reduces the production of matrix metalloproteinase MMP-9 (which is elevated in MS) in cultured T cells [[6954]] Inhibits synovial collagenase activity in vivo (in individuals with rheumatoid arthritis) and in vitro [[6957]] Inhibits the T cell response to an antigen (tetanus toxoid) in vitro, via inhibition of antigen processing by antigen presenting cells [[6958]] Inhibits T cell proliferation and reduces the expression of interleukin 2, interferon-gamma, and tumor necrosis factor-alpha in vitro, in experiments involving T cell clones from an individual with rheumatoid arthritis [[6959]] Inhibits expression of tumor necrosis factor-alpha and interferon-gamma, but not interleukin 6, in stimulated T cells [[6960]] Enhances expression of tumor necrosis factor-alpha and interleukin 6 in stimulated monocytes [[6960]] In combination, glatiramer acetate and minocycline exert effects on the induction, maturation, and phenotype of blood monocyte-derived dendritic cells (from individuals with and without MS) that are stronger than those of glatiramer acetate alone [[6953]] [[6961]] Inhibits toxin-induced apoptosis in the human dopaminergic cell line SH-SY5Y [[6962]] May inhibit caspase-independent programmed cell death pathways, on the basis of experiments in the human dopaminergic cell line SH-SY5Y [[6962]] Active against the respiratory pathogen Chlamydia pneumoniae, which has been associated with MS, suggesting a possible route by which the drug could be effective against MS [[6953]]	Strongly suppresses the severity of experimental autoimmune encephalomyelitis, inhibiting ongoing disease activity and reducing disease progression, an effect that is linked with inhibition of central nervous system inflammation [[6963]] Inhibits microglial activation in experimental autoimmune encephalomyelitis [[6963]] Promotes T helper cell differentiation from a Th1 phenotype to a Th2 phenotype in vivo in an experimental autoimmune encephalomyelitis model [[6963]] Pretreatment delays the course of severe experimental autoimmune encephalomyelitis [[6954]] Reduces the severity of experimental autoimmune encephalomyelitis and reduces numbers of CD4+ and CD8+ T cells in the spinal cord, but does not affect their cytokine production profile [[6964]] Treatment with a combination of interferon beta-secreting mesenchymal stem cells and minocycline reduces the severity of experimental autoimmune encephalomyelitis, primarily by promoting blood-spinal cord barrier integrity [[12224]] Inhibits the expression of major histocompatibility complex class II (which functions in reactivation of T cells that have infiltrated the central nervous system) by microglia and macrophages via inhibition of protein kinase C (alpha/beta II) and transcription factors that affect expression of inflammatory genes [[6968]] Reduces the expression of some but not all proteins induced by lipopolysaccharide in cultured mouse macrophages, as shown by a proteomic analysis, indicating that minocycline only partially inhibits macrophage activation [[6975]] A combination of suboptimal doses of minocycline and interferon-beta reduces the severity of experimental autoimmune encephalomyelitis, whereas either suboptimal dose alone does not [[6965]] A combination of suboptimal doses of minocycline and prednisone reduces the severity of experimental autoimmune encephalomyelitis better than either drug alone [[6966]] A combination of suboptimal doses of minocycline and atorvastatin reduces the severity of experimental autoimmune encephalomyelitis in both chronic and acute phases [[6967]] Prevents microglia activation and increases hippocampal neuronal survival in a gerbil model of ischemic stroke [[6969]] Exerts a neuroprotective effect against glutamate-induced excitotoxicity, and prevents proliferation and activation of microglia (which contributes to excitotoxicity), in primary neuronal cultures [[6970]] Exerts neuroprotective effects on retinal ganglion cells in an experimental autoimmune encephalomyelitis model by inducing anti-apoptotic signaling and decreasing glutamate excitotoxicity; these effects are independent of the drug's anti-inflammatory effects [[6971]] Inhibits the excessive tissue collagenase activity produced by explanted gingival tissue from diabetic rats, and this activity is independent of the drug's antimicrobial function [[6972]] Displays antioxidant activity, as determined by in vitro rat brain homogenate lipid peroxidation and radical scavenging assays [[6955]] Binds to mitochondrial membranes in a Ca(2+)-dependent manner and forms ion channels in the inner mitochondrial membrane, thus causing selective permeability for small ions, in rat liver mitochondria [[6956]] May indirectly prevent induction of the mitochondrial permeability transition by partly uncoupling mitochondria, as suggested by experiments using rat liver mitochondria [[6956]] Reduces iron neurotoxicity in mouse cortical neuron cultures [[6973]] Reduces iron overload and iron-induced brain injury after experimental intracerebral hemorrhage in rats [[6974]] Protects mice against experimentally-induced colitis [[6976]] Reduces expression of inducible nitric oxide synthase, proinflammatory cytokines, and matrix metalloproteinases 2, 3, 9, and 13 in mouse models of colitis [[6976]] Inhibits nitric oxide production in a mouse model of colitis [[6976]] Increases the expression of Sox10, HIF-1α, EPO, BDNF, pAKT, cleaved notch1, YAP, survivin, Gpr124, CD31, PCNA, MAG, MOBP, PLP, and synapsin in the the subventricular zone of mouse pups reared under reduced oxygen conditions [[22576]] Reduces caspase 3 activation in the the subventricular zone of mouse pups reared under reduced oxygen conditions [[22576]] Improves the performance of mouse pups, which were reared under sublethal hypoxic conditions, in open field testing [[22576]]
[+]	MIS416	IM	Innate immune system [[13783]] [[9622]] Pathogen-associated molecular pattern recognition receptors of the innate immune system [[13783]] Myeloid cells of the innate immune system, which might be able to remodel the deregulated immune system activity that occurs in SPMS [[13783]] [[14089]]	Derived from Propionibacterium acnes, an anaerobic, Gram-positive bacterium (formerly called Corynebacterium parvum) that has a strong stimulatory effect on phagocytic cells [[13783]] Manufactured by extracting hydrophobic components from the bacterium Propionibacterium acnes to produce biodegradable microparticles, which consist of a minimal cell wall skeleton, which forms a cage-like structure, and covalently attached bacterial DNA [[13783]] [[13859]] Retains the rod-shape of the parent microorganism Propionibacterium acnes [[13783]] Microparticle dimensions are about 0.5 x 2.0 microns [[13783]] Shell comprises crosslinked muramyl dipeptide, a peptidoglycan unit from the bacterial cell wall that exerts immunostimulatory activity via the pathogen-associated molecular pattern recognition receptor NOD-2, a nucleotide-binding oligomerization domain-like receptor [[13783]] [[13859]] Contains bacterial DNA, which is recognized by the pathogen-associated molecular pattern recognition receptor Toll-like receptor 9 [[13783]] Nucleic acid component consists of fragments less than 1 kb in size [[13783]] Bioactivity is stable across a range of temperatures (including room temperature, 2 to 8 degrees C, and freeze-thaw cycles) for >24 months [[13875]] Can be covalently attached to an antigen [[13783]]	Developed as a vaccine adjuvant, but may be useful for treating inflammatory disorders such as MS, an idea that is supported by the finding that ligands for pathogen-associated molecular pattern recognition receptors may be protective in animal models of MS [[9622]] Anecdotally, reduces pain and fatigue and improves bladder control and social functioning in SPMS and PPMS, based on a compassionate use program involving 24 individuals with a median time of treatment of 24 months (June, 2014) [[14089]] Increases serum levels of interferon-gamma, and proteins upregulated by interferon-gamma, in individuals with SPMS [[9622]] Exhibits characteristics of a broadly immunostimulatory vaccine adjuvant in vitro [[13783]] Readily internalized by human whole blood monocytes and myeloid dendritic cells, and to a lesser extent by plasmacytoid dendritic cells [[13783]] Not internalized by human natural killer cells, natural killer-like T cells, T cells, or B cells [[13783]] Stimulates human peripheral blood mononuclear cells to secrete inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha, and IL-1beta, as well as regulatory cytokine IL-10 [[13783]] Stimulates human peripheral blood mononuclear cells to secrete low levels of the Th1-associated cytokine interferon-gamma [[13783]] Stimulates an inflammatory and regulatory response from human peripheral blood mononuclear cells that appears to be mediated by signaling associated with the pathogen-associated molecular pattern recognition receptor NOD-2 [[13783]] Stimulates interferon-alpha secretion by human plasmacytoid dendritic cells, which appears to be mediated by signaling associated with the pathogen-associated molecular pattern recognition receptor Toll-like receptor 9 [[13783]] Stimulates an inflammatory response from human peripheral blood mononuclear cells that does not depend on the pathogen-associated molecular pattern recognition receptor Toll-like receptor 2 (which recognizes highly inflammatory lipotechoic acid, a major component of the Gram-positive bacteria cell wall), confirming that lipotechoic acid had been removed from the microparticle [[13783]] Induces maturation of myeloid dendritic cells, which secrete tumor necrosis factor-alpha, macrophage inflammatory protein-1-alpha, interleukin-10 (IL-10), and IL-6, but not Th1-associated IL-12-p70, from human peripheral blood mononuclear cells [[13783]] Induces maturation of plasmacytoid dendritic cells from human peripheral blood mononuclear cells in a manner that requires engagement of the CD40 receptor [[13783]]	Reduces the severity of experimental autoimmune encephalomyelitis, even when administered after the onset of disease [[9622]] Ability to protect against experimental autoimmune encephalomyelitis requires interferon-gamma [[9622]] Supresses the development of systemic (as observed in the spleen) antigen-specific Th1-, Th17-, and Th2-associated responses in experimental autoimmune encephalomyelitis mice [[9622]] Does not affect strong, local (draining lymph node) antigen-specific Th1 and Th17 cytokine responses in experimental autoimmune encephalomyelitis mice [[9622]] Causes an expansion of CD4+ T cells in both experimental autoimmune encephalomyelitis and normal mice [[9622]] Causes an expansion of monocytic myeloid derived suppressor cells and red pulp macrophages in the spleen of experimental autoimmune encephalomyelitis and normal mice [[9622]] Induces the production of interferon-gamma and nitric oxide by splenocytes from experimental autoimmune encephalomyelitis mice [[9622]] Increases serum levels of interferon-gamma and interleukin-6 in experimental autoimmune encephalomyelitis and normal mice [[9622]] Exhibits characteristics of a broadly immunostimulatory vaccine adjuvant in vivo [[13783]] Induces functional, antigen-specific Th1 cellular immunity when used as an adjuvant to a model vaccine in mice [[13783]] Stimulates cross-priming of responses by antigen-specific cytotoxic CD8+ T cells when used as an adjuvant to a model vaccine in mice [[13783]] Promotes anti-tumor immunity when used as an adjuvant to a model vaccine (against an antigen expressed by melanoma cells) in mice [[13783]] Exhibits a favorable safety profile in acute and chronic toxicity studies in mice and rabbits; adverse events such as granulomas are not induced by therapeutic doses [[13783]]
[+]	Mitoxantrone	IS	T cells [[511]] B cell proliferation [[511]] Macrophages [[511]]	Antineoplastic drug [[511]] Crosslinks DNA [[516]] Exhibits extensive tissue distribution [[520]] Eliminated primarily via biliary excretion, and to a lesser extent in the urine [[520]] Half-life measurements in MS patients are available [[523]]	Inhibits DNA replication and DNA-dependent RNA synthesis [[519]] Interferes with DNA repair mechanisms in vitro [[519]] Can cross the blood brain barrier, where it is thought to interact with cells in the central nervous system [[522]] Inhibits proliferation of activated peripheral blood mononuclear cells, B lymphocytes, and antigen-specific T cell lines in vitro in a dose-dependent manner [[518]] Interferes with the antigen-presenting capability of dendritic cells in vitro [[518]] Induces apoptosis of peripheral blood mononuclear cells, monocytes, and dendritic cells in vitro [[518]] Induces cell membrane scrambling and suicidal death of human erythrocytes, effects that involve formation of reactive oxidant species and ceramide but not entry of extracellular Ca2+ [[15729]] Suppresses B cells, enriches neutrophils and immunomodulatory CD8(low) T cells, and promotes natural killer (NK) cell enrichment and NK cell maturation in SPMS patients [[2379]] Generally does not influence intrathecal IgG production or oligoclonal IgG band patterns, as shown by a 2-year study of 22 individuals with MS [[8055]] Normalizes CXCL13, a chemokine that regulates B cells, in individuals with MS [[8055]] Does not affect the activity of the antioxidant enzyme paraoxonase 1 in MS patients [[3008]] Increases the concentration of the lipid peroxidation marker malondialdehyde in serum and cerebrospinal fluid in MS patients [[4884]] Decreases the activity of manganese superoxide dismutase in serum and cerebrospinal fluid (CSF), and of catalase and glutathione peroxidase in CSF, in MS patients [[4884]] Increases the activity of copper/zinc superoxide dismutase in serum in MS patients [[4884]] Reduces levels of soluble triggering receptor expressed on myeloid cells-2 in the cerebrospinal fluid, which are increased in individuals with RRMS, SPMS, or PPMS [[25556]] Appears to reduce axonal damage (as determined by measuring levels of the axonal damage biomarker neurofilament light protein in cerebrospinal fluid) in progressive MS (after 12 to 24 months of treatment) [[6160]] Associated with a decrease in levels of the glial marker YKL-40 in the cerebrospinal fluid (CSF) from individuals with MS; CSF YKL-40 levels are increased in MS relative to healthy controls [[10087]] Therapeutic response to mitoxantrone in highly active MS (relapsing-progressive/SPMS) might be predicted by polymorphisms in genes encoding the ATP-binding cassette transporters ABCB1 and ABCG2, such that genotypes associated with decreased ABCB1/ABCG2 function are linked with increased clinical response rate, based on retrospective analysis [[15728]] Therapeutic response to mitoxantrone in PPMS is not predicted by specific ABC transporter gene polymorphisms, based on retrospective analysis [[15598]] Less effective in individuals with PPMS than in those with relapsing-progressive/SPMS [[15598]]	Reduces B cell number and inhibits B cell proliferation in mice in vivo and in vitro [[521]] Reduces the immune response in experimental autoimmune encephalomyelitis rodents by depressing myelin-directed T- and B-cell responses 3- to 9-fold and inhibiting macrophage-mediated demyelination [[511]] Appears to block inwardly rectifying K(+) channels in mouse osteoclast precursor cells that have been differentiated with lipopolysaccharide [[2737]] Represses lipopolysaccharide induction of nitric oxide, tumor necrosis factor alpha, and interleukin-1 beta (which are pro-inflammatory, potentially cytotoxic molecules) by primary mouse astrocytes [[2789]] Represses lipopolysaccharide induction of MCP-1 (a chemokine that affects monocyte migration to inflammatory lesions in the central nervous system) by primary mouse astrocytes [[2789]] Represses lipopolysaccharide induction of interleukin-12 and -23 (which play a role in autoimmune encephalomyelitis pathogenesis by contributing to the development of Th1 and Th17 T cell lineages) by primary mouse astrocytes [[2789]] Represses lipopolysaccharide induction of C-reactive protein in primary mouse astrocytes [[2789]] Represses lipopolysaccharide induction of NF-kB DNA-binding activity in primary mouse astrocytes [[2789]]
[+]	Mycophenolate mofetil	IS	Purine synthesis [[597]] [[457]]	2-morpholinoethyl ester of mycophenolic acid [[439]]	Selectively inhibits inosine 5’-monophosphate dehydrogenase type II, an enzyme critical for synthesis of the nucleotide guanine, a pathway used for T and B cell proliferation [[457]] [[439]]	Impairs dendritic cell maturation and function in mice [[874]] Improves neurological function and reduces weight loss in a rat experimental autoimmune encephalomyelitis model [[9626]] Decreases the ratio of CD4+ to CD8+ T cells in blood in a rat experimental autoimmune encephalomyelitis model [[9626]]
[+]	Naltrexone	IM	Opioid receptors [[9776]] [[9971]] Toll-like receptor 4 [[10092]]	Competitive opioid receptor antagonist [[9776]] [[9971]] Toll-like receptor 4 antagonist [[10092]] Synthetic congener of oxymorphone [[9975]] Molecular weight, 341.4 [[9975]] Oral form is rapidly absorbed in the gastrointestinal tract [[9973]] Peak concentrations in the plasma occur within 1 hour after oral dosing [[9973]] Metabolized to 6-β-naltrexol, the primary active metabolite, in the liver [[9973]] Elimination half-life of 6-β-naltrexol is 13 hours [[9973]]	Purportedly reduces the frequency of relapses and slows the progression of MS, according to anecdotal evidence and a patient-organized Web survey [[9943]] Increases beta-endorphin levels, as shown by a 6-month study in individuals with PPMS [[9937]] Blocks the activity of the mu- and kappa-opioid receptors, as shown using human embryonic kidney cells that express the human genes for these receptors [[10091]] Blocks signaling from Toll-like receptor 4 (TLR4, which is expressed on microglia and other macrophages), as shown using human embryonic kidney cells that express the human TLR4 gene [[9776]] [[10092]] May exert anti-inflammatory effects through the Toll-like receptor 4, which functions in the innate immune system and is expressed on microglia [[9776]]; activation of TLR4 might lead to chronic inflammation [[10099]] Identity of the low-dose form as an anti-inflammatory agent is supported by the finding that this dose has beneficial effects in inflammatory disorders such as Crohn's disease [[9776]]	Halts progression of experimental autoimmune encephalomyelitis [[9944]] Reverses neurological problems, and prevents the initiation of neurological dysfunction, in a mouse experimental autoimmune encephalomyelitis model [[9944]] Daily low dose (0.1 mg per kg) treatment reduces the severity of experimental autoimmune encephalomyelitis, whereas daily high dose (10 mg per kg) treatment does not [[9946]] Daily low dose (0.1 mg per kg) treatment reduces levels of activated astrocytes and demyelination in a mouse model of experimental autoimmune encephalomyelitis [[9946]] Low dose inhibits the proliferation of peripheral CD4+ and CD8+ T cells and B220+ B cells that occurs in response to immunization with myelin oligodendrocytic glycoprotein in mice (a treatment that induces experimental autoimmune encephalomyelitis) [[18647]] Suppresses neuropathic pain in a rat model involving sciatic nerve injury [[10092]] Low dose impairs infiltration of CD4+ T lymphocytes into the central nervous system of mice with established experimental autoimmune encephalomyelitis [[20384]] Blocks the activity of the delta-opioid receptor, as shown using human embryonic kidney cells that express the mouse receptor gene [[10091]] Increases concentrations of Toll-like receptor 4 at both the mRNA and protein level in a mouse leukemic monocyte macrophage cell line, but does not have this effect when co-administered with the opioid morphine [[10093]] Inhibits the expression of inducible nitric oxide synthase at both the RNA and protein level in rat splenocytes [[10094]]
[+]	Natalizumab	IM	α4 integrins [[300]] Leukocyte trafficking [[379]]	Humanized monoclonal antibody against α4 integrin [[405]] Humanized monoclonal antibody that contains the human framework regions and the murine complementarity-determining regions [[397]] [[592]] Molecular weight, 149 kDal [[592]] Cell-bound drug has a different half-life than free drug, and cells can serve as a reservoir of drug (T. Sehr, meeting presentation, ECTRIMS, Oct 2011) After intravenous administration, the mean half-life is 11 +/- 4 days [[592]] Induces the production of antibodies against natalizumab in over half of treated patients (most of whom later revert to negative status for these antibodies); high titers of such antibodies (and corresponding low serum natalizumab concentrations) are associated with reduced efficacy of the drug [[3217]] Binds to α4 integrin receptors on the surface of peripheral blood leukocytes, such that these receptors are more than 80% saturated 1 month after drug infusion [[394]]	Exact mechanism unknown [[590]] Binds to α4 integrins, integral membrane proteins that are expressed by leukocytes and mediate cell adhesion [[379]] [[592]] [[394]] Is thought to inhibit the binding of circulating immune cells to the blood brain barrier (a process that is mediated by α4 integrin) [[363]] Is thought to inhibit leukocyte adhesion and transmigration across the endothelium into inflammed tissue by blocking the interaction of α4 integrins with their receptors [[592]] Blocks the integrin dimer termed very late antigen-4 and thereby inhibits lymphocyte trafficking into the central nervous system, but promotes alternative routes for migrating across the blood-brain barrier that involve T cell rolling mediated by P-selectin glycoprotein ligand-1 and Th17 adhesion mediated by myeloma cell adhesion molecule [[13099]] T cells from individuals under long-term treatment display enhanced rolling mediated by P-selectin glycoprotein ligand-1, as well as some adhesion, on primary human endothelial cells in vitro, even with blockade of very late antigen-4 [[13099]] TH17 cells [which express myeloma cell adhesion molecule (MCAM)] from individuals under long-term treatment still adhere to primary human endothelial cells in vitro; such adhesion is not prevented by blockade of very late antigen-4 (VLA-4), but is prevented if by blockade of VLA-4 and MCAM [[13099]] Long-term treatment is associated with increased expression of myeloma cell adhesion molecule, but a lack of the integrin alpha subunit CD49d, on T cells in the cerebrospinal fluid [[13099]] Long-term treatment is associated with increased expression of P-selectin glycoprotein ligand-1 (which binds the adhesion molecule P-selectin and mediates rolling on endothelial cell surfaces in blood vessels) on peripheral T cells [[13099]] Long-term treatment is associated with normal central- to effector-memory T cell ratios in the cerebrospinal fluid [[13099]] Reduces levels of soluble vascular cell adhesion molecule 1, a ligand for α4β1 integrin that is upregulated in MS, in MS patients [[350]] Partially inhibits the ability of soluble vascular cell adhesion molecule 1 to impair integrity of the brain endothelial barrier, as shown by studies with primary human brain microvascular endothelial cells [[18035]] Increases peripheral accumulation of newly-produced T and B lymphocytes because of a low level of migration across endothelial cells, and because of a high level of release, in MS patients [[2808]] Reduces counts of leukocytes, CD4+ and CD8+ T cells, B cells, and plasma cells in the cerebrospinal fluid in MS patients, in agreement with the idea that the drug weakens immune surveillance in the central nervous system [[386]] Decreases the ratio of CD4+ T cells to CD8+ T cells in the cerebrospinal fluid in MS patients [[382]] Treatment (every 4 weeks for 48 weeks) strongly increases peripheral CD4 counts, which then decline to baseline when treatment is interrupted (for 12 weeks), and then rise again when treatment is reinitiated, as shown in a study of individuals with relapsing MS [[19022]] Concentrations in the cerebrospinal fluid show high interindividual variability in natalizumab-treated individuals with MS [[16485]] Concentrations of free natalizumab in the cerebrospinal fluid (CSF) do not correlate with the CD4+/CD8+ T cell ratio in the CSF in natalizumab-treated individuals with MS [[16485]] Cell-bound natalizumab levels do not correlate with the CD4+/CD8+ T cell ratio in the cerebrospinal fluid in natalizumab-treated individuals with MS [[16485]] Associated with an increased number of circulating white blood cells, especially B lymphocytes, even after prolonged therapy in MS patients [[4565]] Associated with a decreased circulating CD4:CD8 cell ratio even after prolonged therapy, specifically in MS patients who exhibit a long-term response to therapy [[4565]] Long-term treatment is associated with a reduction in the percentage of CD4+ T cells that express L-selectin [[7134]] Associated with a reduction in the percentage of CD4+ T cells that express L-selectin (which is involved in leukocyte rolling and transmigration) as compared with first-line MS treatments [[20823]] Associated with a reduction in the percentage of CD4+ T cells that express L-selectin that is apparent in the first year of treatment, persists, and then reverses when treatment ends, as shown in a longitudinal study [[20823]] Induces changes in inflammatory cytokine levels in RRMS patients [[342]] Selectively increases levels of effector-memory T cells in the blood, but does not affect the activation state of T cells in the blood, and does not selectively increase myelin-reactive T cells, in MS patients [[4163]] Increases tumor necrosis factor-alpha mRNA expression in T cells, but does not affect the expression of other tested effector cytokines or transcription factors, in MS patients [[4163]] Decreases the expression of the co-stimulatory molecule CD134 on CD26(HIGH)CD4(+) T cells, but otherwise does not affect the response of CD4(+) T cells to myelin basic protein, in MS patients [[4163]] Restricts (and thereby appears to normalize) the T cell receptor repertoire, which is expanded in individuals with MS [[7650]] [[7649]] In vitro, decreases the expression of the co-stimulatory molecule CD134 on myelin basic protein-reactive CD26(HIGH)CD4(+) T-cells [[4163]] Affects the expression pattern of 10 microRNAs in B lymphocytes from RRMS patients [[2013]] Downregulates expression of the microRNA miR-126, which is increased during relapses, in CD4+ T cells from individuals with MS [[10070]] Treatment is associated with downregulation of the microRNA miR-126 (a non-coding RNA that reduces expression of target genes) and upregulation of proteins POU2AF1 and Spi-B; POU2AF1 regulates Spi-B, a transcription factor that interacts with promotor/enhancer sequences of the JC virus (the cause of progressive multifocal leukoencephalopathy) [[10070]] Modifies the expression of certain microRNAs (let-7c, miR-125a-5p, and miR-642), based on a study of blood samples from 19 individuals with RRMS [[11208]] Treatment downregulates microRNA-17 expression, which is upregulated during relapse, in CD4+ T cells from individuals with RRMS [[11445]] Treatment downregulates microRNA-17 expression, which in turn upregulates target genes PTEN, BIM, E2F1, and p21, in CD4+ T cells from individuals with RRMS; inhibition of microRNA-17 in vitro inhibits activation and proliferation of CD4+ T cells [[11445]] Restores patterns of microRNA expression that are dysregulated in MS, as shown by a longitudinal study of 17 individuals with RRMS and 18 matched healthy controls [[16716]] Upregulates expression of microRNAs miR-18a, miR-20b, miR-29a, and miR-103 (which are downregulated in MS), and downregulates miR-326, as shown by a longitudinal study of 17 individuals with RRMS [[16716]] Decreases expression of the proinflammatory micro-RNA miR-155, as shown by studies of monocytes isolated from treated versus untreated individuals with MS [[25798]] Decreases expression of the antioxidant genes HMOX1 and OSGIN1, as shown by studies of monocytes isolated from treated versus untreated individuals with MS [[25798]] Associated with the presence of JC virus DNA in circulating CD34+ stem cells and CD19+ (B lymphocyte) cells (as well as higher levels of CD34+ cells, which are mobilized by natalizumab into the peripheral circulation) in a prospective study that compared individuals with MS beginning or undergoing natalizumab treatment with healthy volunteers, providing a link between the effects of natalizumab and progressive multifocal leukoencephalopathy [[10295]] [[10371]] Long-term therapy might affect T2 intensity of deep gray matter structures, as visualized by MRI, suggesting a potential effect of the drug beyond its anti-inflammatory role [[2767]] May counteract the altered metabolism of amyloid precursor protein (APP) that occurs in MS [which results in reduced levels of amyloid beta and soluble APP fragments in cerebrospinal fluid (CSF)], as determined by analysis of CSF samples from MS patients at baseline and after 1 to 2 years of treatment [[3611]] Inhibits intrathecal antibody production patients in some MS patients [[3699]] Reduces expression of endogenous retroviruses of the HERV-W family, which have been linked with MS pathogenesis, as shown in a longitudinal cohort study of individuals with MS (none of whom relapsed during this study) [[6875]] Reduces the antibody response against the human endogenous retrovirus HERV-Wenv(73-88) peptide (but not the response to peptides from Epstein Barr virus or Mycobacterium avium ss. Paratuberculosis) in individuals with MS after two years of treatment [[20314]] Mildly upregulates interleukin 2 (IL-2), interferon gamma, and IL-17 in activated primary CD4+ T cells (which were propagated ex vivo) from healthy donors [[4405]] Upregulates interleukin 2 (IL-2), interferon gamma, and IL-17 (a pro-inflammatory phenotype) in peripheral blood mononuclear cells from some treated RRMS patients within 24 hours after the first infusion of drug [[4405]] Natalizumab or interferon beta treatment is associated with significantly reduced serum levels of a "cytokine signature" [a summed value of levels of tumor necrosis factor-alpha, interferon gamma, S100B, interleukin-1beta (IL-1beta), IL-6, IL-8, IL-17, and IL-23] in individuals with MS as compared with levels in drug naïve individuals with MS [[12197]] Natalizumab treatment is associated with reduced serum levels of pro-inflammatory cytokines as compared with interferon beta treatment in individuals with MS [[12197]] Enhances phosphorylation of ERK in stimulated human Jurkat (CD4+ T cell line) cells and in primary CD4+ T cells, indicating that natalizumab causes signaling effects that resemble natural integrin signaling [[4405]] Decreases the surface expression of CD49d (integrin α4) by causing the rapid internalization and degradation of CD49d, based on experiments using the human CD4+ T cell line Jurkat and human peripheral blood mononuclear cells [[4405]] Reduces levels of chitinase-3-like protein 1, as well as the inflammation-related proteins Ig mu chain C region and haptoglobin, in the cerebrospinal fluid of RRMS patients, as shown by profiling proteomics experiments [[4667]] Normalizes levels of soluble triggering receptor expressed on myeloid cells-2 in the cerebrospinal fluid, which are increased in individuals with RRMS, SPMS, or PPMS [[25556]] Normalizes the blood level of the transcription factor TBX21, which is decreased in individuals with MS [[25633]] May slightly reduce anti-JC virus and anti-varicella-zoster virus antibody levels, as shown by analysis of stored sera from a Swedish national MS cohort [[5153]] May reduce anti-JC virus antibody levels, but does not affect the seroprevalence of anti-JC virus antibodies, as shown in a study of a Finnish MS cohort [[21381]] Does not appear to affect anti-JC virus antibody prevalence, as shown by a cross-sectional study of a multinational MS cohort [[5143]] Appears to increase the anti-JC virus antibody titer substantially over time, as shown in a longitudinal study involving 485 natalizumab-treated indivduals with MS, 340 of whom had repeat antibody testing [[22465]] Associated with an increase in the incidence of elevated levels of anti-varicella-zoster virus IgG [[17933]] Lowers serum IgM and IgG levels in MS patients, as shown in both cross-sectional and longitudinal analyses [[5076]] Reduces or eliminates oligoclonal IgG bands from cerebrospinal fluid, as shown by a prospective, two-year longitudinal study of 24 individuals with MS [[11825]] Reduces intrathecal IgG production, as shown by a prospective, two-year longitudinal study of 24 individuals with MS [[11825]] Induces the production of anti-natalizumab antibodies (which are associated with reduced drug efficacy) in a subset of patients soon after treatment onset (most commonly, within 1 month); in a study of 134 MS patients, 15.7% produced antibodies, with 8.2% persistently positive [[6409]] Can induce the production of anti-natalizumab antibodies (which reduce the drug's effectiveness); the risk of developing such antibodies is higher in individuals who smoke [[8861]] Increases total natural killer cells, as well as the subset of CD56(bright) (immature) natural killer cells, in peripheral blood of MS patients [[5263]] Reduces expression of natural killer cell receptor 1 in peripheral blood mononuclear cells; such expression is increased in individuals with MS relative to healthy controls [[13172]] Increases the absolute numbers of cells in all primary lymphocyte populations in the blood, especially natural killer cells and B cells, as shown by studies of individuals with RRMS before and after 1 year of treatment [[8855]] Increases the proportion of memory and presumed regulatory B cell subsets and CD3(-)CD56(dim) cytotoxic natural killer cells in the blood lymphocyte population, but decreases the proportion of CD3(-)CD56(bright) regulatory natural killer cells, as shown by studies of individuals with RRMS before and after 1 year of treatment [[8855]] Increases the responsiveness of T cells from individuals with RRMS to recall antigens and mitogens [[8855]] Results in a stable increase in lymphocytes (which is greater than the increase in overall white blood cells) in peripheral blood over long-term treatment in RRMS patients [[9177]] Results in a stable increase in lymphocytes in peripheral blood over long-term treatment in RRMS patients, such that the increase in B cells is greater than that of T cells or natural killer cells [[9177]] Does not significantly alter the CD4/CD8 ratio over long-term treatment in RRMS patients [[9177]] Reduces the peripheral blood population of CD49d+ (α4 integrin subunit+) T cells, and this reduction is greater for regulatory T cells versus Th1 or Th17 cell subsets, as shown in a study of 27 natalizumab-naïve and 8 natalizumab-treated individuals with MS [[28331]] Increases the expression of proinflammatory genes (TBX21, RORC, interferon γ, and interleukin 17A) and reduces the expression of FOXP3 in CD49d+ memory CD4 T cells, as shown in a study of sorted cells from natalizumab-naïve and natalizumab-treated individuals with MS [[28331]] Increases the proportion of Th17 cells in peripheral blood, and this proportion falls to baseline when natalizumab is withdrawn (and becomes nearly undetectable during relapses that occur during washout), as shown in a study of 57 individuals with MS [[28353]] Increases serum levels of endogenous secretory receptor for advanced glycation end-products (esRAGE); serum esRAGE levels are reduced during clinical relapse [[15134]] Does not affect the frequency of CD27+CD43+ B1 cells, which is reduced in RRMS [[10963]] Reduces the frequency of circulating plasmacytoid dendritic cells by 25 to 50%, but does not affect the frequency of myeloid dendritic cells, in individuals with MS, as shown by a cross-sectional observational study [[12689]] Reduces the frequency of circulating plasmacytoid dendritic cells (PDCs) in individuals with MS; the PDCs present exhibit a mature, activated phenotype as compared with those from untreated individuals, as shown by a cross-sectional observational study [[12689]] Does not appear to activate plasmacytoid dendritic cells in vitro [[12689]] May preferentially block activated plasmacytoid dendritic cell (PDC) migration (versus resting PDC migration) to lymphoid tissue, increasing the frequency of activated cells in circulation [[12689]] Associated with an increased proportion of CD19+ B cells in blood, but a decreased proportion in cerebrospinal fluid, in comparison to proportions in individuals with MS not treated with natalizumab [[15155]] Reduces the CD4/CD8 ratio in cerebrospinal fluid, and reduces IgG and IgM levels and the IgG index, as shown in longitudinal studies [[15155]] Reduces the intrathecally produced IgG fraction, as shown in longitudinal studies [[15155]] Increases the number of circulating hematopoietic stem and progenitor cells, and these cells are primarily quiescent, indicating that they had recently mobilized from the bone marrow [[17544]] Increases the number of circulating hematopoietic stem and progenitor cells in some individuals, and this phenomenon is associated with clinical remission as well as an increased frequency of B cells and regulatory T cells [[17544]] Increases the mean total white cell, lymphocyte, and eosinophil counts in peripheral blood by month 1, and these counts then remain at these higher levels, as shown in an 18-month longitudinal study of 44 individuals with RRMS [[20017]] Progressively increases monocyte counts in peripheral blood, as shown in an 18-month longitudinal study of 44 individuals with RRMS [[20017]] Induces the appearance of erythroblasts and neurotrophil precursors in peripheral blood by month 1 in some individuals, as shown in an 18-month longitudinal study of 44 individuals with RRMS [[20017]] Does not affect mean erythrocyte, hemoglobin, hematocrit, thrombocyte, or neutrophil levels in peripheral blood, as shown in an 18-month longitudinal study of 44 individuals with RRMS [[20017]] Increases the relative percentage of certain minor lymphocyte subpopulations in whole blood, including early effector memory CD4+cells, central memory CD8+ T cells, recent thymic emigrants, and transitional B cells, as shown in a study of 11 individuals with RRMS treated with natalizumab and 23 untreated individuals with RRMS [[26219]] Increases expression of surface integrin (CD49d and CD18) on CD14+CD16+ and CD14dimCD16+ peripheral monocyte subsets, as shown in a study of 11 individuals with RRMS followed for 1 year [[22346]] Decreases levels of neurofilament heavy and light chain (markers of axonal damage) in cerebrospinal fluid in RRMS patients, such that the effect is more pronounced for the light chain; in patients in remission, the effect was significant for the light but not heavy chain [[6424]] Associated with a decrease in levels of the glial marker YKL-40 in the cerebrospinal fluid (CSF) from individuals with MS; CSF YKL-40 levels are increased in MS relative to healthy controls [[10087]] Reduces levels of lipocalin-2, which is increased in progressive MS (and has been shown in inhibit remyelination in rat cultures), in the cerebrospinal fluid, as shown in a 60-week study of 17 individuals with this condition [[25649]] Associated with a reduction in serum levels of antibodies against neurofilament light protein, which are increased in individuals with RRMS and SPMS as compared with healthy controls [[9718]] Reduces levels of oxidative damage biomarkers in individuals with RRMS [[7556]] Associated with increased serum melatonin concentrations, increased antioxidants, and decreased oxidative stress biomarkers in individuals with RRMS [[10018]] Reduces concentrations of 24S-hydroxycholesterol in the cerebrospinal fluid, indicating reduced neurodegeneration, as shown in a 12-month study of 31 individuals with RRMS [[21317]] Reduces concentrations of 24S-hydroxycholesterol in the serum, and these serum concentrations correlate with scores on the Symbol Digit Modalities Test (a measure of cognition) before and after treatment, as shown in a 12-month study of 31 individuals with RRMS [[21317]] Reduces concentrations of 27-hydroxycholesterol in the cerebrospinal fluid, indicating improved blood-brain barrier integrity, as shown in a 12-month study of 31 individuals with RRMS [[21317]] Reduces plasma levels of osteopontin (a protein with roles in inflammation and immunity), which are increased in RRMS and SPMS [[7469]] Effectiveness is not increased in patients carrying the CCR5 delta32 deletion allele versus those who do not; this idea was tested because CCR5 (a chemokine receptor) might play a role in recruiting T cells to the central nervous system in MS [[6019]] In individuals switching from natalizumab to fingolimod, a low saturation (<30%) of natalizumab on the surface of CD8+ and CD4+ T cells before beginning fingolimod is associated with disease activity during a 6-month followup, whereas higher levels (66 to 70%) are associated with absence of disease, based on a pilot study of 5 individuals with MS [[7782]] Natalizumab antigen-binding fragment binds outside the ligand-binding groove for vascular cell adhesion molecule domain 1 on the α4 integrin subunit, as shown by X-ray crystallography [[7655]] Non-competitively inhibits binding of vascular cell adhesion molecule to the α4 integrin subunit, as shown by radioligand binding assays [[7655]] Upon binding to integrin, may drive the vascular cell adhesion molecule domain 2 into a non-preferred position, as shown by X-ray crystallography and binding assays [[7655]] During the first year of treatment, decreases the extent and severity of damage to white matter, as shown in a diffusion tensor imaging study of 22 individuals with RRMS [[27835]] Improves performance in walking-related parameters when individuals are asked to walk and perform a cognitive task at the same time, but does not improve such parameters when walking is the only task being performed, based on a study of 9 individuals with MS over 1 year [[9669]] Treatment results in sustained disability improvement in ~30% of individuals with MS, as well as a reduction in the MRI lesion burden; the improvement in disability is associated with shrinkage of the T1 lesion volume [[10821]] Associated with a relative reduction of 42.8%% in the risk of ≥1 relapses during 2 years of treatment and is more cost effective than interferon beta-1a (Avonex or Rebif), interferon beta-1b (Betaferon), or glatiramer acetate, according to a pharmacoeconomic analysis that used pre-existing data [[6325]] and costs of treatment in the Russian healthcare system [[12332]] Effectiveness (measured in terms of a lack of relapses and disease progression) correlates with a decrease in the titer of IgG antibodies against human herpes virus 6A/B, whereas an increase predicts relapse, as shown in a 2-year longitudinal study [[12927]] Early treatment is associated with an increase in the absolute concentration of N-acetylaspartate (a marker of neuronal integrity) and other brain metabolites in lesional white matter (where concentrations are reduced relative to normal white matter), potentially indicating increased axonal metabolism, as shown in a longitudinal study of individuals with RRMS [[17449]] Induces lymphocytosis, and people who exhibit lower-than-expected lymphocytosis may have a higher risk of relapse, indicating that such natalizumab-induced lymphocytosis may be useful as a biomarker of therapeutic efficacy, as shown in a study of 50 individuals with RRMS or progressive-relapsing MS who had been given ≥16 natalizumab infusions [[22483]] Appears to reduce the high risk of post-partum relapse when restarted soon after delivery (on average, 7.8 days later) in women who had stopped therapy during pregnancy, as shown in a retrospective analysis of 6 women with very active MS in whom disease activity disappeared in all but 1 of them after such early redosing [[14397]] Does not affect the response to immunization with either a recall antigen (tetanus toxoid) or a neoantigen (keyhold limpet hemocyanin) in a clinically relevant manner, on the basis of a study of 60 individuals with RRMS, 30 who were natalizumab-naïve and 30 who had received 6 months of natalizumab treatment [[10602]] Does not impair the function of CD4+ CD8+ T cells, which are present in the circulation at similar frequencies in individuals with and without MS; the cells are also present in the cerebrospinal fluid, but not in inflammed MS lesions [[10607]] Treatment can be associated with a transient reactivation of Epstein-Barr virus (EBV), but EBV-specific antibody levels do not appear to be useful as a biomarker for therapeutic natalizumab response, as shown in a 21-month study of 20 individuals with MS [[19767]] Does not affect the percentage of circulating 6-sulfo LacNAc(+) dendritic cells, proinflammatory cells that are present in demyelinated brain lesions and are often present in cerebrospinal fluid in individuals with MS [[14709]] Does not affect human melanoma cell proliferation in vitro, but does reduce migration and invasion of such cells in vitro [[14880]]	Blocks the firm adhesion (rather than the initial contact) of human T cells to the blood brain barrier in experimental autoimmune encephalomyelitis [[363]] Reduces leukocyte migration into the brain parenchyma in experimental autoimmune encephalomyelitis models [[592]] Antibodies against α4β1 integrin (i.e., not natalizumab per se) inhibit binding of lymphocytes and monocytes to inflammed experimental autoimmune encephalomyelitis brain vessels [[413]] Antibodies against α4β1 integrin (i.e., not natalizumab per se) prevent the development of experimental autoimmune encephalomyelitis [[413]] Reduces levels of lipocalin 2 in the cerebrospinal fluid (CSF) and astrocytes in a mouse experimental autoimmune encephalomyelitis model; lipocalin 2 expression is upregulated in CSF in this model and in MS patients [[2849]] Antibodies against α4 integrin (i.e., not natalizumab per se) suppress experimental autoimmune encephalomyelitis (EAE) in wild-type mice, whereas they do not suppress EAE in mice deficient for epithelial V-like antigen (which develop more severe EAE than wild-type mice), suggesting that EVA expression is needed for the best therapeutic response to these antibodies [[7557]] Antibodies against α4 integrin (i.e., not natalizumab per se) reduce the frequency of mature B lymphocytes (as well as T lymphocytes) in the central nervous system in wild-type mice with experimental autoimmune encephalomyelitis (EAE), but not in EAE mice deficient for epithelial V-like antigen [[7557]] Antibodies against α4 integrin reduce expression of chemokine SDF-1/CXCL12 and its receptor CXCR4 in an experimental autoimmune encephalomyelitis (EAE) model; both the chemokine and its receptor are upregulated in EAE [[9541]] Early treatment reduces the severity of a progressive form of experimental autoimmune encephalomyelitis in mice, whereas later treatment is less effective [[11414]] Early treatment reduces the accumulation of CD11b+CD4+ T cells producing granulocyte macrophage colony-stimulating factor in the central nervous system in a progressive experimental autoimmune encephalomyelitis mouse model [[11414]] Early treatment protects neurons against inflammation-driven neurodegeneration in a progressive experimental autoimmune encephalomyelitis mouse model [[11414]]
[+]	Ocrelizumab	IS	B cells [[432]] CD20 [[432]]	Humanized, recombinant, type 1 monoclonal IgG antibody [[441]] Molecular weight, 148 kDa [[653]]	Compared to rituximab (which also targets B cells and CD20), binds to a different (but overlapping) epitope of the large extracellular loop of CD20 [[432]] Depletes B cells via antibody-dependent cell-mediated toxicity (ADCC) and complement-dependent cytotoxicity (CDC) [[432]] Compared to rituximab, induces more ADCC and less CDC, which could reduce infusion-related toxicity [[421]] Depletes B cells in patients with rheumatoid arthritis, and B cell recovery after initial depletion is more rapid at lower doses [[450]]	Toxicology and rate of B cell recovery have been investigated in monkeys [[456]]
[+]	Ofatumumab	IS	B cells [[432]] CD20 [[432]]	Immunoglobulin G1 (IgG1) kappa human monoclonal antibody [[429]] Molecular weight, 149 kD [[429]] Generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line [[429]] Pharmacokinetic data have been obtained in chronic lymphocytic leukemia patients [[429]] [[646]]	Depletes B cells via antibody-dependent cell-mediated toxicity and complement-dependent cytotoxicity [[432]] Antibody is directed against the small 7-mer loop of CD20 and binds in close proximity to the plasma membrane [[432]] Binding target’s proximity to the cell membrane might explain why ofatumumab is more potent than rituximab and ocrelizumab at inducing complement [[432]] Causes greater cell-mediated toxicity than rituximab or ocrelizumab (other anti-CD20 antibodies), perhaps because of its stronger binding to complement protein C1q [[432]] Has a slower off-rate than rituximab, which also targets B cells and CD20 [[441]] Gradual B cell recovery is observed from week 20 [[432]]
[+]	ONO-4641	IM	Sphingosine 1-phosphate receptor [[626]] [[428]]	In cynomolgus monkeys, reduces lymphocyte counts to their lowest levels 4 to 8 hours after administration [[428]] Pharmacokinetic and pharmacodynamic responses in humans have been modeled using data from monkey studies and in vitro human metabolism data [[428]]	Similar to other sphingosine 1-phosphate receptor modulators, thought to reduce circulating levels of lymphocytes [[428]]	Reduces lymphocyte counts in cynomolgus monkeys [[428]] Daily dose of a ONO-4641 prototype molecule improved symptoms in a mouse model of colitis [[418]] Treatment with ONO-4641 prototype molecule reduced Th1 and Th17 cell numbers but did not affect number of regulatory T cells in the lamina propria, a key pathogenic site in colitis [[418]]
[+]	Ozanimod		Sphingosine-1-phosphate receptors S1P1R and S1P5R [[28138]]	Specific agonist for sphingosine-1-phosphate receptors S1P1R and S1P5R [[28138]] Displays better selectivity for the sphingosine-1-phosphate receptors S1P1R and S1P5R than fingolimod, according to a company presentation [[17324]] Displays better tissue penetration than fingolimod, according to a company presentation [[17324]] Cleared more rapidly than fingolimod, according to a company presentation [[17324]] Ozanimod and its two active metabolites have elimination half-lives of 19 to 22 hours [[11097]] Structure not released as of March 2011 [[587]]		Sphingosine-1-phosphate receptor 1 agonist (species not reported as of Nov 2011) [[3777]] Effectively treats rodent models of MS [[3777]] Reduces inflammation and measures of disease in three autoimmune disease models (experimental autoimmune encephalitis, 2,4,6-Trinitrobenzenesulfonic acid colitis, and CD4+ CD45RBhi T cell adoptive transfer colitis) [[28138]] Is tolerated well in animal toxicology studies that lasted as long as 9 months and involved doses that are estimated to include a safety margin relative to human exposures, according to a company press release [[7872]] Not associated with fibrotic changes in animal studies, according to a company press release [[7872]]
[+]	Phenytoin	NP	Sodium channels [[10458]] [[10459]]	Anticonvulsant [[10867]] Blocks sodium channels [[10458]] [[10459]] Phenobarbital analog [[10866]] Contains two phenyl groups linked to a hydantoin ring [[10866]] Molecular weight, 274.25 (sodium salt) [[10868]] After intravenous administration, half-life in plasma ranges from 10 to 15 hours [[10867]] After oral administration, half-life in plasma ranges from 7 to 42 hours, with an average of 22 hours [[10868]] Bioavailability of oral form (Dilantin capsules) is ~90% versus 100% for the intravenous form (IV Dilantin) [[10867]] During oral administration, steady-state therapeutic levels are reached at least 7 to 10 days after therapy begins [[10868]] Metabolized by CYP2C9 and CYP2C19 (cytochrome P450 enzymes) [[10867]] Inactive metabolites are ultimately excreted in the urine [[10868]]	Exhibits potent anticonvulsant properties in epilepsy [[10866]]	Reduces the loss of the dorsal corticospinal tract and dorsal column axons in mice with experimental allergic encephalomyelitis (EAE), when measured through day 28 of EAE [[10457]] Increases the weakened compound action potentials in the spinal cord in mice with experimental allergic encephalomyelitis (EAE), as measured between days 24 and 30 of EAE [[10457]] Improves clinical scores in mice with experimental allergic encephalomyelitis (EAE), when measured through day 28 of EAE [[10457]] Protects spinal cord corticospinal tract and dorsal column axons long term (≤180 days) in two experimental autoimmune encephalomyelitis mouse models [[10462]] Reduces infiltration of inflammatory cells into the dorsal columns in experimental autoimmune encephalomyelitis mice [[10462]] Strengthens the attenuated compound action potentials in the dorsal column and improves clinical status long term (≤180 days) in an experimental autoimmune encephalomyelitis mouse model [[10462]] Reduces the inflammatory cell infiltrate in experimental autoimmune encephalomyelitis (EAE), contributing to the idea that sodium channels are involved in microglia and macrophage activation in EAE lesions [[10461]] Improves the clinical course of murine experimental autoimmune encephalomyelitis, but withdrawal of the drug causes disease exacerbation, increased inflammatory infiltrate in the central nervous system, and an increased risk of death [[10463]] Continuous treatment protects central axons and enhances the conduction of action potentials in experimental autoimmune encephalomyelitis (EAE) mice for ≥180 days after induction of EAE, but withdrawal of the drug leads to worsening of EAE [[10875]] Abrupt withdrawal from experimental autoimmune encephalomyelitis mice results in a large infiltration of inflammatory cells and increased mortality, whereas tapered withdrawal does not (although clinical scores worsen to near non-treated levels) [[10415]] Protects against axonia-induced injury in central nervous system white matter at concentrations lower than that needed to block sodium channels, as shown by experiments involving a rat optic nerve preparation [[10460]] Reduces late sodium channel openings (which are associated with the persistent sodium current), primarily by reducing the number of channel openings, as shown in a study involving cultured rat hippocampal neurons [[10458]] Inhibits the non-inactivating, persistent sodium current, as shown by experiments on neurons isolated from the rat neocortex and neostriatum [[10459]]
[+]	Raltegravir		Retroviral integrase [[9219]] Herpesvirus DNA packaging terminase [[9220]]	Inhibits the DNA strand transfer activity of integrase purified from HIV-1 [[9219]] Blocks HIV replication [[9219]] Displays >1000-fold selectivity for integrase from HIV-1 versus other phosphoryltransferases, such as human polymerases alpha, beta, and gamma [[9219]] Inactivates the nuclease domain of herpesvirus DNA packaging terminase, which displays an RNase H/integrase-like fold [[9220]] Is metabolized by uridine glucuronosyl transferase [[9204]] Because the glucuronidation elimination pathway is low affinity and high capacity, undergoes limited drug interactions [[9202]] Is rapidly eliminated through both urine and feces [[9204]] Elimination half-life is ~9 hours [[9202]] Appears potent and safe at doses ranging from 100 to 600 mg twice daily, on the basis of a 10-day trial [[9198]] MW of raltegravir potassium, 482.51 [[9203]]	Prevents the integration of HIV cDNA into cellular DNA in vitro [[9219]] Reduces viral load in HIV-infected individuals [[9200]] [[9201]] Is being tested in MS because of the hypothesis that viruses, such as herpes viruses (especially Epstein-Barr virus) [[9222]] and human endogenous retroviruses [[1183]] [[9221]], are involved with MS pathogenesis [[8957]]
[+]	Riluzole	NP	Glutamatergic neurotransmission [[13362]] [[13306]] Glutamate uptake and release [[13363]] [[13371]] [[13372]] [[13373]] Voltage-gated sodium channels [[13365]] [[13367]] [[13375]]	Molecular weight, 234.2 [[12916]] Is a benzothiazole [[13304]] Absorbed rapidly after oral administration [[13305]] Crosses the blood-brain barrier easily [[13306]] Metabalized via direct glucuronidation or oxidation followed by glucuronidation in the liver [[13305]] Metabolites are excreted primarily in the urine within 24 hours [[13305]] Clinical pharmacokinetics have been determined [[13305]] After oral administration of 50 mg, time of maximum concentration is 1.4 hours and half-life is 14.03 hours [[13305]]	Exact mechanism is unknown [[13305]] Potential therapeutic role in MS is based on the hypothesis that altered glutamate homeostasis might lead to excitotoxic neuronal injury in MS, and that inhibition of glutamate function might be beneficial [[13300]] Appears to decrease hypointense T1 lesion development and the rate of cervical cord atrophy in PPMS, as assessed by MRI, as shown in a run-in versus treatment pilot study [[13299]] [[13300]] Prolongs survival in amyotrophic lateral sclerosis by about three months, on average, as shown in two placebo-controlled trials [[13301]] Blocks voltage-gated sodium current in human skeletal muscle cells [[13375]] Increases calcium-activated potassium current in human skeletal muscle cells [[13375]]	Exact mechanism is unknown [[13305]] Strongly reduces the severity of experimental autoimmune encephalomyelitis in mice when administered either before or after clinical symptoms appear [[903]] Decreases focal inflammation, demyelination, and axonal disruption in the central nervous system in experimental autoimmune encephalomyelitis [[903]] Does not affect proliferative responses of T cells to myelin oligodendrocyte glycoprotein (MOG) in MOG-induced experimental autoimmune encephalomyelitis [[903]] Displays neuroprotective effects, including reduction in the size of central nervous system lesions and restoration of motor and cognitive function, in models of traumatic brain and spinal cord injury [[13368]] Appears to act as an antagonist of excitatory amino acid neurotransmitters such as glutamate [[13362]] [[13306]] Inhibits convulsions induced by (i) electroshock and (ii) compounds that inhibit synthesis of gamma-aminobutyric acid (an inhibitory neurotransmitter) in rodents [[13362]] Inhibits seizures caused by L-glutamate in rodents [[13362]] Does not affect seizures evoked by the drug pentetrazole in mice when administered alone, but does enhance the anti-seizure effect of standard antiepileptic drugs [[13379]] Antagonizes the increase in cyclic guanosine monophosphate in the cerebellum induced by excitatory amino acids (for example, glutamate) in rats [[13306]] Antagonizes the release of acetylcholine in the olfactory tubercles and striatum induced by excitatory amino acids in rats [[13306]] Inhibits the spontaneous release of glutamate (but not aspartate or other amino acids) when applied to the caudate nucleus in cats [[13363]] Increases the high-affinity uptake of glutamate by synaptosomes from rat spinal cord [[13371]] Increases the update of glutamate by cultured rat astrocytes, particularly at lower (10 microM) concentrations [[13372]] Stimulates the uptake of glutamate by cultured rat astroglial cells in a manner dependent on protein kinase C activity [[13373]] Increases expression of excitatory amino-acid transporter 1 (a glutamate transporter) in cultured rat astroglial cells [[13373]] Decreases the load of reactive oxygen species, but does not affect levels of glutathione, in cultured rat astroglial cells [[13373]] Prevents neuronal damage in the hippocampus and memory deficits in a gerbil model of ischemia [[13364]] Blocks inactivated sodium channels with high specificity, as shown by studies of myelinated nerve fibers isolated from frog [[13365]] Affects voltage-activated sodium and potassium currents, as shown by studies of primary cultures of rat cortical neurons [[13366]] Inhibits gating of voltage-sensitive sodium channels and reduces catecholamine secretion, as shown by studies of primay cultured bovine adrenal chromaffin cells [[13367]] Selectively depresses glutamate excitatory postsynaptic currents via inhibition of voltage-gated sodium channels, as shown by experiments involving solitary cultured rat hippocampal neurons [[13378]] At concentrations higher than those required for presynaptic effects on action potential-driven glutamate release, has postsynaptic effects, potentiating gamma-aminobutyric acid (GABA) receptor function, as shown by experiments involving (i) cultured rat hippocampal neurons and (ii) the expression of rat GABA receptors in Xenopus oocytes [[13377]] Inhibits the activity of protein kinase C, an enzyme that mediates oxidative stress, in cultured mouse cortical cells [[13369]] Inhibits protein kinase C directly, as shown by studies of purified enzyme from rat brain [[13369]] Inhibits the activity of excitatory amino acid transporter type 3 (EAAT3, a neuronal glutamate transporter) via inhibition of protein kinase C, as shown by experiments involving expression of rat EAAT3 in Xenopus oocytes [[13370]] Completely blocks the persistent sodium current, and partially blocks the persistent calcium current, in motoneurons from the neonatal rat brainstem [[13374]] Decreases glutamatergic neurotransmission in motoneurons from the neonatal rat brainstem, probably by inhibiting protein kinase C and its effects on presynaptic N-methyl-D-aspartic acid receptors [[13374]] Inhibits spontaneous calcium oscillations and signaling via potassium channel activation and sodium channel inhibition in rodent neuroendocrine cells [[13376]] Inhibits electrophysiological effects mediated by rat ionotropic glutamate receptors (expressed in Xenopus oocytes) in what appears to be a direct but noncompetitive manner [[13430]] Reduces neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (which destroys dopaminergic neurons and causes symptoms of Parkinson's disease) in mice [[13380]]
[+]	Rituximab	IS	B cells [[481]] CD20 [[481]]	Genetically engineered chimeric murine/human monoclonal antibody that binds to CD20, a B cell antigen [[346]] [[395]] Contains murine anti-CD20 antibody complementarity-determining regions and human kappa and IgG1 heavy-chain constant regions [[388]] Molecular weight: 145 kD [[388]] Produced in Chinese hamster ovarian cells [[388]] Binding affinity for CD20 is ~8 nM [[388]] Mean half-life in serum in patients with B cell lymphoma receiving intravenous infusion is 59.8 hours, although range is wide [[388]] Half life is 20 days in patients with rheumatoid arthritis (after receiving second dose) [[388]] Serum levels generally increase as doses are repeated and levels of CD20 decrease [[395]]	Complete mechanism unknown [[351]] Targets the antigen CD20, which is expressed on pre-B cells and mature B cells [[346]] [[373]], as well as on a small subset of T cells [[11673]] Rapidly eliminates mature circulating B cells for up to 6 to 9 months [[481]] [[482]] [[388]] Decreases or eliminates B cells in the cerebrospinal fluid of MS patients [[351]] Affects chemokine levels in the cerebrospinal fluid of MS patients, such that levels of CXCL13 and CCL19 are reduced [[351]] Reduces T cell levels in the cerebrospinal fluid of many MS patients, possibly because B cells (depleted by drug) influence T cell trafficking into the central nervous system by affecting chemokine production [[351]] Depletes CD3+ CD20(dim) T cells (a subset of cells that is increased in MS) from individuals with MS [[11673]] Initial treatment transiently reduces CD4+ and CD8+ T cells in individuals with MS or neuromyelitis optica, but subsequent treatments do not [[18405]] When given during the remission stage of neuromyelitis optica, eliminates B cells; B cell repopulation then results in a greater number of circulating CD19+ CD24(high) CD38(high) regulatory B cells as compared with CD19+ CD27+ memory B cells, as shown in a study of 9 individuals [[20089]] May induce cell death through apoptotic pathways involving caspase-3 activation, as shown by studies of chronic lymphocytic leukemia patients [[395]] Can cause complement activation, resulting in cell lysis (complement-dependent cytotoxicity), but the strength of the effect varies depending on the B-cell lymphoma cell line studied and does not correlate with clinical responses to the drug [[395]] May act through antibody-dependent cellular cytotoxicity (in which cells are killed by effector cells that have been activated by the Fc portion of rituximab bound to the lymphoma cell) [[395]] Binding to CD20 induces intracellular signaling pathways, and if crosslinked, the degree of signaling increases, as shown with studies of malignant B cells [[395]] Binding to CD20 induces intracellular signaling, and the result of such signaling (such as apoptosis or cell cycle arrest) appears to depend on the cell line studied [[395]] Appears to reduce axonal damage (as determined by measuring levels of the axonal damage biomarker neurofilament light protein in cerebrospinal fluid) in progressive MS (after 12 to 24 months of treatment) [[6160]] Only partially depletes B cells from the cerebrospinal fluid, as shown in a study of 4 individuals with PPMS [[17015]] Single course of treatment results in clonal expansion of IgG memory B cells (implying that specific IgG memory B cells were not eliminated), as shown in three individuals with inflammatory central nervous system demyelination [[25151]] Intrathecal treatment depletes B cells in the central nervous system, which leads to a strong reduction in the increased levels of tumor necrosis factor-alpha (which can cause excitotoxic damage) and neurofilament light protein (a marker of axonal damage) in the cerebrospinal fluid, based on analysis of an individual with progressive MS [[6928]] Repeated intrathecal doses (to target compartmentalized inflammation) reduced (i) peripheral CDC20+ B cells, (ii) several central proinflammatory cytokines, and (iii) neurodegeration markers, but did not affect oligoclonal bands, in an individual with severe progressive MS [[13536]] Intrathecal administration decreases levels of B-cell activating factor (BAFF) in the cerebrospinal fluid and increases levels of BAFF in the serum [[29036]] Intrathecal administration dramatically reduces CD20+ and CD19+ B cells in the blood but not detectably in the cerebrospinal fluid (CSF); this latter finding is presumably because counts in the CSF were too low to allow measurement of changes in this study [[29036]] Intrathecal administration increases levels of kappa free light chain in the cerebrospinal fluid [[29036]] Strongly reduces the risk of SPMS disease progression and the risk of relapse in RRMS and PPMS/SPMS in open-label studies (reports at the European Committee for Treatment and Research in Multiple Sclerosis meeting, October 2015) [[24960]] Generally appeared safe and effective in a study involving 3 pediatric patients (2 with RRMS and 1 with SPMS) [[10782]] Appeared to be effective, safe, and well-tolerated in a retrospective study of 14 individuals with pediatric onset MS [[24167]] Effectively used to control fulminant MS, which developed after natalizumab cessation, in an individual who responded well to plasmapheresis but not corticosteroids in the acute phase [[19564]] Does not reduce the frequency of autoreactive and polyreactive B cells, as shown in a study of 4 individuals with type 1 diabetes, with samples examined before and 52 weeks after treatment [[24491]] Does not appear to reset early B cell tolerance checkpoints that are abnormal in autoimmune conditions; in a study of 4 individuals with type 1 diabetes, 52 weeks after B cell depletion, the frequencies of autoreactive B cells remained elevated, and their limited proliferative history indicated that these cells were newly-generated rather than self-reactive B cells that had avoided depletion [[24491]]
[+]	RTL1000	IM NP	T cell receptors [[427]] T cell proliferation [[430]] Cytokine secretion [[430]]	Human recombinant T cell receptor ligand [[427]] Consists of the beta1 and alpha1 domains of HLA DR2 (HLA DRB1*1501) linked covalently to the myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide [[427]] Half-life in human plasma, <5 minutes [[427]] Design and engineering properties have been described [[447]] Binding interactions between RTL1000 and CD47 [the primary receptor for the cytokine macrophage migration inhibitory factor (MIF), which is involved in autoimmune diseases] have been modeled using a docking program in silico; RTL1000 and CD47 binding appears to involve the same two 5-residue regions as MIF and CD47 binding [[26449]]	Exact mechanism is unknown [[427]] [[625]] Causes a transient increase in dose-dependent cytokines similar to that seen in HLA-DR2 transgenic mice with experimental autoimmune encephalomyelitis treated with RTL1000 [[427]] May exert immune effects by binding to an unknown receptor on blood platelets, possibly CD40 [[463]]	Various other human recombinant T cell receptors tested can prevent or treat experimental autoimmune encephalomyelitis in numerous mouse and rat models [[427]] Binds preferentially to antigen presenting cells such as B cells, macrophages, and dendritic cells, but not to T cells, in mice with experimental autoimmune encephalomyelitis [[426]] Treatment with various human recombinant T cell receptors related to RTL1000 induces interleukin 10 production by T cells [[625]] Treatment with different human recombinant T cell receptors related to RTL1000 promotes remyelination and axonal repair in mice with experimental autoimmune encephalomyelitis [[427]] [[625]] Several human recombinant T cell receptors related to RTL1000 downregulate interleukin 17 and tumor necrosis factor alpha secretion in mice with experimental autoimmune encephalomyelitis [[625]] [[430]] Human recombinant T cell receptors related to RTL1000 can suppress T cells in addition to cognate T cells to which they are targeted [[430]] Human recombinant T cell receptors related to RTL1000 treatment decrease infiltration of encephalitogenic cells into the central nervous system and increase the numbers of those already present [[625]] Human recombinant T cell receptors related to RTL1000 downregulate chemokines and chemokine receptors in experimental autoimmune encephalomyelitis mice [[625]] Predicted to function via a two pronged mechanism, involving (i) binding to T cell receptors on pathogenic (autoreactive) T cells in an antigen-specific manner and reducing CXCL1/2 production and thereby inflammatory damage and (ii) binding to astrocytes or other parenchymal cells in an antigen peptide-independent manner, reducing CXCL1/2 production and oligodendrocyte repopulation and thereby remyelination [[427]]
[+]	Secukinumab	IS	Interleukin 17A, a proinflammatory cytokine that is produced by T helper 17 cells and that is associated with autoimmune diseases [[8226]] [[8227]] [[8242]]	Recombinant, fully human G1κ (IgG1κ) monoclonal antibody that binds and neutralizes the proinflammatory cytokine interleukin 17A [[8225]] [[8226]] [[8242]] [[8228]] Half life is expected to be 3 to 4 weeks [[8225]] Molecular weight, 147.94 kDa [[8241]]	Has broad anti-inflammatory effects in individuals with psoriasis [[8225]] Reduces the expression of genes encoding a variety of cytokines and chemokines associated with autoimmunity in psoriasis plaque samples [[8225]] Reduces the expression of genes encoding interleukin 17A (IL-17A) and IL-22, as shown by reverse transcription PCR and microarray analysis, in psoriasis plaque samples [[8225]] Reduces the expression of genes encoding cytokines that act upstream of interleukin 17A (IL-17A), such as IL-12B, or downstream of IL-17A, such as chemokine (C-C motif) ligand 20, as shown by reverse transcription PCR and microarray analysis, in psoriasis plaque samples [[8225]] Reduces the increase in the pro-inflammatory cytokine interleukin 6 (IL6) that is induced by IL17A and IL17A/tumor necrosis factor-alpha in human astrocytes [[10322]] Reduces the increase in the nuclear translocation of the transcription factor NF-κB that is induced by IL17A and IL17A/tumor necrosis factor-alpha in human astrocytes [[10322]] Reduces the number of T cells in psoriatic skin lesions [[8225]]	Monoclonal antibody that neutralizes interleukin 17 (not secukinumab per se) ameliorates the course of murine experimental autoimmune encephalomyelitis [[8229]] Human-anti-human interleukin 17A antibody delays progression of neurological disease in some cases in a marmoset experimental autoimmune encephalomyelitis model, but not in a statistically significant manner [[8230]]
[+]	Simvastatin	IM	3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (part of the mevalonate pathway, which functions in cholesterol and isoprenoid synthesis, which in turn plays a role in protein isoprenylation) [[11156]] Protein prenylation [[11155]] Expression of a variety of immunoregulatory molecules, including major histocompatibility class II and class I molecules [[11156]] [[11157]]	Derived synthetically from a fermentation product from Aspergillus [[11293]] Contains a 3-hydroxy-3-methylglutaryl (HMG)-like moiety covalently linked to a rigid, hydrophobic group [[11291]] Molecular weight, 418.57 [[11288]] Hydrophobic [[11288]] An inactive lactone that is hydrolyzed to the active, beta-hydroxyacid form after ingestion [[11288]] Plasma concentrations of simvastatin and metabolites peak at 4 hours after ingestion and then fall quickly, reaching 10% of peak values within 12 hours in humans [[11288]] Crosses the blood-brain barrier, based on studies in rats [[11288]] Excreted in urine (13%) and feces (60%) after ingestion [[11288]]	Inhibits human 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase (an enzyme that catalyzes the committed step in the biosynthesis of cholesterol) by blocking access of the normal substrate, HMG-CoA, to the active site in the enzyme [[11291]] Reduces blood levels of low-density lipoprotein cholesterol, triglycerides, and apoliprotein B and increases levels of high-density lipoprotein cholesterol [[11290]] [[11293]] Similar to interferon beta-1b, inhibits proliferation of stimulated peripheral blood mononuclear cells in vitro; the effects of simvastatin and interferon beta-1b are additive [[11153]] Decreases interferon-gamma-induced expression of major histocompatibility complex class II DR molecules on monocytes and thereby reduces their antigen presenting ability [[11221]] Reduces interferon-gamma-induced expression of major histocompatibility complex (MHC) class II, but not MHC class I, at the mRNA and protein level in primary human endothelial cells [[11154]] Reduces levels of the transcriptional coactivator CIITA (class II, major histocompatibility complex, transactivator) at the mRNA level, and reduces activity of the CIITA promoter IV (which is normally activated after interferon-gamma stimulation), in primary human endothelial cells [[11154]] Inhibits interferon-gamma-induced activation of the class II transactivator CIITA promoter IV as well as CIITA transcription, and as a result inhibits human leukocyte antigen-DR (corresponding to major histocompatibility class II) induction by interferon-gamma, in human microvascular endothelial cells; the inhibitory effect involves interference with protein prenylation [[11155]] Reduces constitutive and interferon-gamma-induced cell-surface expression of major histocompatibility complex class I on HeLa cells [[11157]] Reduces the cell-surface expression of major histocompatibility complex class II molecules by disrupting microdomains that contain cholesterol (which are involved in the transport of these molecules to the cell surface), on the basis of experiments in HeLa cells [[11157]] Decreases the cell-surface expression of a variety of immunoregulatory molecules, including CD3, CD4, and CD8 (T cell coreceptors); CD19 (B cell coreceptor); CD28, CD40, CD80, and CD86 (costimulatory molecules); CD11b and CD11c (integrins); CD14 (lipopolysaccharide receptor); CD83 (dendritic cell marker); and CD54 (adhesion molecule) in peripheral blood mononuclear cells [[11157]] Reduces cell-surface expression of CCR5 and CXCR3 (chemokine receptors), as well as cell motility induced by chemokines, in microglial cells [[11158]] Alters the distribution of the actin cytoskeleton in microglial cells [[11158]] Inhibits the maturation (and antigen-presenting function) of monocyte-derived dendritic cells, an effect that is reversed by mevalonate [[11159]] Inhibits the maturation of dendritic cells derived from peripheral blood mononuclear cells from individuals with optic neuritis in in vitro assays [[11267]] Inhibits the T cell proliferation caused by monocyte-derived dendritic cells (DCs) from individuals with optic neuritis (but not by DCs from healthy controls, which have relatively less immunopotency) in in vitro assays [[11267]] Inhibits the expression of adhesion molecules (CD54 and CD18/CD11a) in peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVECs) that is induced by tumor necrosis factor-alpha, as well as binding of PBMCs to HUVECs; such inhibition of leukocyte-endothelial cell interactions may contribute to the anti-inflammatory properties of this drug [[11160]] Inhibits the expression of the transcription factor T-bet, which regulates differentiation of Th1 cells, and inhibits activation of T lymphocytes and their expression of Th1 markers [[11221]] Inhibits the secretion of interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 by T lymphocytes [[11221]] Reduces cell adhesion, such that pretreatment of monocytes reduces their adhesion to human umbilical vein endothelial cells (HUVECs), but pretreatment of HUVECs does not reduce monocyte adhesion [[11187]] Reduces expression of the proinflammatory cytokines interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 at the mRNA level in peripheral blood mononuclear cells and cultured human umbilical vein endothelial cells [[11188]] Increases suppressor of cytokine secretion 3 (SOCS3) AND SOCS7 mRNA in stimulated monocytes from individuals with RRMS [[11225]] Decreases levels of interleukin-23 mRNA in stimulated monocytes from individuals with RRMS [[11225]] Decreases secretion of interleukin-6 from stimulated monocytes from individuals with RRMS or healthy controls [[11225]] Increases secretion of interferon-gamma, interleukin-4 (IL-4), and IL-27 by stimulated monocytes from individuals with RRMS [[11225]] Decreases levels of retinoic acid-related orphan nuclear hormone receptor C [RORC, an interleukin-17 (IL-17) transcription factor)] and IL-17A mRNA in activated CD4+ T cells from individuals with RRMS or healthy controls, an effect that is reversed by mevalonic acid (indicating that the effect is mediated by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A) [[11225]] Decreases secretion of interleukin-17A from activated CD4+ T cells from individuals with RRMS or healthy controls [[11225]] Inhibits the in vitro differentiation of Th17 cells from CD4+ T cells from individuals with RRMS, an effect mediated by suppression of transcription factor interferon regulatory factor 4 expression [[11287]] Inhibits secretion of interleukin-17A (IL-17A), IL-17F, IL-21, and IL-22 in experiments involving CD4+ T cells, differentiated in vitro, from individuals with RRMS [[11287]] Reduces secretion of interleukin-1beta (IL-1beta), IL-23, transforming growth factor-beta, IL-21, IL-12p70, and increases secretion of IL-27, from dendritic cells from individuals with RRMS; such changes would inhibit Th17 and Th1 cell differentiation [[3637]] Causes a loss of dendritic processes from dendritic cells from individuals with RRMS [[3637]] Reduces permeability across human blood-brain barrier-derived endothelial cells (via inhibition of isoprenylation but not via an effect on the expression of tight junction molecules) [[11218]] Reduces the migration of monocytes and lymphocytes (derived from individuals with CIS or MS) across human blood-brain barrier (BBB) in vitro by reducing secretion of certain chemokines (monocyte chemotactic protein-1/CCL2 and interferon-gamma-inducible protein-10/CXCL10) by the BBB endothelial cells [[11218]] Enhances the proteolytic activity of matrix metalloproteinases MMP-2 and MMP-9 released from peripheral blood mononuclear cells [[11216]] Enhances secretion of the neurotrophic factor leukemia inhibitory factor (LIF) from CD4+ T cells from individuals with RRMS; LIF production is reduced in CD4+ T cells from such individuals as compared with healthy controls [[11219]] Short-term treatment (1 day) increases process extension and cell differentiation, and decreases migration, of fetal oligodendrocyte progenitor cells (effects that can be reversed by isoprenoid products), whereas longer treatment leads to process retraction (2 days) and cell death (4 days) [[11222]] Initial treatment (2 days) increases process extension of mature oligodendrocytes, whereas longer treatment leads to process retraction (6 days) and cell death (8 days) [[11222]] Induces adult human glial progenitor cells to differentiate to an oligodendrocyte phenotype, an effect that can be blocked by an antagonist of peroxisome proliferator-activated receptor gamma [[11224]] Induces the nuclear co-receptor peroxisome proliferator-activated receptor gamma (which is regulated by sterols), concomitant with the induction of an oligodendrocyte phenotype, in adult human glial progenitor cells [[11224]] Increases the stability of erythrocyte membranes in individuals with MS, which are less stable than those from healthy controls [[11286]]	Improves clinical outcomes in a mouse experimental autoimmune encephalomyelitis model [[23704]] Increases expression of transforming growth factor-beta mRNA in a mouse experimental autoimmune encephalomyelitis model [[23704]] Reduces secretion of interleukin-6 (IL-6), IL-12p40, IL-12p70, the chemotactic cytokine RANTES, and the macrophage inflammatory protein MIP-1β in a mouse experimental autoimmune encephalomyelitis model [[23704]] Inhibites infiltration of inflammatory mononuclear cells into the central nervous system in a mouse experimental autoimmune encephalomyelitis model [[23704]] Reduces the frequency of pathogenic Th1 and Th17 cells in the central nervous system in a mouse experimental autoimmune encephalomyelitis model [[23704]] Inhibits interferon-gamma-induced major histocompatibility complex class II expression in cultured rat astrocytes (expression that would have allowed these cells to adopt an antigen presenting phenotype), an effect that is reversed by the 3-hydroxy-3-methylglutaryl coenzyme A product mevalonate [[11220]] Promotes Th2 development and reduces Th1 development in vitro, as shown by experiments involving CD4+ T cells isolated from mice that had been primed in vitro [[11189]] Reduces the abundance of cytokine-inducible nitric oxide synthase at the mRNA and protein level in rat cardiac embryonic myoblasts, an effect that is reversible by the addition of L-mevalonate (the hydroxymethylglutaryl coenzyme A product) [[11215]] Decreases Rho GTPase activity in cytokine-treated rat cardiac embryonic myoblasts [[11215]] Inactivates NF-kappaB (a transcription factor that functions in inducible nitric oxide synthase expression) via increased IkappaB (the NF-kappaB inhibitor) and decreased NF-kappaB in the nucleus in cytokine-treated rat cardiac embryonic myoblasts [[11215]] Reduces expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 at the mRNA and protein level by activated murine bone marrow-derived mast cells [[11223]] Does not increase the production of the RNA-binding protein tristetraprolin, which promotes tumor necrosis factor-alpha decay, by activated murine bone marrow-derived mast cells [[11223]] Perturbs process outgrowth in cultured neonatal rat oligodendrocytes and cells in an oligodendrocyte-derived cell line; such outgrowth [the step that occurs before (re)myelination] requires both cholesterol synthesis and protein isoprenylation [[11268]] Does not prevent degeneration of retinal ganglion cells in a rodent model of autoimmune optic neuritis [[11217]] Does not display neuroprotective effects in a rat model of cervical spinal cord injury [[11269]]
[+]	Siponimod	IM	Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P5 [[7168]] B cell distrubution [[7168]] T cell distribution [[7168]]	Derivative of fingolimod [[7168]] Half-maximal effective concentration values for sphingosine 1-phosphate receptor subtypes S1P1 and S1P5 are in the sub-nanomolar range (0.39 nM and 0.98 nM, respectively) [[7168]] Steady-state concentrations are reached after 6 days of once-daily administration in healthy individuals [[7168]] Effective elimination half-life is 22 to 38 hours in healthy individuals [[7168]] Complete wash-out after treatment is discontinued is predicted to take about 6.3 days [[7168]] Potency against the sphingosine-1-phosphate (S1P) receptor subtype S1P1, selectivity against other S1P receptors, and species cross-reactivity have been compared for multiple S1P1 receptor agonists (including fingolimod, siponimod, and CS-0777) [[7461]] Multiple sphingosine-1-phosphate (S1P) receptor subtype S1P1 agonists (including fingolimod, siponimod, and CS-0777) all signal identically through the S1P1 receptor, causing receptor degradation [[7461]]	Predicted to prevent lymphocyte egress from the lymph nodes and thymus, a process that requires sphingosine 1-phosphate (S1P) subtype 1 receptors, by causing the internalization of these receptors so that they cannot respond to S1P [[7168]] Selective agonist for sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P5 [[7168]] Selectivity for sphingosine 1-phosphate (S1P) receptor subtype S1P1 is more than 1000-fold greater than for receptor subtypes S1P2, S1P3, and S1P4 [[7168]] Promotes internalization of sphingosine 1-phosphate (S1P1) receptors to a greater extent than S1P itself, as shown in experiments in which human S1P1 receptors were expressed in Chinese hamster ovary cells [[7168]] Promotes internalization of sphingosine 1-phosphate (S1P1) receptors, which largely remain internal up to 12 hours after the compound is removed, whereas receptors that are internalized by S1P treatment return to the cell surface within 3 hours, as shown in experiments in which human S1P1 receptors were expressed in Chinese hamster ovary cells [[7168]] Reduces the peripheral absolute lymphocyte count in a dose-dependent, reversible manner in healthy individuals [[7168]] Strongly reduces peripheral levels of both B and T cells, with CD4+ T cells affected more than CD8+ T cells, but does not affect monocyte levels, in healthy individuals [[7168]] Reduces peripheral levels of naïve and central memory (CCR7+) CD4+ T cells more than peripheral effector memory (CCR7-) CD4+ T cells in healthy individuals [[7168]] Activates G-protein-coupled inwardly rectifying potassium channels in human atrial myocytes (indicating the potential for reducing heart rate transiently); the effect is about 8 times less potent than that of S1P itself [[7168]] Causes a transient reduction in heart rate after the first dose [[7168]] Activates pERK, pAKT, and Ca2+ signaling in human astrocytes [[26540]] Does not reduce levels of interleukin 6 (IL-6) produced by human astrocyte cultures treated with tumor necrosis factor alpha and IL-17 [[26540]] Fingolimod directly inhibits the human ether-a-go-go-related gene (hERG) current, whereas siponimod does not, in a model in which hERG channels are expressed in human embryonic kidney 293 cells [[13837]]	Suppresses previously established neurological deficits in a Dark Agouti rat model of chronic experimental autoimmune encephalomyelitis [[7168]] Increases levels of myelin basic protein, promoting remyelination, after a transient treatment that causes demyelination in cultures prepared from fetal rat telencephalon [[7169]] Activates pERK and pAKT signaling and causes internalization of the sphingosine-1 phosphate receptor 1 in mouse astrocytes [[26540]] Moderately reduces levels of interleukin 6 produced by mouse astrocyte or microglia cultures treated with lipopolysaccharide [[26540]] Reduces demyelination induced by lysophosphatidylcholine or the Krabbe disease metabolite psychosine in mouse cerebellar slice cultures [[26540]] Causes acute bradycardia in anesthetized rats, as shown in an experiment involving acute intravenous drug infusion [[7170]] Unlike fingolimod, does not affect blood pressure in rats [[7170]] Reduces levels of circulating monocytes and lymphocytes over a similar time course, as shown by experiments in rats and mice [[7177]] Reduces levels of circulating monocytes and increases the total number of monocytes in bone marrow and spleen in rats and mice [[7177]] Both fingolimod and siponimod induce atrioventricular conduction block at high dose, whereas fingolimod but not siponimod prolongs the QT interval at high dose and siponimod but not fingolimod prolongs the PR interval at low dose, in a guinea-pig model [[13837]]
[+]	Teriflunomide	IS IM	Dihydroortate dehydrogenase [[411]] [[410]] Pyrimidine synthesis [[410]] Lymphocyte proliferation [[401]]	Active metabolite of the prodrug leflunomide (approved for treating rheumatoid arthritis), which is rapidly converted to active form in the gut and plasma [[401]] Reversible noncompetitive inhibitor of dihydroorotate dehydrogenase [[341]] Mean half-life in plasma is 15 to 18 days [[341]] Blood plasma levels are relatively quickly and strongly reduced (such that 97% of teriflunomide is eliminated within 19 days) by the oral cholesterol-lowering drug colestipol hydrochloride (meeting report, October 2015) [[22308]] >99% is bound to albumin [[341]]	Inhibits the mitochondrial enzyme dihydroortate dehydrogenase (which functions in pyrimidine synthesis) in human cells [[411]] Leflunomide (the prodrug from which the active metabolite teriflunomide is derived) inhibits de novo pyrimidine synthesis and proliferation of peripheral blood mononuclear cells and mitogen-stimulated T lymphocytes [[410]] [[407]] Through inhibition of de novo pyrimidine synthesis, hinders proliferation of lymphcytes, which require de novo pyrimidine synthesis as well as salvage pathways for meeting pyrimidine needs for DNA synthesis during cell division [[401]] Causes cell cycle arrest in late G1 phase in stimulated human peripheral T lymphocytes [[401]] Inhibits proliferation of T and B cells in vitro in a dose-dependent manner in experiments involving stimulated peripheral blood mononuclear cells, and this effect is reversible by uridine, indicating that the effect is dependent on dihydroorotate dehydrogenase [[8347]] Inhibits proinflammatory cytokine secretion from activated peripheral blood mononuclear cells in vitro, an effect that is not dependent on dihydroorotate dehydrogenase [[8347]] Does not affect activation of lymphocytes in vitro [[8347]] Is not cytotoxic to stimulated peripheral blood mononuclear cells in vitro [[8347]] Displays immunomodulatory effects that are thought to be independent of its effects on pyrimidine synthesis [[341]] [[401]] [[372]] Inhibits tyrosine kinases, which may or may not be clinically relevant in humans at therapeutic concentrations [[401]] [[372]] Downregulates growth factor receptors, suppresses c-Myc and cyclin D1, induces S-phase arrest, induces apoptosis, and reduces migration and invasion of triple-negative breast cancer cells in vitro [[14642]] In general, does not appear to reduce the immune response to influenza vaccination [[6773]]	Reduces inflammation, demyelination, and axonal loss in the Dark Agouti rat model of experimental autoimmune encephalomyelitis [[368]] Reduces levels of T cells, natural killer cells, macrophages, and neutrophils in the spinal cord of Dark Agouti rats with experimental autoimmune encephalomyelitis [[8403]] Reduces experimental autoimmune encephalomyelitis-associated changes in blood and spleen immune cell populations in a Dark Agouti rat model [[8403]] Leflunomide (the prodrug from which the active metabolite teriflunomide is derived) inhibits murine B cell proliferation [[409]] Prophylactic and therapeutic treatment reduces cumulative neurological disease scores in a Dark Agouti rat experimental autoimmune encephalomyelitis model by 99.5% and 75.7%, respectively [[7127]] Prophylactic and therapeutic treatment prevents or reverses alterations (a reduction in waveform amplitude and a delay in waveform latency) seen in electrophysiological recordings in a Dark Agouti rat experimental autoimmune encephalomyelitis model [[7127]] Prophylactic and therapeutic treatment reduces axonal damage (by 88% and 96%, respectively) in motor tracts in the spinal cord in a Dark Agouti rat experimental autoimmune encephalomyelitis model [[7127]] Activates the aryl hydrocarbon receptor (AHR), a transcription factor that binds and is activated by xenobiotics (a process that leads to xenobiotic catabolism via AHR binding to xenobiotic response elements (XREs) in the promoter regions of cytochrome P450 oxidase genes), as shown by experiments using XRE-reporter mice [[21290]] Activates the aryl hydrocarbon receptor, which results in the metabolism and detoxification of teriflunomide, as shown by experiments using xenobiotic response element-reporter mice [[21290]] Causes increased thrombopenia and leukopenia, and increased liver enzymes, in mice deficient for the aryl hydrocarbon receptor, which is normally involved in teriflunomide detoxification; teriflunomide blood levels are higher than usual in this mouse strain [[21290]] Causes severe, lethal gastrointestinal bleeding and ulcers in mice deficient for the aryl hydrocarbon receptor, which is normally involved in teriflunomide detoxification [[21290]]
[+]	Ustekinumab	IM	Subunit P40 on cytokines interleukin 12 and interleukin 23 [[437]]	Fully human IgG1 antibody that binds to p40, a subunit of the cytokines interleukin-12 and interleukin-23 [[620]] Molecular weight, 148.6 kD [[620]] Metabolism has not been characterized [[621]] Mean half-life ranges from 15 to 46 days, as determined in a psoriasis study [[621]]	Neutralizes bioactivity of interleukin 12/23 [[625]] Prevents interleukin 12 and interleukin 23 from differentiating and activating Th1 cells, which are abnormally high in MS patients [[625]] [[437]] [[620]] Prevents the production of the cytokine IGN-gamma and Th17 cells [[625]] [[437]] [[620]] Possible reasons for MS failure include a) the drug’s inability to cross the blood brain barrier, b) the drug is effective in early stages of the disease, so patients with advanced disease did not respond, or c) alternative MS-causing pathways were undisrupted and/or interleukin12/23 not critical to MS [[437]] [[446]]	Antibodies that neutralizing the cytokines interleukin 12 and interleukin 23, the targets of ustekinumab, ameliorate experimental autoimmune encephalomyelitis in mouse and monkey models [[446]] Interleukin 12, one target of ustekinumab, is not essential for demyelinating disease, while interleukin 23, the drug’s other target, appears to be required for its induction [[446]] Blocking p40 subunit of interleukin 12 – one of the targets of ustekinumab -- in mice leads to increase in malignant tumor incidence [[621]]

	Name	Status for MS	Highest status achieved (for any condition)	Other uses	Administration	Negative effects	Commercial
[+]	Alemtuzumab	Approved in the US, EU, and other countries for treating RRMS [[15222]] Used on a research basis in MS since 1991 [[783]] Approved in the EU for treating adults with RRMS (17 September 2013) [[7621]] Approved in Canada for treating adults with RRMS (13 December 2013) [[8951]] Approved in Australia for treating relapsing forms of MS (19 December 2013) [[9102]] Approved in Mexico for treating RRMS (4 February 2014) [[9747]] Approved in Brazil for treating relapsing forms of MS (21 March 2014) [[10285]] Approved in Argentina for treating adults with RRMS (30 June 2014) [[12109]] Approved in the US for treating relapsing forms of MS (14 November 2014) [[15222]]	Approved [[785]] [[786]] [[7621]] [[8951]] [[9102]] [[15222]]	Approved by the US Food and Drug Administration for treating B cell chronic lymphocytic leukemia in 2001 [[785]] Approved by the European Medicines Agency for treating B cell chronic lymphocytic leukemia in 2001 [[786]] Used extensively to induce immunosuppression after organ transplantation [[449]] May be useful for reducing the risk of acute rejection after kidney transplant, as shown in a randomized clinical trial [[12912]] Induced remission in most individuals with refractory and relapsing Behçet disease, an immune-mediated condition, in 32 individuals studied over 20 years [[21190]] Has shown success for treating bone marrow failure syndromes such as aplastic anemia, but no large-scale trials have been done [[419]] In trials for other cancers, such as T cell lymphoma [[787]] Was not effective against a case of Balo's concentric sclerosis (a central nervous system demyelinating disorder) [[6924]] Was not effective in three cases of neuromyelitis optica spectrum disorder [[22805]]	Intravenous [[781]] Administered in two annual treatment courses, the first on five consecutive days and the second, 12 months later, on three consecutive days, according to information from the manufacturer [[6591]] Subcutaneous administration was effective and well tolerated in two patients with highly active relapsing MS [[4208]] Available in the US only through a restricted distribution program, referred to as Lemtrada REMS (Risk Evaluation and Mitigation Strategy) [[15222]]	Label includes a boxed warning about serious, potentially fatal autoimmune conditions and infusion reactions [[15222]] Autoimmune hemolytic anemia [[432]] Autoimmune neutropenia [[432]] Possibly associated with secondary autoimmune diabetes mellitus type I in an individual with MS [[19659]] Burkitt’s lymphoma and other cancers, though relationship to treatment unclear [[790]] Associated with norovirus-related chronic diarrhea in an immunocompromised individual with chronic lymphocytic leukemia [[11848]] Goodpasture syndrome [[435]] Immune thrombocytopenic purpura [[435]] Possibly linked with massive infiltration of the central nervous system by macrophages (seen at autopsy), and associated tissue damage, when used to treat one case of aquaporin-4 immunoglobulin G antibody seropositive neuromyelitis optica [[14708]] Infections [[435]] Infusion reactions, which can be reduced by pre-treatment with corticosteroids [[436]] Associated with the development of Listeria meningitis in two cases [[19952]] Associated with progressive multifocal leukoencephalopathy in an individual being treated for refractory chronic lymphocytic B-cell leukemia [[22309]] Fulminant central nervous system nocardiosis has been reported in an individual with RRMS treated with alemtuzumab [[28800]] Thyroid autoimmunity [[435]] After treatment, ~30% of individuals develop secondary autoimmune conditions and ~30% develop autoantibodies that are asymptomatic; such autoimmunity is driven by post-treatment homeostatic proliferation of T cells that escaped the original depletion, generating a repertoire that is more restricted than that in individuals who do not develop autoimmunity [[8702]] Label indicates that the drug may be linked with an increased risk of malignancies, such as thyroid cancer, melanoma, and lymphoproliferative disorders [[15222]] Graves' hyperthyroidism [[8283]] Hypothyroidism [[8283]] Subacute thyroiditis [[8283]] Ocular findings have been described for a case of alemtuzumab-associated Graves' ophthalmopathy (thyroid eye disease) [[17701]]	Discovered by researchers at Cambridge University, UK [[435]] Rights were acquired by Wellcome (now GlaxoSmithKline) from British Technology Group, which undertook development in the 1990s [[6512]] Fast tracked by the US Food and Drug Administration in June, 2010 [[784]] Rights were next held by Leukosite and then Ilex Oncology, which, in 1999, formed a partnership deal with Schering (now Bayer); Ilex was bought by Genzyme in 2004 and Genzyme was bought by Sanofi in 2011 [[6512]] Clinical trials sponsored and future commercialization to be done by Genzyme (a subsidiary of Sanofi), in partnership with Bayer [[779]] Supplemental biologics license application has been submitted to the US Food and Drug Administration and a marketing authorization application has been submitted to the European Medicines Agency by Genzyme, to seek approval for use of alemtuzumab in the treatment of RRMS (12 June 2012) [[2738]] Withdrawn as a cancer drug (known as Campath/MabCampath) in the US and EU by Genzyme, a Sanofi company, so that this company can concentrate on marketing the drug for MS (as Lemtrada) and reportedly to prevent the off-label use of this drug for MS (August, 2012) [[3014]] In response to the submission of a supplemental biologics license application for approval of Lemtrada as a treatment for MS by Genzyme, the US Food and Drug Administration issued a refuse to file letter and asked that the presentation of data sets be modified (27 August 2012) [[3013]] Supplemental biologics license application, which seeks approval for the use of Lemtrada in the treatment of relapsing MS, has been accepted by the US Food and Drug Administration for review (28 January 2013) [[4732]] Response from the US Food and Drug Administration about Lemtrada approval is expected by Sanofi in the fourth quarter of 2013 and by the European regulator in the third quarter of 2013 (14 February 2013) [[4979]] Limited access to alemtuzumab (for patients who had already started treatment) has been restored by Genzyme in response to protests from doctors after withdrawal of off-label use for MS in 2012 (February 2013) [[4826]] Received a positive opinion for approval (for treating adult RRMS patients with active disease) from the Committee for Medicinal Products for Human Use of the European Medicines Agency (28 June 2013) [[6591]] Marketing authorization has been granted by the European Commission for treating adults with RRMS (17 September 2013) [[7621]] Reviewers for the US Food and Drug Administration raise concerns about serious safety issues and questions about whether the efficacy data from primary trials are adequate (8 November 2013) [[8424]] Advisory panel to the US Food and Drug Administration recommends approval, but only for individuals for whom other therapies have been unsuccessful (13 November 2013) [[8596]] Approved by Health Canada for treating adults with RRMS (13 December 2013) [[8951]] Approved by the Australian Therapeutic Goods Administration for treating relapsing forms of MS (19 December 2013) [[9102]] Supplemental Biologics License Application to the US Food and Drug Administration received a Complete Response Letter (which indicates that an application is not ready to be approved); in this case, the decision is related to how the relevant clinical trials were designed; more active comparator clinical trials would be required for approval (30 December 2013) [[9240]] Rejection by the US Food and Drug Administration will be appealed by Genzyme (30 December 2013) [[9240]] Approved by COFEPRIS, the national regulatory authority in Mexico, for treating RRMS (4 February 2014) [[9747]] Approved by ANVISA, Brazil's national health surveillance agency, for treating relapsing forms of MS (21 March 2014) [[10285]] Will receive a recommendation for funding as a treatment for adults with active RRMS by the National Health Service (NHS) in England and Wales from the National Institute for Health and Care Excellence (NICE) (4 April 2014) [[10432]]; final guidance recommending reimbursement on the NHS has been issued by NICE (27 May 2014) [[11296]] Application for approval will be resubmitted by Genzyme to the US Food and Drug Administration; the appeal of the previous negative decision will not be pursued at this time (7 April 2014) [[10489]] Supplemental Biologics License Application for approval for treating RRMS has been resubmitted to and accepted by the US Food and Drug Administration for review; supplemental analyses and additional information are included in the resubmission (30 May 2014) [[11409]] Approved by the National Administration of Drugs, Food and Medical Technology in Argentina for treating adults with RRMS (30 June 2014) [[12109]] Approved by the Scottish Medicines Consortium for use within the National Health System for Scotland for treating adults with active RRMS (7 July 2014) [[12205]] Approved by the US Food and Drug Administration for treating relapsing forms of MS (14 November 2014); use of the drug is generally limited to individuals who have inadequately responded to two or more MS drugs [[15222]] Genzyme, a Sanofi company, which markets alemtuzumab, will now be referred to instead as Sanofi Genzyme (1 January 2016) (personal communication from Ameet Khara at Sanofi Genzyme)
[+]	Amiloride	Phase II trials are underway (July 2014) [[12584]] [[12599]] [[12600]]	Approved [[12644]]	Approved for use as a diuretic in situations in which reduced extracellular fluid volume is needed, such as in congestive heart failure or hypertension [[12644]] [[12685]] Should rarely be used alone as a diuretic; relative to thiazides, its diuretic and antihypertensive effects are weak [[12685]] Used as a adjunctive therapy with thiazide diuretics or other kaliuretic-diuretic drugs to promote the restoration or maintenance of normal levels of serum potassium in certain situations [[12685]]	Oral [[12643]] [[12685]]	Can potentially cause hyperkalemia (increased serum potassium levels), and is contraindicated in the presence of this condition [[12685]] Abdominal pain [[12685]] Anorexia [[12685]] Diarrhea [[12685]] Flatulence [[12685]] Headache [[12685]] Nausea [[12685]] Mild skin rash [[12685]] Vomiting [[12685]]	Discovered in the late 1960s at Merck Sharp and Dohme Research Laboratories during a screen for compounds that reverse the effects of mineralocorticoids (which increase sodium and water reabsorption in the kidney) [[12658]] Approved by the US Food and Drug Administration in October 1981 [[12644]] Brand-name version was originally produced by Merck, but this company is no longer making the drug; the patent has expired and only the generic version is now produced [[12652]] Produced by Par Pharmaceutical [[12650]] Produced by Perrigo Company [[12651]] Produced by SigmaPharm Laboratories [[12654]]
[+]	ATX-MS-1467	Phase IIa study is in progress (2014) [[14245]]	Phase IIa [[14245]]		Intradermal [[14244]] Subcutaneous [[14244]]	Found to be safe and well-tolerated in a Phase I/IIa study [[14248]]	Is being developed by Apitope (responsible for all Phase I development) in collaboration with Merck Serono (responsible beginning with Phase II studies) [[14247]] Phase I study was sponsored by Apitope Technology (Bristol) Ltd. (completed as of August, 2013) [[14244]] Phase II study is being sponsored by Merck KGaA (ongoing as of June, 2014) [[14245]]
[+]	BGC20-0134	Phase IIa [[473]] [[791]]	Phase IIa [[473]] [[792]]		Oral [[473]] [[791]]		Developed by BTG plc [[473]]
[+]	BIIB033	Phase I results have been published [[13242]] Phase II trial is recruiting as of May, 2014 [[13427]]	Phase II [[13427]]	Has been tested in acute optic neuritis in a Phase II trial; some positive results were reported (January 2015) [[16281]]	Intravenous infusion used in Phase I and Phase II trials [[486]] [[13242]] [[13427]] Subcutaneous injection used in Phase I trial [[13242]]	Adverse events occurred with similar frequencies in drug and placebo groups, and no serious adverse events occurred, in Phase I trials [[13242]]	Discovered by Biogen Idec [[377]] Clinical trials are sponsored by Biogen Idec [[485]] [[486]] Biogen Idec, which is developing BIIB033, has changed its name to Biogen (23 March 2015) [[18038]]
[+]	Cladribine	Approved in Russia and Australia for RRMS in 2010 [[552]]	Approved in Russia and Australia for RRMS [[552]]	Treatment of choice for hairy-cell leukemia; for this condition, it is administered as an intravenous infusion [[793]] [[553]] [[799]] Used for a variety of hematological disorders [[793]]	Oral [[794]] [[795]] [[559]]	Cardiopulmonary arrest secondary to exacerbation of latent tuberculosis [[552]] Headache [[793]] Herpes zoster infections [[793]] Infertility (potential effect based on a study of monkeys who had suppressed testicular cells after intravenous treatment) [[552]] Lymphopenia [[793]] [[9678]] Malignancies (melanoma, pancreas carcinoma, and ovarian carcinoma) [[793]] Not associated with an increased risk of cancer at doses used in the CLARITY and ORACLE MS trials of cladribine, as shown in a meta-analysis comparing the cancer rates in 11 Phase III trials of drugs for relapsing MS (2015 study) [[22592]] Nausea [[793]] Neutropenia [[793]] Upper respiratory tract infections [[793]] Chronic administration to a mouse model of Alzheimer's disease increases the generation of amyloid beta peptide and the amyloid plaque burden and decreases cognitive performance [[3419]]	Developed at Scripps Research Institute for treating hairy cell leukemia [[553]] Clinical trials for use in MS have been sponsored by EMD Serono, a division of Merck KGaA [[794]] [[795]] [[796]] [[797]] [[798]] [[800]] Rejected by the EU in January 2011 and by the US Food and Drug Administration in March 2011 [[552]]; failure to receive authorization in the EU was in part a result of concern about an associated cancer risk [[22592]] As of June 2011, Merck KGaA is no longer seeking approval for cladribine in US, and plans to withdraw the product from the market in Russia and Australia [[552]] Results of a Merck Serono-sponsored Phase III trial were published in February 2014 [[9678]] Merck KGaA plans to seek approval for cladribine from European regulators after evaluating new data (11 September 2015) [[21574]]; new analysis suggests that there is not an increased cancer risk at doses used to treat MS [[22592]]
[+]	Cyclophosphamide	Phase III head-to-head trial is under way (as of 12 Oct 2010) [[926]] Phase III, controlled, randomized, multicenter clinical trial is planned by Accentia Biopharmaceuticals and Johns Hopkins University to study Cyrevia (high-dose Cytoxan) in MS, with the lead trial site at Johns Hopkins (press release May 2012) [[1796]]	Approved [[923]] [[925]] FDA-approved for acute lymphoblastic leukemia in children, acute myeloid leukemia, breast cancer, chronic lymphocyclophosphamidetic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, Mycosis fungoides, neuroblastoma, Non-Hodgkin lymphoma, ovarian cancer, and retinoblastoma [[923]]	Acute lymphoblastic leukemia in children [[923]] Acute myeloid leukemia [[923]] Breast cancer [[923]] Chronic lymphocyclophosphamidetic leukemia [[923]] Chronic myelogenous leukemia [[923]] Hodgkin lymphoma [[923]] Idiopathic nephrotic syndrome [[928]] Multiple myeloma [[923]] Mycosis fungoides [[923]] Neuroblastoma [[923]] Showed efficacy against neuromyelitis optica spectrum disorder in a small retrospective clinical study [[5944]] Non-Hodgkin lymphoma [[923]] Ovarian cancer [[923]] Retinoblastoma [[923]] Recommended treatment for lupus nephritis [[928]] Studied for use in aplastic anemia and a variety of severe autoimmune diseases [[951]] Studied for use in chronic inflammatory demyelinating polyneuropathy [[951]] Studied for use in systemic-onset juvenile rheumatoid arthritis [[951]] Studied for use in interstitial lung disease due to collagen vascular diseases [[951]]	Developed as an oral drug [[929]] Most commonly administered as monthly intravenous pulses [[929]]	Amenorrhea [[939]] Bladder cancer (associated with long-term oral use) [[4496]] Gonadal toxicity [[4496]] Hair loss [[939]] Hemorrhagic cystitis [[928]] [[4496]] Infections (minor) [[940]] Nausea [[939]] Vomiting [[940]] Was not associated with unsuccessful pregnancy outcomes in 10 individuals with MS who were treated before conception (although five preterm deliveries occurred and one newborn was small for its age), based on a retrospective medical record review [[10604]]	Developed by ASTA Werke AG (now Baxter Healthcare) in the 1950s as a chemotherapeutic agent [[927]] [[947]] FDA-approved generic versions are made by Baxter Healthcare and Roxane Laboratories [[925]] Bristol-Myers Squibb produced Cytoxan (25 mg and 50 mg tablets), but decided to discontinue [[924]] Revimmune (high-dose pulsed cyclophosphamide in a proprietary system-of-care) was developed by researchers at Johns Hopkins University, which licensed it to Accentia Biopharmaceuticals, Inc. [[922]] Accentia Biopharmaceuticals plans controlled clinical trials of Revimmune as of May 2011 [[922]] Cytoxan for Revimmune therapy is supplied by an agreement with Baxter Healthcare Corporation [[922]]
[+]	Daclizumab	Phase III trials for RRMS are ongoing as of 2014 [[432]] [[11770]]	Approved by the US Food and Drug Administration in 1997 for acute organ rejection in renal transplantation [[805]]	Renal graft rejection [[454]] Adult T cell leukemia [[454]] HTLV-I associated myelopathy/tropical spastic paraparesis [[454]] HAM/TSP [[454]] Noninfectious uveitis [[454]] Pure red cell aplasia [[454]] Aplastic anemia [[454]]	Subcutaneous [[801]] Intravenous [[431]]	Has been associated with adverse events in multiple organ systems [[9802]] Alopecia [[9802]] Autoimmune attacks (hepatic and renal) [[3771]] Transient formation of autoantibodies requiring corticosteroid therapy [[432]] Breast nodules [[9802]] Cardiotoxicity [[432]] Central nervous system vasculitis developed in one treated MS patient [[4520]] Chest discomfort [[431]] Severe cutaneous events and reactions [[13746]] [[15077]] Associated with cutaneous adverse events that exhibit nonspecific signs of eczematous dermatitis and contain infiltrates of CD56+ lymphoid cells, regardless of clinical severity [[26372]] Fatigue [[432]] Fever [[431]] Gastrointestinal symptoms [[432]] Generalized weakness [[432]] Hepatotoxicity [[15077]] Hypersensitivity [[432]] Severe infections [[433]] Infusion reaction [[432]] Elevations of liver transaminases [[13746]] Diffuse lymphadenopathy [[9802]] Mouth ulcers [[432]] Psoriasis in an individual with a positive family history [[432]] Diffuse rash [[9802]] Viral meningitis [[432]]	Initially marketed by Hoffman-La Roche, but withdrawn in the EU in 2008 and in the US in 2009 for commercial reasons [[806]] [[807]] Trials for MS have been sponsored by Biogen Idec and AbbVie [[801]] [[11770]] Biogen Idec, which has sponsored trials for daclizumab in MS, has changed its name to Biogen (23 March 2015) [[18038]] Marketing Authorisation Application for Zinbryta for treating relapsing forms of MS in the EU has been validated by the European Medicines Agency (EMA), a step that confirms that the submission is complete and indicates that the review process by EMA's Committee for Medicinal Products for Human Use will begin (27 March 2015) [[18037]] Biologics License Application for Zinbryta for the treatment of MS has been accepted for review by the US Food and Drug Administration (29 April 2015) [[18831]]
[+]	Dalfampridine	Approved in US to improve walking in patients with all forms of MS (22 January 2010) [[495]] [[497]] European Medicines Agency's Committee for Medicinal Products for Human Use gave positive opinion for marketing Fampyra (May 2011), a change from a recommendation against approval issued in January 2011 [[496]] [[503]]	Approved [[495]]	Before approval for use in MS by the US Food and Drug Administration, was compounded by pharmicies to treat a variety of neurological conditions, including spinal cord injury, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, and MS [[497]] May be useful for treating hereditary spastic paraplegia, based on a proof-of-concept open trial [[18036]] Is being studied in patients with post-stroke deficits (press release, June 2012) [[2103]] Improved walking in patients with post-stroke deficits (neurological problems that include impaired walking), according to Phase II data described in a company press release (15 April 2013) [[5778]] Is being studied for treating post-stroke walking deficits in a Phase III trial (December, 2014) [[15982]]	First drug approved for improving walking in MS [[495]] Oral; one tablet every 12 hours (this information was provided by the manufacturer) [[494]] Is released slowly (extended release) [[493]] Recommended dose is 10 mg twice a day, according to the US Food and Drug Administration [[495]] Should not be used in MS patients with moderate or severe kidney disease (which results in blood levels of the drug that are high enough to cause seizures) [[495]] Because of associated risk of seizures that increase with higher levels of drug in the blood, and because the drug is eliminated via the kidneys, kidney function must be checked before and during treatment, according to a warning issued by the US Food and Drug Administration (23 July 2012) [[2649]]	Seizures, especially when given at doses higher than recommended [[494]] [[495]] For patients with no previous seizure history, drug-associated seizure risk at the recommended dose may be no greater than the seizure risk that already exists in the MS population, on the basis of clinical trial results and postmarketing experience [[2192]] Accidental overdose (100 mg versus 10 mg dose) was associated with prolonged toxic encephalopathy (initially presenting as status epilepticus) in one individual with progressive MS [[10969]] Anaphylactic reactions [[25187]] Back pain [[494]] Balance problems [[494]] Constipation [[495]] Diarrhea [[495]] Dizziness [[494]] Falling [[25187]] Gait disturbance [[25187]] Headache [[494]] Drug hypersensitivity reactions [[25187]] Indigestion [[494]] Insomnia [[494]] Multiple sclerosis relapse [[494]] Nausea [[494]] Nose and throat irritation [[494]] Skin burning, tingling, or itching [[494]] Case report of 4-aminopyridine toxicity in a progressive MS patient has been published; symptoms included diaphoresis (excessive sweating), delirium, agitation, and choreoathetosis (irregular involuntary movements) [[2439]] May activate or aggravate preexisting trigeminal neuralgia in individuals with MS [[14045]] Urinary tract infection [[494]] Confirmed urinary tract infections were found to occur at similar rates in placebo and dalfampridine groups in a post hoc analysis of data from a clinical trial involving 429 individuals with MS [[16171]] Weakness [[494]]	Benefit in MS was discovered at Rush University Medical Center, where a proof-of-concept study was performed in 1983 [[13031]] Approved by the US Food and Drug Administration on 22 January 2010 [[13031]] Marketed by Acorda Therapeutics [[493]] Manufactured under license from Elan Pharma International [[493]] Commercialization outside the US is handled by Biogen Idec, which has a licensing agreement with Acorda for this purpose [[496]] [[503]] Biogen Idec, which handles commercialization of Fampyra outside the US, has changed its name to Biogen (23 March 2015) [[18038]] 4-Aminopyridine is sold under the name Avitrol as a bird poison [[504]] Patent for Ampyra sustained-release formulation is entitled to a five year patent term extension (such that the patent will now expire in 2018) under the Hatch Waxman Act, as determined by the US Patent and Trademark Office (16 October 2012) [[3770]] Patent (set to expire in 2025) that covers a range of Ampyra doses (which are less than 15 mg twice daily) for improving walking in MS has been issued to Acorda Therapeutics by the US Patent and Trademark Office (20 May 2013) [[6094]] Rush University Medical Center's royalty rights relating to worldwide sales are sold by Rush to the private equity fund Drug Royalty III for ~$42 million (12 August 2014) [[13032]]
[+]	Dimethyl fumarate	Tecfidera is approved in the US, EU, and other countries for treating RRMS [[5512]] [[9746]]	Approved [[5512]]	Esters of fumaric acid, which include dimethylfumarate, have been used to treat psoriasis in European countries for more than 30 years [[380]] Fumaderm, which contains dimethyl fumarate and salts of monoethylfumarate, was approved in 1994 in Germany for the treatment of psoriasis [[380]] Might be useful for treating asthma, based on anecdotal patient reports and in vitro studies of airway smooth muscle cells [[9104]] Might be useful in the treatment of aggressive breast cancers, as shown by experiments with breast cancer cell lines and a xenograft study [[24874]] Might be useful for treating glioblastomas, based on experiments in mouse and human tumor cell lines [[9226]] Might be useful (in combination with other therapy) for treating hematopoeitic tumors, based on experiments in human cell lines [[15701]] Might be useful for treating inflammatory bowel disease, based on studies of a mouse model [[24999]] Might be useful for treating intracerebral hemorrhage, based on studies in rodents [[18919]] Might be useful for treating osteoarthritis, based on studies in primary human chondrocytes [[14392]] Might be useful for treating chronic pancreatitis, based on experiments in rodents [[13682]] Might be useful for treating Parkinson's disease, based on experiments in mice [[28609]] Might be useful for treating autoimmune diseases of the peripheral nervous system, on the basis of studies of experimental autoimmune neuritis in Lewis rats [[24304]] Might be useful for treating retinal ischemia, as shown by studies in mice [[25164]] Might be useful for reducing inflammation and oxidative stress in sickle cell disease, based on studies in mice [[27356]]	Oral [[583]] [[9851]] Starting dose (used for the first 7 days) for Tecfidera is 120 mg twice a day, according to information from the manufacturer [[9851]] Maintenance dose for Tecfidera is 240 mg twice a day, according to information from the manufacturer [[9851]]	Abdominal pain [[370]] Diarrhea [[5512]] Associated with the development of a bilateral eosinophilic fasciitis-like disorder of the thighs in one individual with MS [[13786]] Fatigue [[370]] Flushing [[370]] Flushing; this effect is usually mild or moderate and transient and occurs most frequently during the first month of treatment (flushing occurred in 37% of the treated group and 5% of the placebo group in months 0 to 3 in the DEFINE and CONFIRM trials) [[22710]] Gastrointestinal side effects are very common in individuals starting treatment (causing some to discontinue use of the drug) and these effects are most severe during the initial period of treatment, according to various studies presented at a 2014 meeting [[11435]] Gastrointestinal events; these effects are usually mild or moderate and transient and occur most frequently during the first month of treatment (such events occurred in 27% of the treated group and 17% of the placebo group in months 0 to 3 in the DEFINE and CONFIRM trials) [[22710]] Hot flush [[370]] Headache [[370]] Lymphopenia [[19438]] Caused grade 2 lymphopenia in 24% of treated individuals, and grade 3 lymphopenia in 1 individual, as shown by a retrospective chart review of 23 individuals with MS, with the a mean of 3.9 months between baseline and treatment counts [[20341]] Caused grade 2-3 lymphopenia, which did not resolve during treatment, in 17% of a treated population in a retrospective cohort study involving 221 individuals with MS [[23609]] Dimethyl fumarate-associated lymphopenia does not predict clinical response to the drug, as shown in a retrospective cohort study involving 221 individuals with MS [[23609]] Risk for moderate or severe dimethyl fumarate-associated lymphopenia is increased by recent exposure to natalizumab, age >55 years, and lower absolute lymphocyte counts at baseline, as shown in a retrospective cohort study involving 221 individuals with MS [[23609]] Nausea [[5512]] May have induced acute pancreatitis in an individual with RRMS [[16793]] Progressive multifocal leukoencephalopathy (two cases have been reported in psoriasis patients treated with either fumaric acid or dimethyl fumarate from a compounding pharmacy) (2013) [[6229]] [[6230]] One case of progressive multifocal leukoencephalopathy (PML) (which was associated with death from pneumonia and PML complications) has been reported (October 2014) in an individual who had taken Tecfidera for >4 years in the open-label extension of the DEFINE study; this individual had exhibited severe, prolonged lymphocytopenia, a risk factor for PML [[14789]] [[17977]] Information about the case of progressive multifocal leukoencephalopathy that occurred in an individual treated with Tecfidera, who later died, is being added to the Tecfidera drug label as a result of a warning about this situation by the US Food and Drug Administration (25 November 2014) [[15548]] A second occurrence of progressive multifocal leukoencephalopathy (PML) associated with dimethyl fumarate used for MS has been reported in an individual with PPMS who exhibited severe prolonged lymphopenia; the PML was not fatal (16 July 2015) [[20470]] Has been associated with four cases of progressive multifocal leukoencephalopathy (PML) in individuals with MS, as well as ~10 cases of PML in individuals with psoriasis treated with similar products, as of December 2015; in the fourth identified MS case, the individual had less severe (grade 2) lymphopenia than in previous cases [[24961]] Decreases CD8+ lymphocyte counts, and to a smaller extent, CD4+ lymphocyte counts, which might contribute to the risk of progressive multifocal leukoencephalopathy [[20335]] Urinary tract infections [[20341]] Initiation of treatment was followed by extensive bilateral lower extremity deep venous thrombosis in an individual with MS [[16794]] Associated with a fatal case of West Nile encephalitis in an individual with MS who also exhibited grade 3 lymphopenia, who had been treated for 5 months [[20341]] Disseminated zoster with paresis has been reported in an individual with MS treated with dimethyl fumarate [[28572]] Dimethyl fumarate and teriflunomide are associated with a similar risk of adverse events, and that risk is higher than that of glatiramer acetate, based on meta-analysis of 3 randomized controlled trials involving 3737 individuals with RRMS [[15086]] Exposure during the first trimester of pregnancy does not appear to be associated with increased risk of adverse pregnancy outcomes or fetal abnormalities, based on results from clinical trials (outcomes known for 39 cases) and postmarketing reports (outcomes known for 30 cases) [[24626]]	Tecfidera was jointly developed by Biogen Idec and Fumapharm [[585]] Biogen Idec acquired the company Fumapharm, which has two products, Fumaderm (approved for treating psoriasis in Germany) and BG-12, in 2006 [[585]] Clinical trials for Tecfidera have been sponsored by Biogen Idec [[583]] Marketing applications from Biogen Idec for Tecfidera have been accepted by US and EU regulatory authorities for review (May 2012) [[1792]] Review time for the New Drug Application for Tecfidera has been extended 3 months by the US Food and Drug Administration (meaning a ruling would be made by the end of March 2013), because the agency needs more time to review the application; no additional studies are requested (18 October 2012) [[3767]] [[3781]] Dosing regimen (480 mg per day) for Tecfidera has been granted patent protection by the US Patent and Trademark Office (19 March 2013) [[5317]] Tecfidera is recommended to receive marketing authorization as a first-line therapy for RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency (22 March 2013) [[5367]] Tecfidera is approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]] Dimethyl fumarate in Tecfidera has been determined to be a new active substance by the European Medicines Agency's Committee for Medicinal Products for Human Use, which would mean regulatory exclusivity in the EU for ten years (22 November 2013) [[8664]] Tecfidera is approved by the European Commission as a first-line treatment for RRMS (3 February 2014) [[9746]] Initial decision is against recommendation for Tecfidera as an available treatment for RRMS through the National Health Service in England and Wales; the National Institute for Health and Care Excellence (NICE) has requested further information about cost effectiveness (19 February 2014) [[9852]]; decision is reversed and NICE now intends to recommend dimethyl fumarate for treating RRMS (11 July 2014) [[12365]] Tecfidera is approved by the Scottish Medicines Consortium as a treatment for RRMS in the National Health Service in Scotland [[10490]] Tecfidera is recommended by the National Institute for Health and Care Excellence for treating adults with RRMS; the National Health Service in England and Wales must begin funding this treatment within 3 months (27 August 2014) [[13428]] FP187, which contains dimethyl fumarate and is formulated as a controlled-release, erosion matrix tablet, is being developed for treating MS and psoriasis by Forward Pharma as of 2013 [[14441]] Biogen Idec, which markets Tecfidera, has changed its name to Biogen (23 March 2015) [[18038]] An interference between Forward Pharma and Biogen has been declared by the US Patent Office; this proceeding will decide which company was the first to invent the method of treating MS with a daily 480 mg dose of dimethyl fumarate (14 April 2015) [[18342]] Decision to grant, covering a patent application for the treatment of MS with a 480 mg daily dose of dimethyl fumarate, has been given to Forward Pharma from the European Patent Office (27 April 2015) [[18829]] Costs of introducing dimethyl fumarate for treating RRMS in Canada were calculated to be partly offset by the decreased costs associated with fewer relapses, as determined by an industry-funded budget impact model (September 2015) [[21783]] Phase III program in SPMS has been discontinued by Biogen (21 October 2015) [[23072]]
[+]	Dronabinol	Phase III trial for PPMS and SPMS has been completed [[6803]] [[9467]] Phase III trial for MS with muscle spasticity has been completed [[9470]]		Approved by the US Food and Drug Administration to treat nausea associated with chemotherapy (1985) [[9471]] Approved by the US Food and Drug Administration to stimulate appetite in individuals with HIV/AIDS (1992) [[9471]] Shown to have analgesic effects in a placebo-controlled study involving cancer pain, as well as in a followup, single-dose study [[10058]] Reduced spasticity and pain associated with spinal cord injury in a single case, placebo-controlled, double-blind study [[9499]] Decreased spasticity associated with spinal cord injury in an open-label study [[9500]] Might be useful for treating Alzheimer's disease, based on an ability to inhibit acetylcholinesterase and acetylcholinesterase-induced amyloid beta-peptide aggregation [[9508]] Decreases neurodegeneration in a rat model of Parkinson's disease [[9509]] Has shown potential for therapeutic value in some animal models of Huntington's disease but not others [[9510]] [[9511]]	Oral [[6803]]	Abdominal pain [[9534]] Amnesia [[9534]] Anxiety [[9534]] Asthenia [[9534]] Ataxia [[9534]] Confusion [[9534]] Depersonalization [[9534]] Diarrhea [[9470]] Dizziness [[9502]] Euphoria [[9534]] Hallucination [[9534]] Dose-related effects on mood, cognition, memory, and perception, which are reversible [[9534]] Nausea [[9534]] Palpitations [[9534]] Paranoid reaction [[9534]] Somnolence [[9534]] Tachycardia [[9534]] Vomiting [[9534]] Vasodilation [[9534]]	Approved by the US Food and Drug Administration to treat nausea associated with chemotherapy (1985) [[9471]] Approved by the US Food and Drug Administration to stimulate appetite in individuals with HIV/AIDS (1992) [[9471]] Marinol is manufactured by Banner Pharmacaps for AbbVie Inc. [[9534]]
[+]	Estriol	Phase II [[864]] [[865]]	Approved in Europe and Asia [[866]]	Post-menopausal hot flashes [[443]]	Oral [[864]] Dose was set at 8 mg once daily in a clinical trial [[10842]]	Cannot be used in men [[443]]	Early studies were conducted at the University of California, Los Angeles [[460]] Advanced clinical trials are supported by Synthetic Biologics [[2753]] Exclusive worldwide license to patents covering the use of Trimesta for MS is held by Synthetic Biologics [[5533]] Patent covering the use of a combination of estriol and glatiramer acetate for treating MS has been issued to the Regents of the University of California by the US Patent & Trademark Office (4 April 2013) [[5533]] Patent covering the use of estriol in conjunction with a gestagen (with or without a third standard of care agent for MS) for treating MS and other autoimmune diseases has been issued to the Regents of the University of California by the US Patent & Trademark Office (10 March 2014) [[10088]] Synthetic Biologics has decided to end its estriol-related clinical trial and licensing agreements with the Regents of the University of California after two independent clinical research organizations examined Phase II trial results and found no statistically significant differences between the estriol and placebo groups (2 February 2016) [[26483]]
[+]	Fingolimod	Approved in US, EU, and other countries for RRMS [[466]] [[467]] [[468]] [[469]] License in the EU was for adult individuals with RRMS who have not responded to interferon treatment or whose MS is severe and rapidly evolving (29 April 2014) [[11098]] License in the EU has been expanded to include individuals with RRMS who have not responded to any other disease-modifying therapy (June, 2014) [[11607]]	Approved [[466]]	Initially tested in preclinical trials for ability to prevent rejection of allografts [[301]] Prolongs survival of allografts [[301]] Caused remission of a case of demyelinating polyneuropathy [[11768]] Effectively used to treat a case of Balò's concentric sclerosis, which is considered a variant of MS [[20091]] Showed efficacy in treating MS associated with Sjögren syndrome in one case [[16606]] Approval has been granted by the US Food and Drug Administration for a Phase IIA clinical trial in amyotrophic lateral sclerosis (11 February 2013) [[4978]] Reduced secondary brain injury after intracerebral hemorrhage in a proof-of-concept study in humans [[12178]] Suppressed paroxysmal dysarthria–ataxia syndrome (which involves transient alterations in speech and limb or gait ataxia) in an individual with RRMS [[17133]] Might be useful for treating Alzheimer's disease, on the basis of experiments in primary cortical neurons from mice showing that fingolimod phosphate upregulates neuronal expression of brain-derived neurotrophic factor and thereby protects against neurotoxicity induced by amyloid beta oligomers [[5645]] Might be useful for treating Alzheimer's disease, on the basis of fingolimod's ability to improve learning and memory, and restore brain-derived neurotrophic factor levels, in mice injected with amyloid beta [[10514]] Might be useful for treating autoimmune optic neuritis, based on experiments in mice [[5731]] Might be useful for treating neonatal brain injury, based on experiments in a neonatal model of oxygen toxicity [[22542]] Might be useful as a therapy to help extinguish aversive memories (for example, in post-traumatic stress disorder), based on experiments in mice [[11236]] Alleviates pre-existing cardiac hypertrophy and fibrosis in a mouse model by negatively regulating nuclear factor of activated T cells and periostin [[7783]] Might be useful, in combination with tamoxifen, for treating estrogen receptor-α negative breast cancer, based on experiments in mice and cell lines [[19842]] Might be useful, when applied topically, for treating cutaneous inflammation, as shown by studies in mice and humans [[28372]] Might be cardioprotective during myocardial infarction, based on experiments in a porcine model of ischemia-reperfusion [[26199]] Might be useful for treating colitis-associated colon cancer, based on experiments in mice [[4730]] Might be useful for treating thyroid cancer, based on experiments with thyroid cancer cell lines [[27429]] Might reduce symptoms of depression independently of its effect on MS symptoms, based on experiments in mice [[20155]] Might be useful for treating dry eye disease, based on experiments in mice [[24769]] Inhibits neuroinflammation and decreases the length, frequency, and severity of spontaneous convulsions in a rat model of epilepsy [[3078]] Might be useful for improving motor function in Huntington's disease, based on experiments in mice [[8824]] Might be useful for improving hippocampal synaptic plasticity and memory in Huntington's disease, based on experiments in mice [[20469]] Might be useful for treating Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL), but not for Ph negative ALL, based on human ALL xenograft experiments [[1693]] Limits metastatic melanoma in mice [[10719]] Might be useful for treating myeloproliferative neoplasms, based on experiments in mice [[7133]] Might be useful for drug development for acute myeloid leukemia, M2 subtype, based on experiments with cells and mouse models [[12646]] Inhibits neuroblastoma growth by interfering with the sphingolipid pathway in a pre-clinical model [[7784]] Might be useful for reducing chemotherapy-induced painful peripheral neuropathy, based on experiments in rats [[11313]] Might be useful for treating obstruction-induced renal injury, based on experiments in mice [[10488]] Might be useful for treating proteinuric nephropathy, based in experiments in a rat model [[21191]] By reducing reactive astrogliosis, might be useful for treating spinal cord injury, based on experiments involving local delivery of fingolimod in animal models [[19318]] Exhibits strong, selective activity against Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis [[24756]]	First oral treatment for RRMS available in US [[307]] 0.5 mg orally once daily (information provided by the manufacturer) [[470]] Decreased dosage (such that fingolimod was given every other day or every third day) did not result in clinical relapses, but did improve laboratory abnormalities (involving increased liver function tests and reduced lymphocyte counts), in a study of seven individuals [[18406]] Decreased dosage (such that fingolimod was given every other day or every third day) reversed laboratory abnormalities (involving increased liver function tests and reduced lymphocyte counts) in a study of eight individuals; although no relapses occurred, five individuals exhibited new brain lesions and one converted to SPMS [[20501]] Label has been updated to say that all patients should have an electrocardiogram before the first dose, according to information from the manufacturer (April, 2012) [[1795]] Contraindicated in the presence of specific cardiac conditions, according to information from the manufacturer [[1795]] Contraindicated in the presence of certain cardiac conditions, which were found to be present in 9.2% of individuals with MS in a retrospective cohort study involving 136,542 hospital discharges [[12603]] As a result of a drug safety communication from the US Food and Drug Administration, the label has been adjusted to indicate that one definite case, and an additional probable case, of progressive multifocal leukoencephalopathy have been reported in individuals taking fingolimod, who had not previously been exposed to immunosuppressant drugs (4 August 2015) [[20796]] To minimize fingolimod-associated risks, the European Medicines Agency has issued new recommendations for screening for progressive multifocal leukoencephalopathy and basal cell carcinoma before and during treatment (December 2015) [[24964]] Used in one individual with highly active multiple sclerosis, severe idiopathic pulmonary arterial hypertension, and coronary artery disease; treatment did not change the cardiopulmonary conditions over 9 months [[11503]] Drug-drug interactions are not observed with a combined oral contraceptive (ethinylestradiol/levonorgestrel) [[2271]]	Associated with amenorrhea in three cases [[9719]] Fingolimod-induced deterioration of asthma has been observed in an individual with RRMS [[11279]] Associated with a life-threatening asthma attack after 6 months of treatment in an individual [[12549]] Atrioventricular block [[10486]] Treatment initiation was associated with atrioventricular conduction delays in a low percentage (0% to 1%, depending on the dose and type of delay) of study participants, which generally were well tolerated, as shown by analysis of pooled data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials [[27011]] Intermittent atrioventricular block occurred in one individual with MS after initiation of treatment; this effect was hypothesized to be related to demyelinationg lesions in the spinal cord causing autonomic nervous system dysfunction, perhaps enhanced by fingolimod's parasympathetic effects [[13253]] Severe autoimmune hemolytic anemia has been reported in one patient receiving fingolimod [[6608]] Bradycardia [[307]] [[10486]] Treatment initiation was associated with symptomatic bradycardia in 0.6% (0.5 mg dose) and 2.1% (1.25 mg dose) of study participants, which generally resolved spontaneously, as shown by analysis of pooled data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials [[27011]] Fingolimod-associated bradycardia is usually asymptomatic and spontaneously resolves, but symptomatic bradycardia (33 beats per minute) has occurred in one case after a single dose of fingolimod, which required treatment and a week for recovery [[7560]] The first dose is associated with bradycardia in some individuals; such cardiac responses can be predicted by measures that assess autonomic balance [[11911]] Deliberate overdose (14 mg, with 2 g phenoxymethylpenicillin) resulted in delayed bradycardia and hypotension (21 hours after ingestion) [[8325]] Symptomatic bradycardia after the first dose was found to occur in a higher proportion of individuals (6.7%) in real-life medical settings than in the FREEDOMS clinical trial (in which the rate was <1%), based on a review of data from 180 individuals with MS in Brazil [[13947]] Cardiac effects associated with the first dose are not affected by concomitant use of selective serotonin-reuptake inhibitors, as shown in a posthoc analysis involving >3300 individuals with relapsing MS [[19243]] Bradyarrhythmia [[307]] In general, adverse cardiologic events were found to be limited over the long term (mean followup time, 1.5 years) in a study of 212 individuals with relapsing MS; one individual exhibited atrial fibrillation that required treatment and 5 exhibited persistent increases in blood pressure [[18639]] Associated with a maximum heart rate reduction of 8 (0.5 mg dose) or 11 (1.25 mg dose) beats per minute 4 to 5 hours after the first dose, as shown by analysis of pooled data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials [[27011]] Causes prolonged heart-rate slowing upon initiation in some cases; in a study of 21 people with RRMS, 7 displayed this symptom; these individuals also exhibited some autonomic cardiovascular dysfunction before fingolimod initiation, suggesting that MS lesions can affect heart rate re-acceleration when fingolimod begins [[20074]] Initially (at day 1) associated with an increase in cardiac parasympathetic regulation (prolonging the RR interval and increasing heart rate variability), but later (at month 3) is associated with a change toward sympathetic regulation (largely the opposite of parasympathetic regulation), based on a prospective study of 27 individuals with RRMS [[21506]] Breathing problems [[307]] Cancers (?) [[302]] Skin cancer (?) [[302]] May increase risk for basal cell carcinoma; as of December 2015, 151 cases have been reported in individuals taking fingolimod [[24964]] Disseminated cryptococcosis has been reported in an individual with MS who was treated with fingolimod [[20972]] Primary cutaneous cryptococcus has been reported in an individual with MS who was treated with fingolimod [[25528]] Cryptococcal meningoencephalitis has been reported in an individual with MS who was treated with fingolimod [[22535]] Possibly associated with ecchymotic angioedema-like cutaneous lesions [[20966]] Fatigue [[24323]] Potentially associated with glioblastoma in an individual with RRMS; the glioblastoma was diagnosed within 3 years of fingolimod initiation [[27943]] Headache [[20839]] Hypertension [[10486]] Hypothyroidism has been reported in an individual with MS during fingolimod treatment [[15782]] Infections (particularly herpes virus infections) [[307]] [[302]] Associated with reactivation of herpes virus leading to severe herpes simplex encephalitis in one case [[20965]] Kaposi sarcoma has been reported in an individual with RRMS receiving fingolimod [[18412]] Visceral leishmaniasis infection has been reported in an individual with MS treated with fingolimod [[15493]] Acute lymphoblastic leukemia occurred in an individual with RRMS treated with fingolimod, although whether there was a causal relationship is not known [[22125]] Liver problems [[307]] Increased alanine aminotransferase, a measure of hepatocellular injury [[10486]] Associated with lymphomatoid papulosis, a benign subtype of cutaneous T-cell lymphoma that can become malignant, in an individual with MS [[20556]] Lymphomatoid papulosis type D has been reported in an individual with MS treated with fingolimod [[28908]] Lymphopenia [[10486]] Fingolimod-induced lymphopenia risk may be increased in individuals with low initial lymphocyte counts and in women with low body mass index [[14899]] Macular edema; a low incidence of this condition is associated with fingolimod use (0.5 mg dose), based on an assessment of 2615 patients who participated in clinical trials [[307]] [[5427]] Fingolimod-associated macular edema has been successfully managed with topical anti-inflammatory drugs in one case [[7131]] Fingolimod-associated bilateral macular edema has been successfully treated by sub-Tenon injection of triamcinolone without the discontinuation of fingolimod in one case [[7559]] Fingolimod-associated macular edema has been successfully treated with intravitreal triamcinolone in two cases in which topical nonsteroidal anti-inflammatories were not successful; fingolimod use continued [[10420]] Cystoid macular edema [[4539]] Associated with cystoid macular edema, which in one case did not resolve even after early detection and discontinuation of fingolimod [[8682]] Associated with macular hemorrhage in one MS patient [[6752]] Associated with bilateral cystoid macular edema in one individual [[3421]] Associated with bilateral cystoid macular edema after cataract surgery in one individual with RRMS [[19120]] Superficial spreading malignant melanoma has been reported in an individual with MS treated with fingolimod [[23881]] Prolonged, extensive molluscum contagiosum virus infection has been reported in an individual with RRMS treated with fingolimod [[26566]] Causes neural tube defects in embryos when administered to pregnant mice [[25190]] Linked with the development of paroxysmal atrial fibrillation in one individual with MS [[9755]] Associated with retinal hemorrhages in an individual with MS [[22853]] Associated with posterior reversible encephalopathy syndrome in an individual with MS [[17695]] Progressive multifocal leukoencephalopathy has been reported in an individual with MS who had been taking fingolimod for 7 months (who had not been treated with natalizumab) (July 2013) [[7123]] [[7562]] Whether there is fingolimod-associated risk of progressive multifocal leukoencephalopathy (PML) is unclear; one individual who was reported to have PML without previous natalizumab exposure may have had neuromyelitis optica (NMO), not MS, and the brain lesions may have been caused by NMO, not PML (meeting report, September 2014) [[14088]] Progressive multifocal leukoencephalopathy has been reported in an individual with relapsing MS who had been taking fingolimod for over 4 years, according to a notice on the Novartis Web site (16 February 2015) [[17451]] Progressive multifocal leukoencephalopathy (PML)-immune reconstitution inflammatory syndrome was diagnosed in an individual after the discontinuation of natalizumab (at which time PML was missed by MRI) and the initiation of fingolimod [[15955]] To date, 11 cases of progressive multifocal leukoencephalopathy have been identified in individuals with MS previously treated with natalizumab and then treated with fingolimod; in 5 cases, PML began before fingolimod treatment began (based on retrospective review of MRI), whereas in 4 cases, PML was reported 3 weeks to 6 months after fingolimod treatment began (meeting report, September 2014) [[14088]] As a result of a drug safety communication from the US Food and Drug Administration, the label has been adjusted to indicate that one definite case, and an additional probable case, of progressive multifocal leukoencephalopathy have been reported in individuals taking fingolimod, who had not previously been exposed to immunosuppressant drugs (4 August 2015) [[20796]] A third case of progressive multifocal leukoencephalopathy has been reported in an individual with RRMS being treated with fingolimod who had not previously been treated with natalizumab; the individual had previously received chemotherapy and radiation (19 August 2015) [[21071]] Tumefactive demyelinating lesions occurred after initiation of fingolimod in a patient with active disease [[6877]] Associated with the development of a giant cavitating brain lesion (due to an active demyelinating inflammatory process) in an individual with MS; after cessation of therapy, the disease was very active [[12196]] Possibly associated with repeated tumefactive demyelinating lesions in one individual [[7879]] Associated with emerging tumefactive MS after changing treatment from interferon beta in one case [[21396]] Urinary tract infections [[24323]] Varicella-zoster virus encephalitis and vasculopathy have been reported in one patient receiving fingolimod [[3346]] Severe varicella-zoster virus reactivation has been reported in an individual receiving fingolimod [[3345]] Associated with recurrent varicella in an individual with MS, who also received steroids [[8253]] Rates of varicella-zoster virus infections are higher in individuals treated with fingolimod versus placebo (11 versus 6 per 1000 patient-years), based on analysis of clinical trial results, and comparable results are seen in the postmarketing setting [[15349]] Risk of herpes zoster development was found to be 40 per 1000 patient-years among 32 fingolimod-treated individuals with MS in Japan [[28414]] Varicella-zoster virus encephalitis occurred in an immunized individual during treatment with fingolimod [[18640]] Caused peripheral vascular adverse effects in an individual with MS [[21373]] Associated with reversible cerebral vasoconstriction syndrome, which occurred three months after childbirth, in an individual with RRMS [[20929]] Appeared to exacerbate ventricular arrhythmia in an individual with MS [[24767]] Associated with ventricular tachycardia in one individual, such that the episode occurred within one month of fingolimod initiation [[18176]] Decreases left ventricular systolic function, as shown in a study involving 53 individuals with MS, an effect that does not result in clinical consequences in the absence of other cardiac problems [[19489]] Not associated with an increased risk of serious cardiovascular events, malignancies, or infections (including herpes infections and serious infections), based on integrated long-term safety data from Phase II and III studies [[18439]] Concomitant use of either fingolimod or natalizumab is not associated with complications of Dengue fever in individuals with MS, as shown in a study of 15 individuals [[29033]] Withdrawal can lead to a return to pre-treatment disease activity (as measured by clinical and magnetic resonance outcomes) or rebound activity, as shown in a study of six RRMS patients [[2607]] Withdrawal has led to rebound activity during pregnancy [[6791]] Suspension of treatment led to rebound in a pediatric-onset patient [[5916]] Discontinuation led to severe disease reactivation in one individual, potentially due to immune reconstitution inflammatory syndrome [[14532]] Discontinuation led to severe disease reactivation 2 to 4 months later in 4 cases [[18638]] Cessation of therapy was associated with tumefactive demyelinating lesions in 3 individuals who had been free of clinical and radiological disease activity during therapy [[23648]]	Clinical trials have been sponsored by Novartis Pharma [[303]] [[302]] [[304]] Marketed by Novartis [[307]] Licensed from Mitsubishi Tanabe Pharma Corporation [[468]] US patent covering the process of fingolimod preparation has been granted to Mapi Pharma Ltd. of Israel, which plans to develop a generic version in anticipation of the loss of market exclusivity by Novartis (an event that will occur in 2017 in some markets) (18 February 2014) [[9853]] Positive opinion for expansion of EU label to include adult individuals with RRMS who have not responded to at least one other disease-modifying therapy has been issued by the Committee for Medicinal Products for Human Use (29 April 2014) [[11098]]; extended license has been approved by the European Commission (June, 2014) [[11607]] Under a new policy from the National Health Service in England, can now be prescribed to individuals who have not responded to beta interferons or glatiramer acetate or who are at risk for side effects of natalizumab, rather than just those who have not responded to interferon (2 July 2014) [[12110]] Endorsed by the Scottish Medicines Consortium for treating rapidly evolving, severe RRMS (October, 2014) [[14644]] Generic version Neskler has been approved by the Russian Ministry of Health (November 2014) [[25783]] Generic version Neskler has been launched in Russia and other countries in the EuroAsian Economic Union by Biointegrator after Novartis claims against Biointegrator were rejected in a series of court hearings (11 January 2016) [[25783]]
[+]	Firategrast	Phase II [[1338]] [[1339]]	Phase II [[1338]] [[1339]]	Inflammatory bowel disease [[1376]]	Oral [[1338]] [[1339]]	Increase in levels of hepatic enzymes [[1338]] Headache [[1338]] Rash [[1338]] Urinary tract infections [[1338]]	Under development by GlaxoSmithKline [[2718]]
[+]	Flupirtine	Phase II [[1500]]	Approved in Europe [[1342]]	Musculoskeletal pain [[1342]] Neuralgias and neuritis [[1342]] Headache [[1342]] Dysmenorrhea [[1342]] Postoperative cancer and trauma pain [[1342]] Under investigation for fibromyalgia [[1499]] Under investigation for prion disease/ Creutzfeldt-Jakob disease [[1343]]	Oral [[1499]] [[1342]]	Dizziness [[1342]] Drowsiness [[1342]] Dry mouth [[1342]] Fatigue [[1342]] Heartburn [[1342]] Liver function abnormalities in a small number of patients [[1342]] Nausea [[1342]]	Originally developed by Asta Medica [[1497]] [[1340]] Being developed and commercialized to treat fibromyalgia by Synthetic Biologics [[1497]] Marketed for pain indications in various European countries by Meda [[1497]]
[+]	Glatiramer acetate	Approved in US (1996), EU, and other countries for RRMS [[487]] [[488]] Approved in US (2009) and other countries for treating CIS patients in cases suggestive of MS [[487]] [[488]] Generic version has been approved in US (2015) [[18343]] Generic version has been approved in Europe (2016) [[29276]]	Approved [[488]]	Has positive effects in a mouse model of Alzheimer disease [[383]] Safety and tolerability in individuals with Alzheimer's disease will be examined in a Phase I trial launched by Cedars-Sinai (13 August 2013) [[7264]] Did not affect progression of amyotrophic lateral sclerosis (ALS) in a human trial, although it has positive effects in a mouse model of ALS [[358]] [[396]] Reduces risk of developing cerebral malaria, a condition that appears to involve host immune responses, in an experimental mouse model [[366]] Might be useful in treating diseases with endothelial dysfunction, based on studies in human umbilical vein endothelial cells [[15980]] Might be useful for controlling epileptic seizures, based on experiments in rats [[9266]] Inhibits graft rejection in mice [[399]] May be useful in Guillain-Barré syndrome, a demyelinating disease of the peripheral nervous system, on the basis of experiments in experimental autoimmune neuritis rats, which serve as a model of that disease [[8820]] Reduces inflammation and neurodegeneration in a mouse model of HIV1 encephalomyelitis [[378]] Might be useful for treating Huntington's disease, based on experiments in mice and cultured cells [[14643]] Has positive effects in mouse models of inflammatory bowel disease [[387]] [[3236]] Weekly vaccination decreased symptoms of dry age-related macular degeneration in a small human trial [[369]] Might have therapeutic use in osteoarthritis, based on studies of isolated human chondrocytes [[10276]] May be useful in treating acute ischemic stroke, based on studies in rat [[18034]] Did not show potential as a therapy against acute ischemic stroke in a mouse study [[9991]]	Involves daily subcutaneous injection, according to information from the US Food and Drug Administration [[492]] Prefilled syringes contain 20 mg glatiramer acetate in solution [[489]] [[492]] Three-times-weekly (40 mg/1 ml) subcutaneous injection has been approved by the US Food and Drug Administration [[9532]] Intramuscular version (GA Depot, which consists of microspheres containing glatiramer acetate) given once every 4 weeks is being tested in a Phase IIa study that began December, 2014 [[15983]] [[15984]] Nasal administration appears effective in experimental autoimmune encephalomyelitis mice [[5357]]	IgE-mediated allergic reactions to glatiramer acetate after the initial dose have been described in 3 individuals with MS [[16669]] Dyspnea (shortness of breath) [[354]] Associated with a case of eosinophilia that resulted in shock, respiratory distress, and eosinophilic myocarditis [[13030]] May have contributed to the development of Guillain-Barré syndrome in one patient [[1747]] Associated with severe acute hepatitis in one patient [[2752]] Induced acute hepatitis in one case; markers of infection or autoimmunity were not observed [[18444]] Can potentially unmask hepatitis, based on the observation of (possible and definite) autoimmune hepatitis in two individuals during treatment with glatiramer acetate, who had previously exhibited hepatitis exacerbations during treatment with interferon beta-1a [[18404]] Hepatotoxicity (in the absence of positive autoimmune markers) has been reported in a pediatric patient [[6909]] Hypersensitivity [[354]] Rarely induces delayed-type hypersensitivity reactions, and this response involves T(H)1 cells that express skin-homing receptors, as shown by analysis of the responses of two patients [[3066]] Injection-site reactions [[354]] Long-term use (≥2 years) is associated with a high prevalence (75%) of individuals exhibiting ≥1 cutaneous adverse event at a given point in time, based on a cross-sectional study [[8088]] Meralgia paresthetica has been reported after subcutaneous injection [[17249]] Administration was associated with Nicolau syndrome in an individual with RRMS [[12204]] Subcutaneous injections were associated with recurrent Nicolau syndrome in an individual with MS [[24432]] Lipoatrophy [[11849]] Long-term treatment is associated with injection-site indurations and panniculitis/lipoatrophy, which can be reduced through endermology, as shown by a 6-week study, involving endermology twice per week for 70 individuals with RRMS [[12534]] Associated with the development of injection-site cutaneous necrosis and radial nerve palsy in an MS patient with psoriasis [[6463]] Urticaria (hives) [[354]] Reduced the efficacy of vaccination against pandemic H1N1 (swine flu, in 2009) and seasonal influenza (in 2010) [[9326]] Vasodilatation [[354]] Is associated with a lower risk of adverse events as compared with dimethyl fumarate and teriflunomide, based on meta-analysis of 3 randomized controlled trials involving 3737 individuals with RRMS [[15086]] Exposure during pregnancy does not seem to be a major teratogenic risk, based on an analysis of 41 pregnancies [[3117]] Exposure during pregnancy is not associated with an increased risk of spontaneous abortion or other negative pregnancy or fetal outcomes, based on a prospective observational study of 423 pregnancies, 17 of which involved glatiramer acetate exposure [[3681]] Was not associated with an increased incidence of thyroid dysfunction or autoimmunity in an Italian multicenter study [[9717]] Exposure in would-be fathers just before (within 64 days, the duration of spermatogenesis) or at the time of conception does not appear to be associated with lower birth weight or a change in gestational age of newborns, based on an analysis of 16 cases [[10217]] Paternal exposure was not associated with increased risk of spontaneous abortion, congenital malformations, or adverse fetal outcomes, based on a study of 6 pregnancies fathered by men with MS exposed to glatiramer acetate at time of conception as compared with 33 pregnancies fathered by men with MS without disease-modifying therapy exposure at that time [[11360]]	In North America, marketed by Teva Neuroscience, a subsidiary of Teva Pharmaceutical Industries [[487]] In Europe, marketed by Teva Pharmaceutical Industries and Sanofi-aventis [[487]] Sales and marketing rights in the EU have been taken back from Sanofi by Teva (May 2012) [[1768]] Teva has attempted to delay marketing approval of generic versions of Copaxone through legal measures against other companies and regulatory channels; Teva's fourth petition to US Food and Drug Administration, asking that marketing for a generic version would not be approved without clinical trials, was denied, as the previous three had been (5 December 2012) [[4142]] Application for a US patent for a Copaxone-Laquinimod mixed treatment (which would be administered via an injection) for MS has been filed by Teva (13 February 2013) [[4980]] Application for US Food and Drug Administration (FDA) approval for a 40 mg/1 ml three-times weekly dose of Copaxone has been filed by Teva (March, 2013) [[5913]] and accepted for review by the FDA (30 May 2013) [[6234]] Patent covering the use of a combination of estriol and glatiramer acetate for treating MS has been issued to the Regents of the University of California by the US Patent & Trademark Office (4 April 2013) [[5533]] US patent for a long-acting formulation (a prolonged-release version now under development that would be injected once a month rather than daily) has been granted to Mapi Pharma Ltd (6 May 2013) [[6093]] Will lose patent protection in 2014 instead of 2015 on the basis of a US appeals court ruling; Novartis and Momenta Pharmaceuticals are developing a generic version together, as are Mylan Inc and Natco Pharma (26 July 2013) [[6936]] Validity of Teva's patent protection is upheld until May 2015 by the Court of Appeal for England and Wales (29 July 2013) [[7122]] Commercialization rights in Japan have been granted to Takeda Pharmaceutical Company by Teva Pharmaceutical Industries; a New Drug Application to register the drug in Japan will be submitted by Takeda (announced 4 December 2013) [[8821]] New Drug Application for use of glatiramer acetate in Japan to prevent relapses in MS has been submitted by Takeda Pharmaceutical Company to the Japanese Ministry of Health, Labour and Welfare (25 December 2014) [[16158]] Three-times-weekly (40 mg/1 ml) Copaxone dose has been approved by the US Food and Drug Administration (28 January 2014) [[9532]] Generic version is being developed by Synthon; Phase III clinical trial is underway (March, 2014) [[10368]] [[10369]] US Supreme Court will hear Teva's appeal of the decision of a lower court that invalidated the claim of a US patent that covers the manufacture of the active ingredient in Copaxone and that expires in September 2015 (31 March 2014) [[10397]] US Supreme Court will not prevent a lower-court ruling (favoring generic versions of glatiramer acetate) from going into effect while the Supreme Court considers appeal (18 April 2014) [[10839]] US Patent to Mapi Pharma Ltd., covering "glatiramer acetate depot" (a prolonged release formulation), has been extended to December 2030 and an earlier patent has been awarded additional claims (27 May 2014) [[11295]] Abbreviated new drug application from Mylan for generic three times per week glatiramer acetate 40 mg/ml has been accepted for filing by the US Food and Drug Administration (28 August 2014) [[13429]] Three-times-weekly (40 mg/1 ml) Copaxone dose has received a positive outcome in Europe after a Positive Assessment Report from the Reference Member State’s Medicines and Healthcare Products Regulatory Agency and other EU member states (4 December 2014) [[15730]] Phase IIa study of GA Depot for treating RRMS has begun; study is being conducted by Mapi Pharma (December, 2014) [[15983]] US Supreme Court reverses a decision by the Federal Circuit Court that invalidated one of Teva's patents for Copaxone; the case has been remanded to the Federal Circuit for further review (20 January 2015) [[16574]]; the US Court of Appeals for the Federal Circuit again invalidated the patent (18 June 2015) [[19751]] Glatopa (a substitutable generic for Copaxone 20 mg), which was developed in a collaboration between Momenta Pharmaceuticals and Sandoz, has been approved by the US Food and Drug Administration for treating RRMS (16 April 2015) [[18343]] Glatopa, a generic equivalent of Copaxone 20 mg, has been launched in the US by Sandoz, as announced by Momenta Pharmaceuticals (18 Jun 2015) [[19752]] Exclusive commercialization rights in the US for the potential generic version being developed by Synthon have been acquired by Pfizer (3 August 2015) [[20667]] Copaxone (20 mg subcutaneous injection) has been approved in Japan for treating MS; the approval was obtained by Takeda Pharmaceutical Company (September 28, 2015) [[22071]] Three-times-weekly (40 mg/1 ml) Copaxone dose has been approved in Russia for treating RRMS (8 October 2015) [[22567]] Synthon's generic version (20 mg/ml) has been approved in Europe on the basis of results from the GATE trial (12 April 2016) [[29276]]
[+]	GNbAC1	Phase IIa trial results have been published (November 2014) [[15278]]	Phase II [[10315]]		Intravenous infusion [[8947]]	Acute pancreatitis occurred in 1 individual with a history of biliary disease [[10845]]	Clinical trials have been sponsored by GeNeuro SA [[8947]] [[10315]] GeNeuro enters a strategic partnership with Servier for the development and marketing of GNbAC1 (2 December 2014) [[15551]] GNbAC1 development will be carried out by GeNeuro until Phase IIb studies in MS are complete; this work will be financed by $47 million from Servier (agreement announced 2 December 2014) [[15551]] After Phase IIb studies are complete, Servier can exercise an option to license GNbAC1 for markets outside of the US and Japan; GeNeuro will retain full control of US and Japan markets (agreement announced 2 December 2014) [[15551]] Servier will cover the costs of Phase III global development (agreement announced 2 December 2014) [[15551]] Servier has exercised its option to become a minority shareholder in GeNeuro (18 December 2015) [[24962]]
[+]	Idebenone	Phase I/II trial is recruiting as of November, 2013 [[8693]]	Approved for treating Leber's hereditary optic neuropathy in the EU [[22307]]	Approved in the EU for treating Leber's hereditary optic neuropathy (a mitochondrial disorder) [[22307]] Has been studied in clinical trials for use in Alzheimer's disease; in some studies, the drug was associated with clinical improvement, but in another large study, no benefits were observed [[8772]] Phase III trial for use in Duchenne muscular dystrophy is underway (November, 2013) [[8769]] Found to delay loss of respiratory function in Duchenne muscular dystrophy in a Phase III clinical trial (press release, May 2014) [[11093]] Phase III trials for use in the neurodegenerative disease Friedreich's ataxia have been undertaken in North America and Europe [[8696]] Has been successfully used to treat respiratory failure in an individual with Leigh syndrome, a neurometabolic condition that is caused defects in mitochondrial function [[8767]] Phase II trial for use in MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, which is caused by a mitochondrial mutation) has been initiated [[8768]] Has been tested in topical skincare formulations for treating photodamaged skin [[8754]]	Oral [[8693]] Dose in clinical trial for PPMS is 2250 mg per day (750 mg dose, 3 times per day) [[8693]] [[8764]]	Long-term (2 year) treatment (60 or 300 mg per day) was not associated with any remarkable side effects in a study of elderly people with cerebral arteriosclerosis [[8759]] Attention disturbances [[8766]] Fatigue [[8766]] Headache [[8766]] Loose stool [[8766]]	Initially developed in Japan, where it was licensed for treating Alzheimer's disease [[8696]] Patented by Takeda Chemical Industries, Japan [[8759]] Introduced into the Japanese market in 1986 [[8759]] Post-marketing data are available from over 8 million people [[8696]] Withdrawn from the Japanese market in 1998 because of lack of proven efficacy in Alzheimer's disease [[8773]] Under development for orphan mitochondrial and neuromuscular conditions by Santhera Pharmaceuticals [[8762]] Conditionally approved by Health Canada for the treatment of Friedreich's ataxia (24 July 2008) [[8763]] Can be obtained in some European countries on a "named patient" basis for treating Friedreich's ataxia as of November 2008 [[8773]] Clinical trial to assess use in PPMS involves a collaboration between the US National Institutes of Health (which is conducting the trial) and Santhera Pharmaceuticals (which is supplying idebenone) (24 June 2009) [[8764]] Sales in Canada for the treatment of Friedreich's ataxia were discontinued voluntarily by Santhera Pharmaceuticals after additional clinical studies (30 April 2013) [[8765]] Marketing authorization for treating Leber's hereditary optic neuropathy has been recommended by the European Medicines Agency's Committee for Medicinal Products for Human Use (26 June 2015) [[19919]] Marketing authorization for treating Leber's hereditary optic neuropathy has been granted by the European Commission (9 September 2015) [[22307]]
[+]	Imilecleucel-T	Phase II trial is ongoing as of September, 2013 [[7755]]	Phase II [[7755]]	Phase I study of inoculation with attenuated autologous T cells has been undertaken in individuals with rheumatoid arthritis [[7701]] Vaccination with attenuated autologous T cells has been tested in two individuals with Crohn's disease [[7702]] Vaccination with attenuated T cells can prevent the development of autoimmune diabetes in mice [[7703]] Lose-dose T cell vaccination induces resistance to experimental autoimmune uveoretinitis in rats [[7704]] Vaccination with activated, alloantigen-primed T lymphocytes improves survival of cardiac allografts in rats [[7705]]	Subcutaneous [[7692]] [[7755]] Given 5 times per year, according to information from the manufacturer [[7692]]	Injection site erythema [[7706]] Injection site inflammation [[7706]] Injection site pain [[7706]] Injection site pruritus [[7706]]	Clinical trials have been sponsored by Opexa Therapeutics [[7709]] [[7755]] [[7759]] [[7760]] Tovaxin for treating SPMS has been given a Fast Track Designation by the US Food and Drug Administration (8 November 2011) [[7756]] Name for this therapy has been changed from Tovaxin to Tcelna by Opexa Therapeutics (21 May 2012) [[7757]] An agreement has been executed between Opexa Therapeutics and Merck Serono, such that Merck has been given the option for an exclusive license to develop and commercialize imilecleucel-T and Opexa has been given a $5 million payment (5 February 2013) [[7758]] The option and license agreement between Opexa Therapeutics and Merck Serono has been amended; Opexa will receive additional funding ($3 million) to support the Phase IIb Abili-T trial of imilecleucel-T (9 March 2015) [[17450]]
[+]	Interferon beta-1a	Approved [[1063]] [[1064]]	Approved [[1063]] [[1064]]	Early stage trials for Alzheimer’s disease [[1088]] Has been studied for HTLV-1-associaed myelopathy [[1089]] Early stage trials for stroke [[1090]]	Intramuscular [[1063]] Subcutaneous [[1064]] Plegridy dose is 125 microg injected subcutaneously once every 2 weeks, according to information from the manufacturer [[13074]] Missing a dose within the first month of observation is associated with reduced adherence to treatment and increased chance of relapse [[21584]]	Peginterferon beta-1a is associated with lower frequencies of adverse events than subcutaneous interferon beta-1a (Rebif), as shown in a crossover study involving 30 healthy individuals [[29067]] Abdominal pain [[1064]] Asthenia (weakness) [[1063]] Autoimmune disorders [[1063]] Cardiovascular events [[1063]] Reversible cerebral vasoconstriction syndrome has been reported in an individual with MS treated with interferon beta-1a [[28471]] Chills [[1063]] Depression [[1063]] [[1064]] Fever [[1063]] Flu syndrome [[1063]] [[1064]] Associated with flu-like syndrome (FLS); individuals carrying a G>C polymorphism at position -174 in the interleukin 6 (IL-6) promoter in at least 1 copy of the IL-6 gene exhibit reduced levels of serum IL-6 and are less likely to develop FLS (which is less severe when it does occur), as shown in a prospective observational study involving 190 individuals with MS beginning treatment with intramuscular interferon beta-1a [[20912]] Associated with flu-like syndrome (FLS); individuals carrying a G>A polymorphism at position -376 in the tumor necrosis factor-alpha promoter do not exhibit a reduced risk for FLS, as shown in a prospective observational study involving 190 individuals with MS beginning treatment with intramuscular interferon beta-1a [[20912]] Associated with tip variant focal segmental glomerulosclerosis in one individual with MS [[9670]] Headache [[1063]] [[1064]] Rebif was associated with the development of an autoimmune hepatitis-like syndrome after therapy began in one individual [[10897]] Associated with severe acute autoimmune hepatitis in two individuals with MS [[16896]] Injection site reactions [[1063]] [[1064]] Long-term use (≥2 years) is associated with a high prevalence (82% for subcutaneous administration and 41% for intramuscular administration) of individuals exhibiting ≥1 cutaneous adverse event at a given point in time, based on a cross-sectional study [[8088]] Leukopenia [[1064]] Myalgia [[1063]] [[1064]] Can induce the production of neutralizing antibodies (NABs) against interferon beta, which might suppress the anti-viral effects of endogenous interferon beta, as suggested by a case study in which a woman with MS exhibited genital herpes reactivation after stopping and re-starting interferon beta-1a treatment; she displayed high NAB titers [[17848]] Seizures [[1063]] Elevated liver enzymes [[1064]] Severe liver injury [[1063]] [[1078]] Associated with acute liver failure, which occurred 4 weeks after initiation of treatment with interferon beta-1a, in an individual with MS [[24692]] Pulmonary arterial hypertension has been reported in two individuals with RRMS on long-term interferon beta-1a therapy; symptoms stabilized in one case after interferon beta-1a treatment ceased [[23759]] Interferon beta treatment has been associated with the development of severe systemic side effects in MS patients with rare variants in MEFV (Mediterranean fever gene) in a Belgian population [[4609]] May have promoted the relapse of non-seminomatous testicular cancer in the lung and lymph nodes in one individual with MS [[14287]] Interferon beta has been associated with thrombotic microangiopathy caused by acquired ADAMTS13 deficiency, which was in turn the result of anti-ADAMTS13 IgG antibodies that developed after interferon beta therapy in one MS patient [[5053]] Rebif has been associated with an unanticipated number of cases of thrombotic microangiopathy linked with severe hypertension; the cases have occurred in individuals with MS who had been treated for years with this drug but who did not exhibit other potential causal factors, including genetic factors [[2552]] Rebif has been linked with 4 cases of thrombotic microangiopathy associated with severe or malignant hypertension in Scotland; in each case, the individuals had previously tolerated treatment well for years [[10838]] Association of interferon beta drugs with thrombotic microangiopathy and nephrotic syndrome has led the European Medicines Agency to require stronger label warnings for Avonex, Plegridy, and Rebif (August 2014) [[13174]] The rate of thrombotic microangiopathy, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome reports associated with subcutaneous interferon beta-1a was found to be 7.2 per 100,000 patient-years in a cumulative review of a global safety database [[18399]] Warning about a risk of thrombotic microangiopathy has been added to the patient package insert of Avonex, Plegridy, and Rebif by the US Food and Drug Administration (December 2015) [[26159]] Interferon beta has been associated with an increased incidence of thyroid dysfunction and thyroid autoimmunity during the initial year of treatment in an Italian multicenter study [[9717]] Has been associated with the development of tumefactive brain lesions in neuromyelitis optica [[15853]] Does not affect thyroid or salivary gland function in individuals with RRMS, as assessed with quantitative salivary gland scintigraphy [[11939]] Exposure to interferon beta during pregnancy does not seem to be a major teratogenic risk, based on an analysis of 78 pregnancies [[3117]] Exposure in would-be fathers just before (within 64 days, the duration of spermatogenesis) or at the time of conception does not appear to be associated with lower birth weight or a change in gestational age of newborns, based on an analysis of 37 cases of exposure to interferon beta [[10217]] Paternal exposure was not associated with increased risk of spontaneous abortion, congenital malformations, or adverse fetal outcomes, based on a study of 39 pregnancies fathered by men with MS exposed to interferon beta at time of conception as compared with 33 pregnancies fathered by men with MS without disease-modifying therapy exposure at that time [[11360]] Does not cause teratogenic effects at the macroscopic level in cultured rat embryos, but does retard embryonic growth [[25145]] Interferon beta did not reduce the efficacy of vaccination against pandemic H1N1 (swine flu, in 2009) or seasonal influenza (in 2010) [[9326]] Interferon beta was not found to be associated with an increased risk of cancer (overall or specifically breast, colorectal, lung, or prostate) over 12 years in a case-control study involving 5146 individuals with RRMS, but a non-significant trend toward an association with breast cancer was detected [[10079]] Does not appear to affect pure-tone hearing sensitivity at test frequencies ranging from 250 to 6000 Hz, but it is unclear whether there is an ototoxic effect at 8000 Hz [[15005]]	Avonex was developed and is manufactured and marketed by Biogen Idec [[1063]] Rebif is manufactured by EMD Serono and is co-marketed by Serono and Pfizer in the US as of 2003 [[1064]] Plegridy (a form of interferon beta-1a that is pegylated to increase its half-life, allowing dosing less frequently) was developed by Biogen Idec [[13074]] CinnoVex was engineered and developed by the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB in Germany in a collaboration with CinnaGen in Iran [[14168]] CinnoVex has been approved as a biogeneric by the Iranian Food and Drug Administration (2006) [[14168]] CinnoVex is manufactured and marketed by CinnaGen [[1065]] Rebif Rebidose (a single-use auto-injector for interferon beta-1a) has been approved by the US Food and Drug Administration (3 January 2013) [[4437]] Biologics License Application for Plegridy has been submitted to the US Food and Drug Administration by Biogen Idec (21 May 2013) [[6231]] Biologics License Application for marketing approval of Plegridy has been accepted by the US Food and Drug Administration; a standard review timeline (about 10 months) will be used (19 July 2013) [[6894]] [[6895]] Marketing Authorisation Application for review of Plegridy in the EU has been accepted by the European Medicines Agency (19 July 2013) [[6894]] Rebif will lose patent protection at the end of 2013 [[8383]] Date for review of the Biologics License Application for marketing approval of Plegridy by the US Food and Drug Administration has been extended by three months (March 2014) [[10176]] Plegridy has been recommended for approval for treating RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency (23 May 2014) [[11227]] Plegridy has been approved in the EU for treating adults with RRMS (23 July 2014) [[12567]] Plegridy has been approved in the US for treating individuals with relapsing forms of MS (15 August 2014) [[13074]] Biogen Idec, which markets Avonex and Plegridy, has changed its name to Biogen (23 March 2015) [[18038]] Plegridy has been approved in Canada for treating adults with RRMS (13 August 2015) [[20911]] Sole rights to Rebif in the US have been taken on by EMD Serono as of 1 January 2016 [[25784]]
[+]	Interferon beta-1b	Approved in US, EU, and other countries for relapsing forms of MS [[1131]] [[1134]] [[1170]] [[1161]] Approved in EU for CIS, RRMS, and SPMS with active disease [[1131]] First disease-modifying therapy approved by the US Food and Drug Administration for use in MS (July, 1993) [[1179]] [[1161]]	Approved [[1179]]	Has been tested in pilot studies for use in chronic viral dilated cardiomyopathy [[1162]] Has been tested but not found to be effective for use in neuromyelitis optica [[1163]]	For Betaseron, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer [[1170]] For Extavia, the recommended dose is 0.25 mg by subcutaneous injection every other day, according to information from the manufacturer [[1178]] The Betaconnect autoinjector was associated with a high level of patient satisfaction in an industry-funded study involving 118 individuals with MS [[24625]]	Anaphylaxis [[1170]] Decreased neutrophil count [[1131]] Decreased white blood cell count [[1131]] Depression [[1170]] Elevated liver enzymes [[1131]] One case of severe liver dysfunction has been reported in a patient who received interferon beta-1b and who had taken a melilot (sweet clover) supplement containing coumarin for three years [[1965]] Flu-like symptoms (which generally decrease after the first year) [[1131]] Injection site necrosis [[1170]] Injection site reactions (such as redness, swelling, pain, and hypersensitivity) (generally decrease after the first year) [[1131]] Associated with multiple cutaneous necrotic lesions after 3 months of treatment in an individual with RRMS [[19123]] Associated with severe septal panniculitis at the injection site in an individual with MS [[16333]] Long-term use (≥2 years) is associated with a high prevalence (75%) of individuals exhibiting ≥1 cutaneous adverse event at a given point in time, based on a cross-sectional study [[8088]] Lymphopenia [[1131]] Lymphadenopathy [[1131]] Nephrotic syndrome, with membraneous nephropathy revealed by histology, has occurred in two MS patients after long-term therapy [[4628]] Nephrotic syndrome (suggestive of lupus nephritis) has been observed in one patient (with no evidence of systemic lupus erythematosus) after long-term treatment, which partially subsided after the patient switched to glatiramer acetate [[4835]] Associated with pulmonary and cutaneous sarcoidosis in one individual with MS [[9103]] Seizures [[1170]] Interferon beta treatment has been associated with the development of severe systemic side effects in MS patients with rare variants in MEFV (Mediterranean fever gene) in a Belgian population [[4609]] Suicide [[1170]] Induced Sweet's syndrome in one MS patient [[6510]] Interferon beta has been associated with thrombotic microangiopathy caused by acquired ADAMTS13 deficiency, which was in turn the result of anti-ADAMTS13 IgG antibodies that developed after interferon beta therapy in one MS patient [[5053]] Association of interferon beta drugs with thrombotic microangiopathy and nephrotic syndrome has led the European Medicines Agency to require stronger label warnings for Betaferon and Extavia (August 2014) [[13174]] Warning about a risk of thrombotic microangiopathy has been added to the patient package insert of Betaseron and Extavia by the US Food and Drug Administration (December 2015) [[26159]] Interferon beta has been associated with an increased incidence of thyroid dysfunction and thyroid autoimmunity during the initial year of treatment in an Italian multicenter study [[9717]] Has been associated with the development of tumefactive brain lesions in neuromyelitis optica [[15853]] Associated with livedo reticularis and secondary Raynaud phenomenon in one individual with MS, which, along with complications seen in other individuals, suggest that the drug can have vasoconstrictive and procoagulant effects [[9241]] Exposure to interferon beta during pregnancy does not seem to be a major teratogenic risk, based on an analysis of 78 pregnancies [[3117]] Not associated with increased rates of pregnancy-related adverse events or birth defects in a prospective observational study involving a registry of 99 pregnant women with MS [[10970]] Exposure to Betaferon/Betaseron during pregnancy is not associated with an increased rate of birth defects or spontaneous abortion, according to data on 423 prospective pregnancies (pregnant at time of reporting) with known outcomes in a pharmacovigilance database [[13457]] Exposure in would-be fathers just before (within 64 days, the duration of spermatogenesis) or at the time of conception does not appear to be associated with lower birth weight or a change in gestational age of newborns, based on an analysis of 37 cases of exposure to interferon beta [[10217]] Paternal exposure was not associated with increased risk of spontaneous abortion, congenital malformations, or adverse fetal outcomes, based on a study of 39 pregnancies fathered by men with MS exposed to interferon beta at time of conception as compared with 33 pregnancies fathered by men with MS without disease-modifying therapy exposure at that time [[11360]] Does not cause teratogenic effects at the macroscopic level in cultured rat embryos, but does retard embryonic growth [[25145]] Interferon beta did not reduce the efficacy of vaccination against pandemic H1N1 (swine flu, in 2009) or seasonal influenza (in 2010) [[9326]] Interferon beta was not found to be associated with an increased risk of cancer (overall or specifically breast, colorectal, lung, or prostate) over 12 years in a case-control study involving 5146 individuals with RRMS, but a non-significant trend toward an association with breast cancer was detected [[10079]]	Betaferon/Betaseron was developed by Schering AG (which operated as Berlex Laboratory in North America), a company that was taken over by Bayer HealthCare [[1177]] Betaferon/Betaseron is marketed by Bayer HealthCare [[1177]] Novartis introduced Extavia in 2009; Extavia is manufactured by Bayer HealthCare and distributed by Novartis [[1177]] [[1178]] Zist Daru Danesh Ltd (Iran) began producing ZIFERON in 2010 [[1175]] [[1176]] Mountain View Pharmaceuticals received a European patent for polyethylene glycol conjugates of interferon beta-1b with enhanced biological potency (press release, June 2012) [[2104]] Filing of a supplemental Biologics License Application by Bayer for Betaconnect, a new means of delivering Betaseron, has been accepted by the US Food and Drug Administration (22 April 2015) [[18495]] Betaconnect, the first electronic autoinjector for use in treating RRMS, has been approved by the US Food and Drug Administration; this device is used for delivering Betaseron (September 25, 2015) [[22069]]
[+]	Laquinimod	Phase III trial for treating RRMS has been completed (press release 2011; publ 2012) [[809]] [[883]] Received a negative opinion for use in treating RRMS from the Committee for Medicinal Products for Human Use of the European Medicines Agency (24 January 2014) [[9529]]	Phase III trial for treating RRMS has been completed (press release 2011; publ 2012) [[809]] [[883]]	Studied for treating systemic lupus erythematosus patients with active lupus nephritis (Phase II trial) [[814]] Because of improvement in kidney function seen in lupus nephritis patients in mid-stage study, Teva plans a larger study (12 June 2013) [[6511]] Studied for treating Crohn’s disease (Phase IIa trial) [[815]] Positive data have been reported from a Phase IIa clinical trial testing the drug in active Crohn's disease (22 October 2012) [[3774]] and published (October 2014) [[14222]] Studied to examine neuroprotective effects in animal models of rheumatoid arthritis, insulin-dependent diabetes mellitus, and Guillain Barre Syndrome [[813]] Potential interactions between laquinimod and pathways in Huntington disease will be explored by an international research collaboration announced by Teva (29 July 2013) [[7125]] Will be tested for efficacy in Huntington's disease in a Phase II clinical trial that will be initiated by Teva (Aug 2014) [[13073]]	Oral dose of 0.6 mg per day has been used in clinical trials for RRMS [[809]] Tolerability was established at 0.1 to 1.2 mg per day by unpublished Phase I studies [[560]]	Abdominal and back pain [[823]] Arthralgia (joint pain) [[823]] Budd-Chiari syndrome (obstruction of hepatic veins) occurred in one patient in a Phase IIb trial [[823]] Elevations of liver enzymes [[823]]	Developed by Active Biotech [[813]] Licensed to Teva Pharmaceutical Industries for development and commercialization, through an agreement with Active Biotech [[813]] Granted fast-track review status by the US Food and Drug Administration in 2009 [[818]] [[348]] After a meeting with the US Food and Drug Administration, Teva decided that filing a New Drug Application would be premature and that another clinical trial should be undertaken (2 November 2011) [[9530]] Validation process for marketing authorization for RRMS has been completed by the European Medicines Agency, indicating that the formal scientific review process can begin, according to Active Biotech (17 July 2012) [[2565]] Application for a US patent for a Copaxone-Laquinimod mixed treatment (which would be administered via an injection) for MS has been filed by Teva (13 February 2013) [[4980]] Decision about whether to approve laquinimod by the Committee for Medicinal Products for Human Use of the European Medicines Agency is expected in January, 2014 (20 December 2013) [[9105]] Received a negative opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency, which indicated that laquinimod should not receive marketing authorization in the EU because of the risk-benefit profile (24 January 2014) [[9529]] Opinion recommending against approval for treating RRMS in the EU is confirmed by the Committee for Medicinal Products for Human Use, but Teva and Active Biotech plan to continue clinical development (23 May 2014) [[11226]]
[+]	Masitinib	Phase III [[1378]] [[1381]]	Marketing Authorization Application for the treatment of pancreatic cancer has been filed with the European Medicines Agency (16 October 2012) [[3768]] Marketing Authorization Application for the conditional approval in the treatment of pancreatic cancer has been accepted by the European Medicines Agency (30 October 2012) [[3769]]	Canine mast cell tumors (registered for veterinary use in US and UK) [[1384]] Phase III trial for use in Alzheimer's disease has been launched (20 May 2013) [[6092]] Phase III trial for use in amyotrophic lateral sclerosis has begun (2013) [[8382]] Asthma (investigational) [[1378]] Gastrointestinal stromal tumors (investigational) [[1378]] May have neuroprotective effects after ischemic stroke, based on a study in rats [[14923]] Mastocytosis (investigational) [[1378]] Metastatic solid tumors (investigational) [[1378]] Multiple myeloma (investigational) [[1378]] Pancreatic cancer (investigational) [[1378]] Rheumatoid arthritis (investigational) [[1378]]	Oral [[1378]]	Abdominal pain [[1335]] [[1337]] Anemia[ [1337]] Asthenia [[1337]] Diarrhea [[1335]] [[1337]] Edema [[1335]] [[1337]] Nausea [[1335]] [[1337]] Neutropenia [[1337]] Rash [[1335]] [[1337]]	Under development by AB Science [[1378]] Trials in a variety of non-life-threatening conditions, including MS, have been halted by French regulators because of the risk of adverse events that might be fatal (2012) [[20145]]
[+]	MEDI-551	Phase I trial for relapsing forms of MS is underway as of June 2014 [[11917]] Phase II/III trial for neuromyelitis optica and neuromyelitis optica spectrum disorders is underway as of October 2015 [[24768]]	Phase II/III [[24768]]	Is being evaluated in relapsed or refractory advanced B cell malignancies in an open-label Phase I study as of 2014 [[11923]] Is being evaluated for use in relapsed or refractory chronic lymphocytic leukemia in an open-label Phase II study as of 2014 [[11918]] Is being evaluated in combination with other treatments in relapsed or refractory diffuse large B-cell lymphoma in an open-label Phase II study as of 2014 [[11921]] Is being evaluated in combination with known anti-myeloma drugs in untreated multiple myeloma in a Phase 0 study as of 2014 [[11920]] Is being evaluated for use in scleroderma in a placebo-controlled Phase I study as of 2014 [[11919]]	Intravenous [[11917]] Subcutaneous [[11917]]		Developed by MedImmune [[11914]] Clinical trial for RRMS sponsored by MedImmune [[11917]] Clinical trial for neuromyelitis optica and neuromyelitis optica spectrum disorders sponsored by MedImmune [[24768]]
[+]	Minocycline	Phase III trial is underway (as of July, 2013) [[6986]]	Approved [[6938]]	Approved by the US Food and Drug Administration for treating numerous bacterial infections, including Rocky Mountain spotted fever, respiratory tract infections, plague, cholera, urinary tract infections, and conjunctivitis, that are caused by susceptible strains of specific microorganisms [[6938]] Indicated by the US Food and Drug Administration as a useful adjunctive therapy in severe acne [[6938]] Approved by the US Food and Drug Administration for treating peridontal disease [[6943]] May be useful for treating rheumatoid arthritis, on the basis of open-label studies and placebo-controlled trials [[6977]] [[6978]] [[6979]] [[6980]] May be useful in treating acute ischemic stroke, on the basis of a single-blinded, placebo-controlled trial [[6981]] Is being studied as part of a combination therapy for treating strokes in a randomized pilot study (August 2013) [[7208]] May be useful in treating acute spinal cord injury, on the basis of a Phase II, placebo-controlled, randomized trial [[6982]] Further studies of effects in Parkinson disease may be warranted, on the basis of a Phase II, randomized, double-blind futility clinical trial [[6983]] May show a neuroprotective effect in Huntington's disease, on the basis of a 2-year study [[6984]] Displayed harmful effects on individuals with amyotrophic lateral sclerosis in a Phase III, randomized, placebo-controlled trial [[6985]] May be useful in inflammatory bowel disease, on the basis of experiments in mice [[6976]]	Oral [[6938]] Available as pellet-filled capsules and an oral suspension [[6942]]	Development of autoimmune syndromes [[6943]] Benign intracranial hypertension [[6938]] Central nervous system side effects, such as light-headedness or dizziness [[6938]] Diarrhea [[6938]] Drug Rash with Eosinophilia and Systemic Symptoms; this syndrome indicates that the drug should be immediately discontinued [[6938]] Hepatotoxicity [[6938]] May reduce the effectiveness of oral contraceptives [[6938]] Overgrowth of microorganisms that lack susceptibility, including fungi [[6938]] Photosensitivity [[6938]] Toxic effects during fetal development (often associated with effects on skeletal development); therefore, use is contraindicated during pregnancy [[6938]] Tooth discoloration, especially during fetal development and infancy and in children up to age 8 [[6938]]	Arestin is marketed by Orapharma as a topical sustained-release formulation for periodontal disease [[6943]] Dynacin is marketed by Par Pharmaceuticals [[6946]] Minocin is marketed and distributed by Triax Pharmaceuticals [[6938]] Minocin is manufactured by Patheon Pharmaceuticals for Triax Pharmaceuticals [[6938]] Myrac is marketed by Glade Pharmaceuticals [[6948]] Solodyn is marketed by Medicis for treating acne [[6945]] Ximino is marketed by Ranbaxy Laboratories for treating acne [[6949]] [[6950]]
[+]	MIS416	Phase II trial is underway (2014) [[13757]]	Phase II [[13757]]	First developed as a vaccine adjuvant [[13783]]	Intravenous [[13756]] [[13757]]	Fatigue [[9622]] Headache [[9622]] Muscle stiffness [[9622]] Myalgia (muscle pain) [[9622]] Pyrexia (fever) [[9622]]	Designed and manufactured by Innate Immunotherapeutics [[13859]] Manufacture as a medicine is approved by Medsafe, the New Zealand medicines regulator (2008) [[13875]] Clinical trials have been sponsored by Innate Immunotherapeutics [[13756]] [[13757]]
[+]	Mitoxantrone	Approved in US, EU, and other countries for RRMS, SPMS, and PRMS [[511]]	Approved in US, EU, and other countries for RRMS, SPMS, and PRMS [[511]]	Approved for acute non-lymphocyclophosphamidetic leukemia in 1987 [[522]] Approved for breast, hormone-refractory prostatic, and hepatic cancer [[505]] Decreased the frequency of relapses in neuromyelitis optica spectrum in an observational study [[3870]]	Recommended administration is as a short intravenous infusion every 3 months, according to information from the US Food and Drug Administration [[920]] Cumulative lifetime dose should be limited [[511]]	Alopecia [[505]] Amenorrhea [[505]] Bilirubin [[505]] Birth defects [[507]] Cardiomyopathy [[8224]] Cardiotoxicity [[505]] [[526]] Associated with a risk of cardiotoxicity; plasma levels of N-terminal pro-brain natriuretic peptide (evaluated before, during, and after therapy in individuals with MS) appear useful for identifying those at risk for such cardiotoxicity [[10973]] Mitoxantrone-associated cardiac dysfunction (milder forms; symptomatic congestive heart failure was not observed) occurred at a frequency of 4.1% in a German cohort of 639 MS patients, as seen in a retrospective study; the only relevant risk factor for this dysfunction was cumulative dose exposure [[14575]] Hemorrhages in central nervous system [[506]] Infertilty [[505]] Leukemia [[505]] Associated with the development of acute leukemia; when used to treat aggressive MS, the risk of therapy-related acute leukemia has been estimated to range from 0.07% to 0.81% in meta-analyses, and the estimated risk also varies by country (Italy, 0.93%; Germany and France, 0.25% to 0.41%) [[5626]] Risk of therapy-related acute leukemia is estimated as 1 in 139, based on a literature review covering 12,511 individuals with MS who had been treated with a mean dose of 90.1 mg per m[2] [[7962]] Associated with lethal acute myeloid leukemia (with a 11q23 MLL gene rearrangement) in one child with MS [[18203]] Leukopenia [[505]] Remote, standard-dose treatment may be associated with subclinical myocardial dysfunction (persistent diastolic dysfunction), based on an analysis of 50 consecutive MS patients treated in one center [[7068]] Nausea and vomiting [[505]] Palpitations [[8224]] Phlebitis [[505]] Respiratory tract infections [[505]] Thrombocyclophosphamidetopenia [[505]] Urinary tract infections [[505]] Drastically reduced or eliminated the efficacy of vaccination against pandemic H1N1 (swine flu, in 2009) and seasonal influenza (in 2010) [[9326]]	Marketed by EMD Serono, Inc. [[917]]
[+]	Mycophenolate mofetil	Phase II [[425]] [[599]]	Approved [[600]]	Autoimmune hepatitis [[439]] Autonomic ganglionopathy [[439]] Blistering dermopathies [[439]] May be useful for treating inflammatory bowel disease [[9748]] Chronic inflammatory demyelinating polyradiculoneuropathy [[439]] Inflammatory myopathies [[439]] Systemic lupus erythematosus [[439]] In combination with rituximab, controlled lupus nephritis without the use of oral steroids in a prospective observational study (publ 2013) [[6896]] Multifocal motor neuropathy [[439]] Myasthenia gravis [[439]] Neuromyelitis optica [[439]] Reduced the relapse rate in neuromyelitis optica by up to 87.4% (with a failure rate of 36%) in a retrospective, multicenter analysis [[9379]] Reduced the frequency of relapses (such that median annualized relapse rate declined from 1.5 to 0.0 after mycophenolate mofetil) and stabilized or improved disability in individuals with neuromyelitis optica spectrum disorder in a retrospective, observational study involving 59 individuals [[17414]] Psoriasis [[439]] Approved for prevention of transplant organ rejection [[597]] Vasculitic neuropathies [[439]] Vasculitides [[439]]	Oral [[600]]	Birth defects [[597]] Diarrhea [[597]] Fungal infections [[597]] High blood pressure [[597]] Miscarriage [[597]] Neutropenia [[597]] Pure red cell aplasia [[597]] Stomach pain [[597]] Swelling of lower legs, angles and feet [[597]] Viral infections (such as progressive multifocal leukoencephalopathy and BK virus-associated nephropathy) [[597]] Vomiting [[597]]	Manufactured by Genentech [[597]]
[+]	Naltrexone	Phase II [[9937]]	Approved [[9939]]	Approved by the US Food and Drug Administration for treating opioid and alcohol dependence [[9972]] [[9973]] Low dose form may provide a benefit in Crohn's disease, on the basis of a small randomized controlled trial [[9970]] Low dose form may be useful for treating some individuals with gastrointestinal disorders [[9945]] Low-dose form may be useful for treating the pain associated with fibromyalgia, as shown in two small clinical trials [[9776]] High dose (250 to 350 mg per day) had little or no effect on levodopa-induced dyskinesias in a short-term, placebo-controlled trial involving 8 individuals with Parkinson's disease [[10096]] Although the low-dose form is used as an off-label therapy for amyotrophic lateral sclerosis, there are no convincing data that it is useful for this condition [[10097]]	Given at low doses (3 to 4.5 mg per day) in oral form when used off-label for MS or in clinical studies for MS [[9935]] [[9943]] "Low-dose naltrexone" (or "LDN") indicates daily doses that are about one tenth those used for opioid addiction [[9776]] Low-dose naltrexone causes analgesia and anti-inflammatory effects that have not been observed at higher doses [[9776]] Depade (for alcohol and opioid dependence) is supplied as 25, 50, and 100 mg tablets and is taken orally once daily [[9973]] ReVia (for alcohol and opioid dependence) is supplied as 50 mg tablets and is taken orally once daily [[9973]] Vivitrol (for alcohol and opioid dependence) is given at a dose of 380 mg, administered by intramascular injection once per month, according to information from the manufacturer [[9942]]	Loss of appetite [[9935]] Asthenia (weakness) [[9937]] Enuresis [[9937]] Epigastric pain [[9936]] Facial peripheral palsy [[9937]] Fatigue [[9935]] Gastrointestinal infection [[9937]] Headache [[9936]] Prescribing information for high-dose form (Vivitrol) contains a black box warning about possible hepatotoxicity [[10098]] Hematological abnormalities [[9937]] Irritability/mood alteration [[9936]] [[9937]] Joint pain [[9936]] [[9937]] Decreased libido [[9937]] Nausea [[9936]] Renal failure [[9937]] Sinus infection [[9935]] Vivid dreaming [[9935]]	Initially synthesized at Endo Laboratories in 1963; received US patent protection in 1967 as Endo 1639A [[9972]] [[9973]] Rights acquired by DuPont in 1969, when DuPont purchased Endo Laboratories [[9972]] Development as a treatment for opioid and alcohol dependence was supported by the US National Institute on Drug Abuse and the US National Institute on Alcohol Abuse and Alcoholism [[9972]] Approved by the US Food and Drug Administration as a treatment for opioid addiction in 1984 and marketed by DuPont with trade name Trexan [[9972]] [[9973]] Approved by the US Food and Drug Administration as a treatment for alcohol use disorders in 1994, at which time DuPont changed the trade name to ReVia [[9973]] ReVia, as well as a generic version, are manufactured by Barr Pharmaceuticals [[9973]] Manufactured under the trade name Depade by Mallinckrodt [[9973]] Injectable form Vivitrol was approved by the US Food and Drug Administration for treating alcohol and opioid dependence in 2006 and 2010 [[9939]] [[9940]] Vivitrol is manufactured by Alkermes, Inc. [[9939]] [[9942]] Proprietary and legal rights for LDN (US) / Lodonal (outside of US), which has been used as an immune modulator for treating autoimmune diseases, viral infections, and cancer in clinical trials and through off-label prescription use, are held by Immune Therapeutics, Inc. [[16576]] [[16577]] Immune Therapeutics, Inc. has signed an agreement with KRS Global Biotechnology, Inc. to compound, package, and distribute naltrexone tablets in various strengths; the tablets will be prepared for shipment in the US (23 January 2015) [[16577]] Immune Therapeutics, Inc. plans to use payments from KRS Global Biotechnology, Inc. to fund the biotechnology company Cytocom Inc. to undertake clinical trials with low-dose naltrexone in conditions including MS (23 January 2015) [[16577]]
[+]	Natalizumab	Approved in the US for treating relapsing forms of MS (November, 2004) [[300]] [[593]] [[18832]] Approved in the EU for treating highly active RRMS (June, 2006) [[18832]]	Approved [[300]]	Effectively used to treat a case of Balò's concentric sclerosis, which is considered a variant of MS [[20091]] Approved for treating moderate to severe Crohn's disease in patients who do not respond to or are intolerant of other treatments [[357]] Tested in a Phase II trial for treating rheumatoid arthritis, but study was terminated because effect was not sufficient to support further development [[591]] Was unsuccessful for treating neuromyelitis optica (which later responded to immunosuppressive therapy) in one case [[11346]]	300 mg via intravenous infusion every four weeks (this information was provided by the manufacturer) [[592]] Extending the dose schedule (from 4 weeks to 5 to 8 weeks) did not reduce efficacy and was not associated with progressive multifocal leukoencephalopathy, as shown in a retrospective analysis involving 1964 individuals (meeting report, April 2015) [[18494]]; further analysis indicated that an 8-week dosing interval might reduce relapse rates and MRI lesions as compared with the 4-week interval (meeting report, October 2015) [[22569]] Review to assess whether the current approach for managing the risk of progressive multifocal leukoencephalopathy needs to be revised has been requested by the European Commission (May 2015) [[18832]]; new guidelines have been issued by the European Medicines Agency (February 2016) [[26715]]	Allergic reactions [[589]] Anaphylaxis [[589]] Associated with anaphylactoid reactions in some individuals; specific human leukocyte antigen (HLA) alleles (HLA-DRB113 and HLA-DRB114) were present at increased frequency in a group of 54 such individuals, whereas the HLA-DRB1*15 allele was present at increased frequency in a group of 65 who lacked such reactions, suggesting that HLA-DRB1 genotyping before natalizumab therapy could be useful [[15882]] Associated with severe anemia in one individual with MS [[11782]] Severe anemia has been reported in one individual with MS treated with natalizumab [[17201]] Arm and leg pain [[589]] Breathing problems [[589]] Cerebellar granule cell neuronopathy, a central nervous system disease associated with JC virus, has been observed in one patient [[6937]] Associated with granule cell neuronopathy (GCN) in a second individual, who carried JC virus containing GCN-type mutations in the VP1 capsid gene [[12474]] Associated with human papilloma virus-positive cervical dysplasia in 4 individuals with MS [[12363]] Chest pain [[589]] Chills [[589]] Cryptococcal meningitis developed in one individual with MS who was being treated with natalizumab [[10360]] Depression [[589]] Associated with acquired perforating dermatosis [[6790]] Diarrhea [[589]] Dizziness [[589]] Associated with eosinophilic fasciitis (a sclerosing syndrome) in one individual with MS [[9116]] Causes erythroblastemia (the presence of erythroblasts in the peripheral blood, a condition linked with serious disorders) in most treated individuals [[9609]] Fatigue [[589]] Flushing skin [[589]] Three individuals with apparent granule cell neuronopathy (JC virus infection of cerebellar granule cell neurons, characterized by cerebellar atrophy) were identified among 44 individuals with natalizumab-associated progressive multifocal leukoencephalopathy (PML); no cases were found in a control group of 25 natalizumab-treated individuals without PML [[26076]] Headache [[589]] Natalizumab-induced autoimmune hepatitis has been observed in one MS patient [[3607]] Herpes zoster has been reported in three cases [[5006]]; central nervous system herpesvirus infection has been confirmed in 20 cases [[6251]] Varicella-zoster virus myelitis has been reported in one patient [[5769]] Hives [[589]] Immune reconstitution inflammatory syndrome, which mimicked progressive multifocal leucoencephalopathy, has been reported in one individual with RRMS treated with natalizumab [[14937]] Acute immune reconstitution inflammatory syndrome-associated cryptococcal meningoencephalitis has been reported in an individual with MS treated with natalizumab [[28332]] Infections [[589]] Itching [[589]] Joint pain [[589]] Liver damage [[589]] Severe natalizumab-associated liver injury has been reported in 12 individuals and almost 30 cases of natalizumab-associated liver failure have been listed in the postmarketing US Food and Drug Administration's adverse event reporting system (November 2015) [[24047]] Low blood pressure [[589]] Asymptomatic lung disease resulting from an opportunistic infection of Mycobacterium kansasii has been observed in an individual with RRMS treated with natalizumab [[7280]] Possibly causally associated with primary central nervous system lymphoma in one individual [[9130]] Possibly causally associated with non-Hodgkin lymphoma of the stomach in one individual with RRMS [[20467]] Associated with melanoma in two individuals [[10178]] Likely associated with toxic acute myocardial damage in an individual with RRMS [[25832]] Nausea [[589]] Acute neuroborreliosis occurred in one individual with RRMS during long-term treatment with natalizumab [[7128]] Fatal neuroinflammation occurred in one patient with anti-natalizumab antibodies [[4881]] Can potentially exacerbate neuromyelitis optica (NMO); a single dose was associated with a catastrophic brain relapse in an individual with NMO who was seronegative for aquaporin-4 antibodies [[9990]] Progressive multifocal leucoencaphalopathy [[391]] As of 2013, has been associated with 399 cases of progressive multifocal leukoencephalopathy throughout the world [[8075]] Changes in T cell responses that are specific to JC virus [which causes progressive multifocal leukoencephalopathy (PML) only with immunodeficiency or immunosuppression] may be a risk factor for PML [[3883]] Progressive multifocal leukoencephalopathy has been detected in a patient in which four samples of cerebrospinal fluid were negative for JC virus DNA, as assayed by PCR, but a brain biopsy eventually was shown to be positive, as assayed by immunohistochemistry [[4294]] Presumptive progressive multifocal leukoencephalopathy has been detected in an RRMS patient 14 weeks after the discontinuation of natalizumab, after 36 months of therapy; cerebrospinal fluid was negative for JC virus [[4615]] Natalizumab-associated progressive multifocal leukoencephalopathy, detected presymptomatically with MRI in an MS patient, was effectively treated with plasma exchange and steroid treatment [[5018]] Increases the risk of progressive multifocal leukoencephalopathy (PML), but early detection of this condition (by brain scans and spinal fluid tests, before symptoms occur) may be associated with improved survival, as shown in an industry-sponsored study of 319 natalizumab-treated MS patients diagnosed with PML [[5224]] During prolonged natalizumab therapy, some MS patients display signs of replication of JC virus (which causes progressive multifocal leukoencephalopathy) [[5327]] Rate of JC virus seroconversion (from negative to positive) in individuals with MS receiving natalizumab has been quantified in a French cohort [[7767]] Risk for natalizumab-associated progressive multifocal leukoencephalopathy is associated with low body weight, potentially because higher drug concentrations occur in patients with lower weight [[5531]] Risk for natalizumab-associated progressive multifocal leukoencephalopathy (PML) is considered relatively low in patients testing negative for anti-JC virus antibodies, but about a third of MS patients (in a group of 49) who tested negative for such antibodies had active viremia, indicating they might in fact be at high risk for PML [[6333]] [[6312]] Risk for natalizumab-associated progressive multifocal leukoencephalopathy (PML) is higher in patients who exhibit an increased anti-JC virus antibody index more than 6 months before the PML diagnosis (relative to those without a PML diagnosis) [[6513]] Risk for natalizumab-associated progressive multifocal leukoencephalopathy may be further defined among individuals positive for anti-JC virus antibodies by the serum or plasma level of such antibodies (measured as an index); this idea would apply to individuals without prior immunosuppressant use [[14162]] Associated with a risk of progressive multifocal leukoencephalopathy (PML); a very low percentage of L-selectin-expressing CD4+ T cells is highly correlated with a risk for PML, indicating a possible biomarker for risk [[7134]] Associated with a risk of progressive multifocal leukoencephalopathy (PML); a correlation between the level of soluble L-selectin and the anti-JC virus antibody index in the sera of natalizumab-treated (but not interferon beta-treated) individuals with RRMS has been observed, indicating that soluble L-selectin might serve as a biomarker for PML risk [[20342]] Associated with a risk of progressive multifocal leukoencephalopathy (PML); a single risk algorithm that incorporates both the anti-JC virus antibody index and L-selectin (CD62L) level may be useful for reducing the incidence of PML [[22235]] A risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML) is not predicted by the percentage of CD3+ CD4+ CD62L+ cells in cryopreserved peripheral blood mononuclear cells (PBMCs), as shown in a study of cell samples from 21 individuals treated with natalizumab who developed PML and 104 matched individuals who did not [[25196]] Natalizumab-associated progressive multifocal leukoencephalopathy (PML) diagnosis might be improved by use of an anti-JC virus "antibody specificity index," a measure of the proportion of anti-JC virus antibodies in cerebrospinal fluid (CSF) versus serum (such that increased levels in CSF are associated with PML) [[8353]] Estimated occurrence of progressive multifocal leukoencephalopathy (PML) among natalizumab-treated individuals with MS (with an average of 17 months of treatment) was 1 per 1000 in 2006; with more individuals receiving treatment for longer times, the occurrence is now about 1 per 330, but rises to 1 per 90 in those with additional PML risk factors (August 2013) [[7137]] Risk for natalizumab-associated progressive multifocal leukoencephalopathy, based on the most recently available data, is higher in 2015 than in 2012, such that an individual with three risk factors (positive JC virus antibody status, >2 years of natalizumab therapy, and previous immunosuppressive therapy exposure) has ~1:44 chance of developing this disorder [[26376]] Model of natalizumab-associated progressive multifocal leukoencephalopathy risk in individuals who are sero-negative for JC virus has been developed [[8369]] Immune reconstitution inflammatory syndrome occurred in a natalizumab-treated patient with progressive multifocal leukoencephalopathy [[6789]] Initiation of progressive multifocal leukoencephalopathy and reconstitution inflammatory syndrome in natalizumab-treated individuals with MS is associated with or preceded by clonal T cell expansions [[7650]] [[7649]] Natalizumab-related risk for progressive multifocal leukoencephalopathy appears to be lower in individuals with lipid-specific IgM antibodies in the cerebrospinal fluid [[7943]] Despite the increased risk of natalizumab-associated progressive multifocal leukoencephalopathy in individuals positive for JC virus antibodies, the decision to continue natalizumab treatment is largely unaffected by JC virus antibody status, based on a study of 112 individuals [[8047]] Risk of natalizumab-associated progressive multifocal leukoencephalopathy may be increased by splenectomy, on the basis of a single case study [[8045]] Associated with progressive multifocal leukoencephalopathy (PML), but in one postmortem study of an individual with MS who developed PML after natalizumab therapy, the extensive PML lesions (which contained JC virus DNA), located in the neocortex and cerebral white matter, were distinct and separate from chronic inactive MS lesions nearby [[8075]] Associated with progressive multifocal leukoencephalopathy (PML); in one individual with RRMS treated with natalizumab, brainstem lesions were first interpreted to be MS plaques, but later became confluent and were identified as a PML lesion [[8050]] Occurrence of progressive multifocal leukoencephalopathy (PML) within 6 months after discontinuation of natalizumab for reasons not related to suspected PML has been documented in 17 patients, most (16) of whom were determined to have had at least 1 risk factor for PML at the time of natalizumab withdrawal [[8556]] JC virus-negative natalizumab-associated progressive multifocal leukoencephalopathy has been diagnosed [[9242]] Association with a risk for progressive multifocal leukoencephalopathy has led to natalizumab's use as a second-line therapy; an algorithm has been developed to select individuals for whom use as a first-line therapy might be appropriate [[9998]] Outcomes of either discontinuing natalizumab or obtaining additional screening in those at risk for natalizumab-associated progressive multifocal leukoencephalopathy have been described with decision tree models [[10121]] Benefit of continuing natalizumab treatment appears to outweigh the risk of progressive multifocal leukoencephalopathy for most individuals according to theoretical calculations [[10121]] More than 400 cases of natalizumab-associated progressive multifocal leukoencephalopathy have occurred as of March 2014 [[10173]] During prolonged natalizumab therapy, asymptomatic JC virus reactivation can occur in the cerebrospinal fluid [[10379]] Differences between natalizumab-associated progressive multifocal leukoencephalopathy with and without initial manifestations in infratentorial brain structures have been described [[10436]] Three factors (anti-JC virus antibodies, previous use of immunosuppressants, and length of natalizumab therapy) have been found to contribute to the risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML), but risk stratification did not reduce the incidence of PML in natalizumab-treated individuals with MS in the period between April 2010 and February 2014 [[10922]] Individual risk of natalizumab-associated progressive multifocal leukoencephalopathy might potentially be assessed by monitoring the expression of certain microRNAs (miR-320, miR-320b, and miR-629) in blood samples [[11208]] Associated with a risk of developing progressive multifocal leukoencephalopathy; 430 cases have been reported to date (July 2014) [[12645]] Associated with a risk of developing progressive multifocal leukoencephalopathy, especially in individuals seropositive for JC virus (JCV); individuals can be seronegative for JCV (based on serological tests) but still shed JCV DNA into the urine; furthermore, natalizumab might accelerate JCV shedding into the urine [[12645]] Associated with progressive multifocal leukoencephalopathy (PML); the number of plasmapheresis/immunoadsorption treatments (important for PML outcome) required to reach subtherapeutic serum natalizumab concentrations varies depending on the serum natalizumab concentration at the time of PML diagnosis [[12739]] Asymptomatic natalizumab-associated progressive multifocal leukoencephalopathy manifests as relatively localized disease on MRI, often affecting the frontal lobe, based on a study of 18 individuals with MS [[13640]] Early natalizumab-associated progressive multifocal leukoencephalopathy (PML) with immune reconstitution inflammatory syndrome exhibits certain characteristics in MRI; the most common first sign is patchy or punctate contrast enhancement in the border of the PML lesion, based on a retrospective study of 26 individuals with MS [[21596]] Natalizumab-associated progressive multifocal leukoencephalopathy (PML) is associated with a punctate pattern in MRI, as shown in a study of 20 individuals with PML, and this pattern might represent the first imaging feature detectable during presymmptomatic stages of PML [[28426]] Natalizumab-associated asymptomatic progressive multifocal leukoencephalopathy (PML) is associated with certain features in MRI; the most predictive features are hyperintensity on diffusion-weighted images and U fiber involvement, as shown in a retrospective study of 11 individuals with MS with such a diagnosis and 40 individuals with MS treated with natalizumab but without PML [[22284]] Natalizumab-associated progressive multifocal leukoencephalopathy (PML) is preceded by high serum anti-JC virus antibody indexes, although an increase just before PML diagnosis was not observed, as shown by a longitudinal study in 4 individuals with MS who developed PML [[17007]] Increases the risk of developing progressive multifocal leukoencephalopathy, which requires exposure to JC virus; the JC virus antibody index correlates with ultrasensitive C-reactive protein serum levels and with JC virus DNA levels in the urine [[14635]] Individuals with natalizumab-associated progressive multifocal leukoencephalopathy (PML) exhibit low total IgG levels in blood and cerebrospinial fluid at the time of PML diagnosis [[15155]] Survival and disability outcomes for individuals with natalizumab-associated progressive multifocal leukoencephalopathy (PML) are better for those who are asymptomatic at the time of PML diagnosis (by MRI and JC virus detection) than for those who are symptomatic [[15770]] Progressive multifocal leukoencephalopathy (PML)-immune reconstitution inflammatory syndrome was diagnosed in an individual after the discontinuation of natalizumab (at which time PML was missed by MRI) and the initiation of fingolimod [[15955]] Risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML) is lower in individuals with lipid-specific IgM oligoclonal bands in cerebrospinal fluid (a marker of highly inflammatory MS), as shown in a study of 24 individuals who developed PML and 343 who did not [[16259]] Survival of natalizumab-associated progressive multifocal leukoencephalopathy is more likely in those who are younger at diagnosis and have lower Expanded Disability Status Scale scores before diagnosis, lower loads of JC virus in the cerebrospinal fluid at diagnosis, less functional disability in general, and localized rather than widespread disease at diagnosis as assessed by MRI, as shown in a study of 336 individuals, 76% of whom survived this condition [[17673]] Risk of natalizumab-associated progressive multifocal leukoencephalopathy might be lower in pediatric versus adult MS patients, because the seroprevalence of JC virus antibody is lower in this pediatric population (33.3%) than reported in adults (60%), as shown in a study of 109 pediatric MS patients [[22774]] In a case of severe natalizumab-associated progressive multifocal leukoencephalopathy (PML), four neurotropic variants of the JC virus were detected in blood cells, serum, and urine, suggesting that detection of such a variant in blood might aid in the prevention of severe PML [[23040]] Natalizumab-associated progressive multifocal leukoencephalopathy (PML) has been reported in an individual using extended dosing intervals (300 mg every 6 weeks), a method that has been suggested for lowering the risk of PML [[23201]] Natalizumab-associated early progressive multifocal leukoencephalopathy (PML) lesions were distinguished from MS lesions by 7T MRI in a case in which PML and ongoing MS activity presented simultaneously [[23804]] Associated with a high annualized rate of seroconversion for anti-JC virus antibodies (7.1%, with a cumulative seroconversion rate of >25% over 4 years), as shown in a Dutch cohort of 179 individuals with RRMS; such seropositivity is a risk factor for natalizumab-associated progressive multifocal leukoencephalopathy [[28511]] Might increase seroconversion to positive JC virus antibody status, and increase JC virus index values, as shown in a study of 525 German and 711 French individuals with MS who were followed longitudinally (such that 10.3% of the German group and 8.5% of the French group converted per year); such seropositivity is a risk factor for natalizumab-associated progressive multifocal leukoencephalopathy [[29283]] Aggravated psoriasis in one patient [[3715]] Rash [[589]] Acute retinal necrosis, followed by immune reconstitution inflammatory syndrome, has been reported in an individual with MS treated with natalizumab [[18602]] Progressive outer retinal necrosis has been reported in an individual with MS being treated with natalizumab [[25801]] Reversible leukoencephalopathy syndrome (which can mimic progressive multifocal leukoencephalopathy) [[1831]] Stomach pain [[589]] Suicidal ideation might be an uncommon secondary effect of treatment (suicidal behavior has been observed in one individual with MS who was being treated with natalizumab) [[8994]] Cyclical suicidal ideation after infusion for MS has been reported [[17055]] Urinary tract infection [[589]] Reduced the efficacy of vaccination against pandemic H1N1 (swine flu, in 2009) and seasonal influenza (in 2010) [[9326]] Vaginitis [[589]] Associated with combined retinal and central nervous system vasculitis, which was linked with varicella zoster, in one individual [[9563]] Might increase the risk of subclinical varicella-zoster virus (VZV) reactivation or reinfection, based on the increased incidence of elevated levels of anti-VZV IgG in natalizumab-treated individuals with MS [[17933]] Wheezing [[589]] Use in pregnancy was associated with a reduction in CXCL12-induced T-cell chemotaxis in neonates in two cases, a change that might compromise the neonatal immune system [[3049]] Use during the entire gestational period was not associated with any problems in the pregnancy or resulting child in one case [[9822]] Use during the third trimester of pregnancy caused modest hematological alterations that included thrombocytopenia and anemia in 10 of 13 infants monitored [[10978]] Transferred to, and appeared to accumulate in, breast milk in one woman with MS who was breastfeeding her infant, but the safety of this effect was not determined [[16289]] Associated with drug-induced immune thrombocytopenia in one case [[11328]] Concomitant use of fingolimod or natalizumab is not associated with complications of Dengue fever in individuals with MS, as shown in a study of 15 individuals [[29033]] Discontinuation of treatment led to progressive multifocal encephalopathy immune reconstitution inflammatory syndrome and related malignant cerebral edema in an individual with MS [[19883]] Cessation of natalizumab [to avoid risk of progressive multifocal leukoencephalopathy (PML) or because PML was detected] was associated with immune reconstitution inflammatory syndrome in four cases; the case in which no PML was detected was fatal [[26539]] End of dosing cycle is associated with a return of MS symptoms (such as fatigue, weakness, impaired walking, and difficulties with cognition) in about two thirds of those receiving treatment, based on a study of 100 individuals; such symptoms began a median of 21 days after infusion [[12610]] Discontinuations (due to pregnancy planning) led to recurrent disease-activity rebound in an MS patient [[6438]] Discontinuation during pregnancy was associated with a strong increase in disability and a high load of MRI lesions in 4 women with MS, despite the fact that pregnancy is generally associated with disease stability [[16424]] Discontinuation due to pregnancy leads to strong rebound activity (resulting in a relapse rate of 32.2% in this study), indicating that the protective effects of pregnancy do not extend to this situation, based on an analysis of 59 women who discontinued natalizumab during pregnancy (meeting report) [[22573]] Withdrawal led to a lethal MS relapse in one patient [[3734]] Cessation of treatment is followed by relapses (with a cumulative probability of 52.9% in the year after cessation) associated with abnormal inflammatory activity (>5 gadolinium-enhancing lesions, exceeding the number before treatment), as shown in a study of 32 individuals with MS [[11314]] Withdrawal from long-term treatment, followed by a single dose after a relapse beginning 3 months after withdrawal, was associated with a massive exacerbation of MS symptoms in one individual [[13398]] Each of two episodes of natalizumab discontinuation in a study of 15 individuals was followed by disease reactivation, despite immunomodulant treatment (after the first withdrawal) or a second-line therapy such as fingolimod (after the second withdrawal) [[13969]] After natalizumab withdrawal, significant clinical worsening is associated with a higher Expanded Disability Status Scale (EDSS) score at baseline and with a 1-step increase in the EDSS during treatment [[15277]] Treatment discontinuation (as a result of concerns about the risk of progressive multifocal leukoencephalopathy) is associated with a 1 in 3 risk of disability worsening, and that risk increases to 1 in 2 if the Expanded Disability Status Scale Score is >3 when treatment begins, based on a study of data from 318 individuals who did not exhibit worsening disability in the first 2 years of treatment and a followup time of 6 years [[17250]] Discontinuation is followed by a period of high risk for disease activation (between the second and eighth months), during which most individuals return to pre-natalizumab levels of disease activity and 10% exhibit rebound activity, and neither immunomodulant therapy nor fingolimod protects sufficiently against this activity, based on a study of 110 individuals [[18438]]	Jointly developed by Elan Pharmaceuticals and Biogen Idec [[379]] Clinical trials sponsored by Biogen Idec and Elan Pharmaceuticals [[391]] [[397]] [[390]] Manufactured by Biogen Idec [[592]] Distributed by Elan Pharmaceuticals [[592]]; Biogen Idec will take full control of Tysabri in 2013 [[4904]] Available only through a special restricted distribution program (TOUCH), because of the risk of progressive multifocal leukoencephalopathy [[592]] Marketing applications for first-line use in anti-JC virus antibody negative MS patients have been submitted to the US Food and Drug Administration and the European Medicines Agency by Biogen Idec and Elan (16 January 2013) [[4629]] Full rights for and control of Tysabri will be acquired by Biogen Idec from Elan Pharmaceuticals for cash ($3.25 billion) and future contingent payments; the deal is expected to close by the end of the second quarter of 2013 (6 February 2013) [[4904]] Using some of the proceeds from the Tysabri restructuring, Elan Corporation will repurchase $1 billion of stock after the restructuring transaction with Biogen Idec is closed (22 February 2013) [[5085]] Full rights for and control of Tysabri have been purchased by Biogen Idec from Elan Pharmaceuticals (2 April 2013) [[5532]] Biogen Idec, which markets Tysabri, has changed its name to Biogen (23 March 2015) [[18038]]
[+]	Ocrelizumab	Phase III trials [[655]] [[875]] [[876]]	Phase III [[655]] [[875]] [[876]] Phase III program for rheumatoid arthritis was suspended in 2010 because of safety concerns [[877]]	Phase III trials for rheumatoid arthritis and systemic lupus erythematosus was discontinued in 2010 because of safety concerns (serious infections, some fatal, and opportunistic infections) by the Data and Safety Monitoring Board [[877]] In trials for B-cell lymphoma [[882]] A modified version of the antibody, PRO131921, with improved binding to FCγRIIIa, has been tested in relapsed or refractory chronic lymphocytic leukemia and indolent non-Hodgkins lymphoma [[441]]	Intravenous [[655]] [[875]] [[876]] [[878]]	In 24-week data announced in 2010, 1.8% of the lower-dose group and 5.5% of the higher-dose group experienced serious adverse events [[881]] Infusion-related reactions [[880]] One patient in the high-dose group of Phase II 24-week study died of acute-onset thrombotic microangiopathy [[881]] Serious opportunistic infections in rheumatoid arthritis trial [[877]]	Clinical trials have been funded by Hoffmann-La Roche Ltd and Biogen Idec [[5528]] Genentech, a wholly-owned member of the Roche Group, is now fully responsible for development and commercialization of ocrelizumab in MS; Biogen Idec will receive royalties on sales of ocrelizumab in the US (21 October 2010) [[23294]] Biogen Idec, which originally funded trials for ocrelizumab, has changed its name to Biogen (23 March 2015) [[18038]] Granted Breakthrough Therapy Designation by the US Food and Drug Administration for treating PPMS; this designation aims to speed the development and review of ocrelizumab (17 February 2016) [[26945]]
[+]	Ofatumumab	Phase I/II trial is ongoing [[432]] [[648]] [[649]] Phase II trial is ongoing [[645]] [[651]] [[8042]]	Approved [[647]]	Approved for chronic lymphocytic leukemia by the US Food and Drug Administration in 2009 [[646]], by the European Medicine Agency in 2010 [[652]], and in Japan in 2013 [[5368]] Currently in Phase III trials for relapsing or refractory follicular lymphoma and rheumatoid arthritis (2010) [[432]] Will be investigated for use in neuromyelitis optica (30 May 2014) [[11410]] Subcutaneous formulation is being investigated in a Phase III study for use in pemphigus vulgaris, a rare autoimmune disease of the skin (4 July 2013) [[6793]]	Intravenous [[648]] Subcutaneous [[645]] [[8042]]	Anemia [[429]] Anxiety [[10841]] Bronchitis [[429]] Cough [[429]] Diarrhea [[429]] Dizziness [[10841]] Dyspnea (4) Fatigue [[429]] Fever [[10841]] Infections (most commonly upper respiratory tract infections) [[429]] Infusion reactions [[429]] Injection-related reactions [[8042]] Nerve pain [[10841]] Nausea [[429]] Neutropenia [[429]] Pneumonia [[429]] Pyrexia [[429]] Rash [[429]] May lead to immunosuppression-related reactivation of the hepatitis B virus in previously-infected individuals; the US Food and Drug Administration requires this information to be displayed in a boxed warning (25 September 2013) [[7787]]	Marketed and developed by Genmab together with GlaxoSmithKline (2013) [[7637]] Clinical trial conducted by GlaxoSmithKline [[8042]] Plans for a Phase III trial for testing the subcutaneous formulation in RRMS, beginning in 2015, have been announced by Genmab after a decision was made by its partner GlaxoSmithKline (30 May 2014) [[11410]] Plans for filing an Investigational New Drug Application for a pivotal study of the subcutaneous formulation in neuromyelitis optica have been announced by Genmab after a decision was made by its partner GlaxoSmithKline (30 May 2014) [[11410]] All remaining rights for development as a treatment for MS and other autoimmune conditions have been acquired by Novartis from GlaxoSmithKline (21 August 2015); Novartis had obtained the rights for oncology indications previously [[21072]]
[+]	ONO-4641	Phase II [[626]]	Phase II [[626]]	Preclinical study in colitis has been undertaken [[418]]	Oral [[626]] [[428]]	Reduces heartbeat at the beginning of treatment [[2754]] Elevates liver enzymes [[2754]] Grade 4 lymphopenia [[2754]]	Discovered by Ono Pharmaceutical Co. [[626]] Developed by Ono Pharmaceutical Co.for commercialization in Japan, Korea, and Taiwan [[626]] Licensed to Merck Serono for development and commercialization outside of Japan, Korea, and Taiwan (October 2011) [[626]] [[11845]] License agreement between Merck KGaA and Ono Pharmaceutical has been terminated because the drug does not meet Merck's conditions for continued investment (17 June 2014) [[11845]]
[+]	Ozanimod	Positive Phase II results have been published (February 2016) [[26787]] Phase III trial is underway as of December 2014 [[15985]] [[15986]]	Phase III trial for relapsing MS is underway as of December 2014 [[15985]] [[15986]] Phase II results for relapsing MS have been published (February 2016) [[26787]] Phase II trial is planned to test efficacy in inflammatory bowel disease (May 2012) [[1841]]	Phase II trial is planned to test efficacy in inflammatory bowel disease (May 2012) [[1841]] Phase II study to test efficacy in ulcerative colitis is underway (4 January 2013) [[4438]] and has met its primary endpoint (27 October 2014) [[14922]]	Oral [[3775]] [[3776]]	No serious problems have been observed in a Phase II trial (press release 2013; publ 2016) [[8906]] [[26787]] Has some effect on heart rate, but no serious cardiac events were observed in a Phase II trial [[8906]] [[26787]] Macular edema was not observed in a Phase II trial [[17324]] [[26787]] Headache [[26787]] Nasopharyngitis [[26787]] Urinary tract infections [[26787]]	Discovered at the National Institute of Health’s Molecular Libraries Probe Production Center at The Scripps Research Institute [[3777]] Relevant patents were exclusively licensed to Receptos from The Scripps Research Institute [[3777]] Developed by Receptos [[3777]] Phase I, II, and III clinical trials sponsored by Receptos [[3777]] [[8906]] Composition of matter patents covering ozanimod have been issued by the US Patent and Trademark Office to Receptos, which have an initial term that extends to May 2029 (13 August 2013) [[7265]] Phase III trial will be initiated (5 December 2013) [[8906]] Receptos will be acquired by Celgene; this transaction should close in 2015 (14 July 2015) [[20496]]
[+]	Phenytoin	Results from a Phase II trial for optic neuritis, which is often associated with MS, have been published (2016) [[26174]]	Approved [[10867]] [[10874]]	Approved by the US Food and Drug administration for controlling generalized tonic-clonic status epilepticus [[10867]] Approved by the US Food and Drug administration for preventing and treating seizures that happen during neurosurgery [[10867]] Used for treating cardiac arrhythmias [[10876]] Used for treating oral and facial pain [[10901]] Used for treating painful dysesthesias in individuals with MS [[10902]]	Intravenous [[10867]] Intramuscular (less favored option) [[10867]] Oral [[10867]] [[10868]]	Anaphylaxis [[10867]] Decreased bone mineral density and bone fractures [[10868]] Cardiovascular reactions (associated with rapid intravenous administration), including severe hypotension and cardiac arrhythmias [[10867]] Drug reaction with eosinophilia and systemic symptoms [[10867]] Toxic epidermal necrolysis [[10867]] Hematopoietic complications [[10867]] Hepatic Injury [[10867]] Hypersensitivity [[10867]] Nervous system reactions, including ataxia, slurred speech, reduced coordination, and mention confusion, as well as dizziness, insomnia, and headaches [[10867]] Peyronie’s disease [[10867]] Rash [[10867]] Stevens-Johnson syndrome [[10867]] Suicidal thoughts and behavior [[10874]] Local toxicity at the site of injection (includes "purple glove syndrome," which consists of pain, edema, and discoloration distal to the injection site) [[10867]]	First synthesized at the University of Kiel in 1908 [[10866]] Synthesized as a phenobarbital analog at Parke-Davis in the 1920s in an effort to identify sleep-inducing (hypnotic) drugs, although it was found to lack such activity [[10866]] Found to exhibit potent anticonvulsant activity in animal studies at Parke-Davis in 1936 [[10866]] Marketed as Dilantin by Parke, Davis and Company as an anticonvulsant treatment beginning in 1938 [[10866]] Dilantin was approved by the US Food and Drug Administration on 6 January 1953 [[10874]] Continued as a first-line treatment for epilepsy until the 1980s [[10866]] Dilantin is produced by Parke-Davis, a division of Pfizer [[10867]] Phenytek is produced by Mylan Bertek Pharmaceuticals [[10868]]
[+]	Raltegravir	Phase II study is underway (as of 2013) [[8957]]	Approved [[8955]]	Approved for treating infection with human immunodeficiency virus (HIV)-1 by the US Food and Drug Administration (12 October 2007) [[8955]] Associated with stable remission of autoimmune chronic idiopathic urticaria in one case [[9199]] Associated with resolution of autoimmune thrombocytopenia in an individual with HIV [[9246]]	Oral [[9203]] 400 mg tablet twice daily, according to information from the manufacturer [[9203]]	Diarrhea [[8955]] Dizziness [[9198]] Fatigue [[9203]] Headache [[8955]] Insomnia [[9203]] Elevated muscle enzyme in blood, indicating that caution is needed for individuals at risk for some kinds of muscle problems [[8955]] Nausea [[8955]] Severe skin reactions, including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis [[9203]]	Received accelerated approval for treating HIV-1 (in combination with other drugs) from the US Food and Drug Administration (12 October 2007) [[8955]] Clinical trials for efficacy in treating HIV have been sponsored by Merck [[9200]] [[9201]] Distributed by Merck [[8955]]
[+]	Riluzole	Phase II trial is underway as of 2014 [[12584]] Phase II trial data have been published (May 2014) [[14874]]	Approved [[13301]]	Approved by the US Food and Drug Administration for treating amyotrophic lateral sclerosis in December, 1995 [[13301]]	Oral [[13304]]	Abdominal pain [[13304]] Anorexia [[13304]] Asthenia [[13304]] Circumoral paresthesia [[13304]] Diarrhea [[13304]] Dizziness [[13304]] Decreased lung function [[13304]] Nausea [[13304]] Pneumonia [[13304]] Somnolence [[13304]] Vertigo [[13304]] Vomiting [[13304]]	Synthesized by scientists at Rhône-Poulenc Rorer [[13305]] When approved by the US Food and Drug Administration in 1995, was manufactured by Rhône-Poulenc Rorer Inc. [[13301]] Marketed by sanofi-aventis after Rhone-Poulenc Rorer merged with Hoechst Marion Roussel to create Aventis (December 1999) and Aventis was acquired by Sanofi-Synthelabo to create sanofi-aventis (31 December 2004) [[13303]] [[13304]] Full commercial rights in the US are acquired by Covis Pharma from Sanofi [the new name of sanofi-aventis as of 2011 [[13303]]]; Sanofi retains existing rights outside the US (4 April 2013) [[13302]]
[+]	Rituximab	Results from Phase II trials for RRMS have been published (2009, 2010) [[359]] [[352]] Used off-label to treat MS [[345]]	Approved [[480]] [[481]]	First monoclonal antibody approved for treating cancer [[395]] Approved by the US Food and Drug Administration for treating CD20-positive, B-cell, non-Hodgkins lymphoma (November, 1997) [[480]] [[481]] Approved in the EU, under the tradename MabThera, for treating non-Hodgkin's lymphoma (June, 1998) [[484]] Approved by the US Food and Drug Administration for treating rheumatoid arthritis (February, 2006) [[481]] [[484]] Approved by the US Food and Drug Administration for treating additional non-Hodgkins lymphomas (2006) [[484]] Approved for treating two forms of vasculitis, the autoimmune diseases granulomatosis with polyangiitis and microscopic polyangiitis, in the UK (19 August 2013) [[7564]] Prescribed off-label for treating certain other diseases, such as systemic lupus erythematosus [[481]] Prevents recurrences of steroid-dependent or frequently relapsing nephrotic syndrome [[9749]] Has been used to treat transplant patients, but results have not been tested in randomized trials (2006) [[483]] Has shown some success for treating several autoimmune diseases, including Sjorgren's syndrome, vasculitis, thrombocytopenic purpura, neuromyelitis optica, and longitudinally extensive transverse myelitis [[373]] [[5388]] Reduces the relapse rate in neuromyelitis optica by up to 88.2%, on the basis of a retrospective, multicenter analysis [[9379]] Increases the time to next attack (by 4.26 times) in neuromyelitis optica, based on a retrospective study involving 58 individuals [[9020]] Low-dose (100 mg) therapy (given 7 months before an anti-AQP4 antibody-seropositive woman with neuromyelitis optica became pregnant) was not associated with any problems with pregnancy outcome, although the newborn displayed low B lymphocyte counts and anti-AQP4 antibody in umbilical cord blood; resumption of low-dose therapy after delivery was associated with neurological stability [[6929]] Stabilized severe relapsing neuromyelitis optica in 4 individuals; after treatment was discontinued, the disease remained in remission for prolonged periods (3 to 9 years with no therapy) [[15273]] A single course was as effective as continuous conventional immunosuppressive therapy for treating severe (organ-threatening) antineutrophil cytoplasmic antibody-associated vasculitis in a clinical trial (publ 2013) [[7130]] In combination with mycophenolate mofetil, controlled lupus nephritis without the use of oral steroids in a prospective observational study (publ 2013) [[6896]] May be useful for treating immunoglobulin G4-related disease, a multiorgan fibroinflammatory disorder, as shown by results from an open-label study (meeting report, 2013) [[8356]] Used successfully to treat systemic sclerosis with refractory digital infarcts and ulcers in one individual [[10721]] Effective in treating skin conditions in diffuse systemic sclerosis over 12 months in a study of 20 individuals with and without lung disease; the drug may be useful for lung as well as skin involvement [[14641]] May be useful for treating voltage-gated potassium channel-complex/leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy, on the basis of studying 5 individuals [[11228]] Not useful in treating a case of neuromyelitis optica [[15853]] Did not alleviate symptoms of primary Sjögren syndrome, an autoimmune disease, over the short term (24 weeks) in a randomized, placebo-controlled clinical trial (publ February 2014) [[10836]]	Intravenous infusion [[388]] Example of frequency of intravenous infusions in clinical trials is two 1000 mg infusions every 24 weeks [[359]] Results presented at a meeting indicate that subcutaneous administration is a non-inferior alternative to intravenous infusion, which would allow administration over 5 minutes rather than 2.5 hours (8 December 2012) [[4141]] Subcutaneous formulation is approved by the European Commission for treating non-Hodgkin lymphoma, allowing administration over 5 minutes (28 March 2014) [[10370]]	Angina [[484]] Anthralgia [[484]] Bronchospasm [[482]] Cardiac arrhythmias [[484]] Hypertension [[484]] Hypotension [[482]] Hypoxia [[482]] Infections [[484]] Infusion-related reactions [[345]] Nausea [[484]] Pyrexia [[484]] Progressive multifocal leukoencephalopathy [[481]] Posterior reversible encephalopathy syndrome (which can be indistinguishable from progressive multifocal leukoencephalopathy on MRI) [[22949]] Strongly reduces antibody response to pandemic H1N1 influenza vaccine in individuals with arthritis [[9373]] Viral reactivation [[484]] May lead to immunosuppression-related reactivation of the hepatitis B virus in previously-infected individuals; the US Food and Drug Administration requires this information to be displayed in a boxed warning (25 September 2013) [[7787]]	Discovered by Biogen Idec [[484]] Co-marketed by Genentech and Biogen Idec in the US [[484]] Biogen Idec, which co-markets Rituxan in the US, has changed its name to Biogen (23 March 2015) [[18038]] Co-marketed by Chugai and Zenyaku Kogyo Co. Ltd in Japan [[484]] Marketed by Roche as MabThera elsewhere in the world [[484]] Biosimilar version has been launched by Intas Pharmaceuticals in India (May 2013) [[5912]]
[+]	RTL1000	Phase I completed [[427]]	Phase I [[427]]	Pre-clinical studies for stroke [[445]] Pre-clinical studies for autoimmune uveitis [[417]] Pre-clinical studies for autoimmune optic neuritis [[434]]	Intravenous [[427]] [[624]]	Diarrhea and hypotension in patients receiving 100mg or more [[427]]	Invented by researchers at Oregon Health and Science University and the Portland Veteran Affairs Medical Center [[622]] Under development by Artielle ImmunoTherapeutics [[623]]
[+]	Secukinumab	Phase II trials are underway [[8243]] [[8244]]	Approved [[24815]]	Approved for treating moderate-to-severe plaque psoriasis (2015) [[24815]] Effective in treating moderate-to-severe plaque psoriasis in Phase II and Phase III trials [[8242]] [[8232]] [[8233]] Reduced signs of active ankylosing spondylitis in a Phase II trial [[8234]] Caused clinically relevant responses in the immune-mediated diseases psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis in proof-of-concept clinical trials [[8225]] Did not meet primary efficacy endpoints in 3 placebo-controlled Phase III trials for different forms of noninfectious uveitis, but there may have been a positive effect in terms of decreasing the use of concomitant immunosuppressive medication [[8231]] Did not meet the primary endpoint (the American College of Rheumatology 20% response) in a Phase II trial for rheumatoid arthritis, although the disease activity decreased with some doses [[8235]] Associated with an improvement in rheumatoid arthritis symptoms in a Phase II, placebo-controlled trial [[10054]] Found to be ineffective for moderate to severe Crohn's disease in a placebo-controlled trial [[8236]] Did not reduce the effects of ozone-induced airway neutrophilia [[8237]]	Intravenous; doses ranged from 3 to 10 mg per kg, given as a 2-hour intravenous infusion either once or twice (3 weeks apart) in clinical studies [[8225]] Given in monthly subcutaneous injections (25 mg to 300 mg) in a clinical trial for rheumatoid arthritis [[8235]]	Generally appears safe in proof-of-concept studies [[8225]] Infections [[8246]]	Developed by Novartis Pharmaceuticals [[8248]] Clinical trials have been sponsored by Novartis Pharmaceuticals [[8243]] [[8244]] [[8245]] Approved in Japan for treating adults with psoriasis or psoriatic arthritis (26 December 2014) [[24815]] Approved in the US and EU for treating moderate-to-severe plaque psoriasis (early 2015) [[24815]]
[+]	Simvastatin	Phase III [[11147]] [[11285]]	Approved [[11288]]	Approved by the US Food and Drug Administration for treating conditions related to coronary heart disease, including hyperlipidemia, mixed dyslipidemia, and hypertriglyceridemia [[11288]] Has antiinflammatory actions that may be useful for treating disorders that include asthma, rheumatoid arthritis, and stroke as well as conditions such as graft rejection [[11293]]	Oral [[11288]] In general, doses range from 5 to 40 mg per day for treating dyslipidemia [[11288]] In trials for MS, doses range from 40 to 80 mg per day [[11145]] [[11147]] [[11148]] [[11149]] [[11150]] [[11151]] [[11284]] [[11285]]	Abdominal pain [[11288]] Arthralgia [[11288]] Constipation [[11288]] Gastrointestinal disorders [[11288]] Headache [[11288]] Liver dysfunction [[11288]] Myalgia [[11288]] Myopathy, which sometimes manifests as rhabdomyolysis that can include acute renal failure; these effects are dose related and the risk at the 80 mg per day dose is disproportionately high [[11288]] Nausea [[11288]] Upper respiratory infections [[11288]]	Discovered by scientists at Merck in 1985 [[11289]] Approved by the US Food and Drug Administration in 1991 for conditions related to coronary heart disease [[11288]] Marketed by Merck as Zocor [[11288]] Loses US patent protection, allowing generic versions to be sold (23 June 2006) [[11294]]
[+]	Siponimod	Phase III trial is underway as of July, 2013 [[7172]]	Phase III [[7172]]	Effectiveness in polymyositis (a chronic inflammatory condition of muscles) is being tested in a Phase II trial (as of May, 2013) [[7173]]	Oral [[7168]]	Initiation of treatment in an individual with SPMS was followed by acute optic neuritis in one eye; visual function was not regained after siponimod discontinuation and corticosteroid treatment [[27017]] Dizziness [[7168]] Headache [[7168]] Elevations in liver enzymes (generally not significant clinically) [[7168]]	Clinical trials have been sponsored by Novartis Pharma [[7168]] [[7174]] [[7171]] [[6418]] [[7175]]
[+]	Teriflunomide	Approved in the US, EU, and other countries for RRMS [[3139]] [[4011]] [[5779]] [[7563]] [[8613]] [[10089]]	Approved [[3139]] Leflunomide (the prodrug from which the active metabolite teriflunomide is derived) is approved for treating rheumatoid arthritis [[404]] [[582]]	Leflunomide (the prodrug from which the active metabolite teriflunomide is derived) is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis [[404]] [[582]] Displays anti-cancer effects in triple negative breast cancer cells in vitro [[14642]]	Oral [[341]]	Increases in the liver enzyme alanine aminotransferase [[8052]] Back pain [[8052]] Diarrhea [[339]] Hair thinning [[339]] Headache [[579]] Influenza [[8052]] Lymphopenia [[28364]] Nasopharyngitis (the common cold) [[8052]] Nausea [[579]] [[339]] Associated with fatal toxic epidermal necrolysis in an individual with relapsing MS [[20502]] Neutropenia [[28364]] Paraesthesia (a sense of tingling and burning of the skin) [[8052]] Upper respiratory tract infections [[13550]] No new safety issues (other than those seen in individual clinical trials) were detected using pooled data from four placebo-controlled trials and their extensions, which represented >6800 patient years [[26522]] Dimethyl fumarate and teriflunomide are associated with a similar risk of adverse events, and that risk is higher than that of glatiramer acetate, based on meta-analysis of 3 randomized controlled trials involving 3737 individuals with RRMS [[15086]] Does not appear to have negative effects on the health of babies born to pregnant women who discontinued the drug after becoming pregnant (usually within 11 weeks) and underwent an accelerated elimination procedure to remove the drug from their systems [[7126]] Not associated with a risk of teratogenicity, as assessed by analysis of pregnancies that occurred in the clinical development program (83 in female participants and 22 in partners of male participants, with 31 terminated electively); treatment was discontinued, and participants underwent an accelerated elimination procedure to reduce plasma drug concentrations, upon discovery of pregnancy [[18443]]	Clinical trials have been sponsored by Sanofi-Aventis and Genzyme, a Sanofi company [[578]] [[580]] [[2006]] Marketing authorization application has been filed with the European Medicines Agency by Genzyme (23 February 2012) [[2108]] Approved by the US Food and Drug Administration as a once-daily, oral treatment for RRMS, on the basis of efficacy data from the TEMSO trial (12 September 2012) [[3139]] Approved by the Australian Therapeutic Goods Administration as a once-daily, oral treatment for relapsing forms of MS (21 November 2012) [[4011]] Given a recommendation for approval for adults with RRMS by the Committee for Medicinal Products for Human Use of the European Medicines Agency, but was not recommended to receive a new active substance designation (22 March 2013) [[5366]] Approved by the National Administration of Drugs, Food and Medical Technology (Argentina) for treating relapsing forms of MS (8 April 2013) [[5779]] Received a positive opinion for a new active substance designation from the Committee for Medicinal Products for Human Use of the European Medicines Agency, reversing an earlier decision (28 June 2013) [[6591]] Planned registration and launch in MENA (Middle East and North Africa) will be handled by a partnership between Genpharm and Genzyme (5 August 2013) [[7124]] Approved by the European Commission as a once-daily, oral treatment for adults with RRMS (30 August 2013) [[7563]] Approved by Health Canada as a once-daily, oral treatment for RRMS (20 November 2013) [[8613]] Approved for use by the National Health Service in England and Wales as a treatment for adults with RRMS (January 2014) [[10102]] Approved for use as a treatment for adults with RRMS in Northern Ireland (February 2014) [[10102]] Approved for use by the National Health Service in Scotland as a treatment for adults with RRMS (10 March 2014) [[10089]] [[10102]] Inclusion of TOWER and TOPIC clinical trial data about efficacy and safety on the US label has been approved by the US Food and Drug Administration (20 October 2014) [[14788]] Genzyme, a Sanofi company, which markets teriflunomide, will now be referred to instead as Sanofi Genzyme (1 January 2016) (personal communication from Ameet Khara at Sanofi Genzyme)
[+]	Ustekinumab	Discontinued after Phase II trials showed a lack of efficacy [[625]]	Approved in the US, Canada, and Europe for treatment of moderate to severe plaque psoriasis [[619]]	Approved by the US Food and Drug Administration for treating moderate to severe plaque psoriasis (25 September 2009) [[13538]] Approved for treating psoriatic arthritis in the US and EU (September 2013) [[7786]] Successfully used to treat psoriasis in two individuals with psoriasis and MS; the MS did not progress [[22280]] In trials for Crohn’s disease [[437]] May be beneficial in treating Crohn's disease that is resistant to treatment with anti-tumor necrosis factor, according to results from a Phase II clinical trial (publ October 2012) [[3780]] [[3779]] May be beneficial for treating psoriatic arthritis in patients for whom conventional drugs have failed, according to results from a Phase III study (press release, November 2012) [[3930]]	Subcutaneous injection [[625]]	Linked with an increased risk of major adverse cardiovascular events in a meta-analysis of clinical trials involving individuals with chronic plaque psoriasis [[10398]] Fatigue [[625]] Headache [[625]] Injection site reactions [[625]] Infections [[625]] Could reactivate latent tuberculosis [[621]] Could increase incidence of malignant tumors [[621]]	Clinical trials have been sponsored by Centocor, a subsidiary of Johnson & Johnson [[452]] [[625]] Centocor merges with Ortho Biotech to become Centocor Ortho Biotech Inc. (2008) [[13539]] Approved by the US Food and Drug Administration for treating plaque psoriasis (25 September 2009) [[13538]] Manufactured by Centocor Ortho Biotech Inc. at the time of approval for treating plaque psoriasis (25 September 2009) [[13538]] Before June 2011, marketed by Centocor Ortho Biotech Inc. in the US and Janssen-Ortho, Inc. outside the US [[619]] [[437]] [[13537]] Centocor Ortho Biotech Inc. changes its name to Janssen Biotech, Inc. (22 June 2011) [[13537]] Marketed by Janssen Biotech, Inc. as of 2011 [[13537]] [[13540]]

Name	Placebo-controlled Trials	Head-to-Head Trials	Other Trials
Alemtuzumab		Trial name: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (reported 2011, 2013; publ October 2012) [[784]] [[3822]] [[1536]] Phase: Phase III trial [[784]] [[3822]] Study Design: Industry-sponsored, randomized, multicenter, rater-blinded, controlled trial to compare the effects of two cycles of intravenous alemtuzumab (12 mg per day, once a day for 5 consecutive days at baseline and once a day for 3 days at 12 months) with interferon beta1a (44 mcg given subcutaneously three times a week) on relapse rate and time to 6 month sustained accumulation of disability (coprimary endpoints) [[784]] [[3822]] Disease Stage: Treatment-naïve, early, active RRMS [[784]] [[3822]] Enrollment/Number of Patients: 581 patients who had received no prior MS therapy [[784]] [[3822]] Duration: 2 years [[784]] [[3822]] Status/Outcome: In the group receiving alemtuzumab (376 patients included in the primary analyses), 82 (22%) relapsed, whereas in the group receiving interferon beta-1a (195 patients included in the primary analyses), 75 (40%) relapsed, which corresponds to a 54.9% improvement with alemtuzumab; at 2 years, 78% in the alemtuzumab group were relapse free versus 59% in the interferon beta-1a group; 30 (8%) in the alemtuzumab group displayed sustained accumulation of disability versus 20 (11%) in the interferon beta-1a group [[784]] [[3822]]; over 24 months, the alemtuzumab group displayed improvements in visual acuity at low contrast levels, unlike the interferon beta-1a group [[1536]] Trial name: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) (reported November 2011; publ October 2012; conference report, May 2013) [[789]] [[3823]] [[6337]] Phase: Phase III trial [[789]] [[3823]] Study Design: Industry-sponsored, randomized, multicenter, rater-blinded, controlled trial to compare the effects of two cycles of intravenous alemtuzumab [either 24 mg (a dose that was discontinued) or 12 mg per day, once a day for 5 consecutive days at baseline and once a day for 3 days at 12 months] with interferon beta-1a (44 mcg given subcutaneously three times a week) on relapse rate and time to 6 month sustained accumulation of disability (coprimary endpoints) [[789]] [[3823]] Disease Stage: RRMS, relapsed while on prior therapy [[789]] [[3823]] Enrollment/Number of Patients: 840 patients who had experienced relapse while on prior therapy [[789]] [[3823]] Duration: 2 years [[789]] [[3823]] Status/Outcome: In the group receiving alemtuzumab (12 mg dose) (426 patients included in the primary analyses), 147 (35%) relapsed, whereas in the group receiving interferon beta-1a (202 patients included in the primary analyses), 104 (51%) relapsed, which corresponds to a 49.4% improvement with alemtuzumab; at 2 years, 278 (65%) in the alemtuzumab group were relapse free versus 94 (47%) in the interferon beta-1a group; 54 (13%) in the alemtuzumab group displayed sustained accumulation of disability versus 40 (20%) in the interferon beta-1a group [[789]] [[3823]]; in a subgroup of patients with the most active disease who received alemtuzumab, 24.2% were free of disease activity after 2 years, versus 0% of a subgroup of similar patients who received interferon beta-1a [[6337]] Trial name: International Campath-1H in Multiple Sclerosis (CAMMS223) (publ 2008, 2011, 2013, 2016) [[448]] [[422]] [[8283]] [[28392]] Phase: Phase II trial [[448]] Study Design: Industry-sponsored, randomized, multicenter, rater-blinded trial to compare the efficacy of an annual infusion of alemtuzumab (12 mg or 24 mg) to thrice-weekly subcutaneous interferon beta-1a (44 micrograms) [[448]] Disease Stage: Early, active RRMS; participants were treatment-naive [[448]] [[28392]] Enrollment/Number of Patients: 334 (with 333 completing the study) [[448]] Duration: 36 months [[448]] Status/Outcome: Alemtuzumab was associated with a lower rate of sustained disability accumulation (9.0% versus 26.2% for interferon beta-1a) and a lower annualized relapse rate (0.10 versus 0.36 for interferon beta-1a) (primary endpoints); alemtuzumab was also associated with a greater reduction in lesions (T2-weighted MRI) than interferon beta-1a and an increase in brain volume (compared to a decrease with interferon beta-1a); alemtuzumab was associated with a higher proportion of patients who were relapse-free after 3 years (80% for alemtuzumab versus 52% for interferon beta-1a) (secondary endpoints), but was associated with immune thrombocytopenic purpura in 3 patients, leading to suspension of alemtuzumab therapy during the trial [[448]]; posthoc analysis showed that alemtuzumab benefited patients equally in all subgroups of CAMMS223 cohort studied, including age, sex, geographical region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and Expanded Disability Status Scale (EDSS) score [[422]]; additional analyses (after a median followup of 57.3 months) showed that 34% of individuals on alemtuzumab experienced thyroid dysfunction (with 22% with Graves' hyperthyroidism, 7% with hypothyroidism, and 4% with subacute thyroiditis) versus 6.5% of individuals on interferon beta-1a; serious episodes were rare [[8283]]; alemtuzumab was associated with broad improvement in preexisting disability, resulting in better outcomes than interferon beta-1a in most individual functional system scores (FSSs), especially sensory, pyramidal, and cerebellar FSSs, of the EDSS at month 36 [[28392]]	Trial name: ALemtuzumab in Autoimmune Inflammatory Neurodegeneration: Mechanisms of Action and Neuroprotective Potential (ALAIN01) (recruiting as of 2015) [[28081]] [[27832]] Phase: Phase IV study [[28081]] [[27832]] Study Design: Industry-supported, monocenter, exploratory, single arm study to examine the effects of alemtuzumab (2 courses at an interval of 1 year, with the first course consisting of intravenous infusions of 12 mg per day for 5 days and the second course infusions of 12 mg per day for 3 days) on a variety of immunological parameters in blood and cerebrospinal fluid, to understand better both the positive and negative consequences of alemtuzumab [[28081]] [[27832]] Disease Stage: Highly active RRMS [[28081]] [[27832]] Enrollment/Number of Patients: 15 (estimated) [[28081]] Duration: 3 years [[27832]] Status/Outcome: Estimated study completion date, September 2019 [[28081]] Trial name: Willis et al., Mult. Scler., October 2015 study [[23227]] Phase: Observational/open-label study [[23227]] Study Design: Observational study to examine the efficacy and safety of alemtuzumab over the long-term in a multicenter cohort [[23227]] Disease Stage: MS [[23227]] Enrollment/Number of Patients: 100, with 40 individuals retreated with ≥1 additional cycles [[23227]] Duration: 6.1 years (mean followup) [[23227]] Status/Outcome: Alemtuzumab was associated with a reduction in the annualized relapse rate from 2.1 to 0.2, sustained for as much as 8 years, but not with a reversal of disability (the mean change in the Expanded Disability Status Scale score was +0.14); 47% of participants developed secondary autoimmunity, which could be managed [[23227]] Trial name: Tramacere et al., Cochrane Database Syst. Rev., September 2015 study [[21732]] Phase: Retrospective clinical trial analysis [[21732]] Study Design: Retrospective network meta-analysis to compare the benefits of alemtuzumab, azathioprine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1a (Avonex, Rebif), pegylated interferon beta-1a, interferon beta-1b, laquinimod, mitoxantrone, natalizumab, and teriflunomide; data were extracted from 39 randomized controlled trials that compared one or more of the 15 drugs used as monotherapy to placebo or another drug [[21732]] Disease Stage: Adults with RRMS [[21732]] Enrollment/Number of Patients: 25,113 individuals were randomized in the studies included in the analyses [[21732]] Duration: 24 months (median duration of studies) [[21732]] Status/Outcome: Alemtuzumab was found to be the most protective against relapses during the first 24 months of therapy (moderate quality evidence); the next most protective were found to be mitoxantrone (very low quality evidence), natalizumab (high quality evidence), and fingolimod (moderate quality evidence); mitoxantrone (low quality evidence) was found to be the most effective at delaying disability worsening, followed by alemtuzumab (low quality evidence) and natalizumab (moderate quality evidence); these results must be interpreted conservatively because few trials have been performed for most of the drugs [[21732]] Trial name: Le Page et al., J. Neurol., February 2015 study [[17248]] Phase: Observational/open-label study [[17248]] Study Design: Observational study to examine the effects of alemtuzumab (either 20 mg per day or 12 mg per day for 5 days) when used as last-line therapy in individuals previously treated with mitoxantrone [[17248]] Disease Stage: Aggressive MS (8 individuals with RRMS and 8 with SPMS) [[17248]] Enrollment/Number of Patients: 16 [[17248]] Duration: 6.2 years (mean followup) [[17248]] Status/Outcome: Alemtuzumab controlled aggressive RRMS, such that 7 participants with RRMS showed improvement on the Expanded Disability Status Scale and 4 were disease free up to the last visit (a time period ranging from 1 to 7 years), whereas 2 participants with SPMS were disease free up to the last visit (4.7 and 8 years) [[17248]] Trial name: Tuohy et al., J. Neurol. Neurosurg. Psychiatry, May 2014 study [[11170]] Phase: Observational/open-label study [[11170]] Study Design: Observational cohort study to examine the safety and efficacy of alemtuzumab in all individuals treated in investigator-led studies in Cambridge, UK [[11170]] Disease Stage: RRMS [[11170]] Enrollment/Number of Patients: 87 [[11170]] Duration: 7 years (median followup) [[11170]] Status/Outcome: 52% of participants required two alemtuzumab cycles, with relapses leading to additional cycles (≤5) in the remaining participants; disabilty (6-month sustained accumulation of disability) improved or was unchanged as compared with baseline in 67.8% of participants; the most common adverse event, affecting 47.7% of participants, was secondary autoimmunity (usually involving the thyroid gland) [[11170]] Trial name: CARE-MS I extension study (conference reports, 2013, 2014, 2015; publ 2014) [[5365]] [[11035]] [[13708]] [[18398]] [[22565]] Phase: Extension phase of Phase III trial [[784]] [[3822]] [[5365]] [[18398]] Study Design: Company-sponsored extension of a trial comparing alemtuzumab with interferon beta-1a in patients new to treatment [[5365]]; in the original trial, participants received alemtuzumab or subcutaneous interferon beta-1a; in the extension, those in the alemtuzumab arm received alemtuzumab re-treatment as needed ≥1 year apart or other therapy, whereas those in the crossover cohort received 2 courses of alemtuzumab 12 months apart [[18398]] Disease Stage: RRMS [[5365]] [[18398]] Enrollment/Number of Patients: 349 (95% of the eligible participants) from the core study alemtuzumab group and 144 (83%) from the interferon beta-1a group [[18398]] Duration: 2 years [[18398]] Status/Outcome: Among patients who received alemtuzumab in the original 2-year study, 67% remained relapse-free during the extension; the relapse rate for patients receiving alemtuzumab was 0.24 in the first year of the extension; 72.4% of patients had improved or stable disability over 3 years; >80% of participants who received alemtuzumab in the original trial did not receive additional treatment during year 1 of the extension (for which they were eligible if they experienced relapse or new or enlarging lesions) [[5365]]; additionally, in year 3 of treatment, the rate of brain atrophy continued to slow and >70% of patients lacked MRI lesions indicating acute inflammation [[11035]]; 73% of participants who received alemtuzumab in the original trial did not receive additional alemtuzumab through year 2 of the extension (with <5% receiving another disease-modifying therapy), whereas most (92%) of those from the interferon beta-1a group who continued in the extension received 2 alemtuzumab courses [[18398]]; annualized relapse rates (ARRs) remained low (0.14 in year 4, comparable to rates in the original trial among treated participants) and disability scores remained stable or improved in 74% of participants [[13708]]; the ARR (0.l8) of those participants receiving alemtuzumab in the original trial (68% of whom did not receive additional alemtuzumab during the next 4 years) remained low from years 3-5 (0.19-0.15), and 80% of such participants exhibited no worsening of disability progression confirmed over 6 months through year 5 [[22565]] Trial name: CARE-MS II extension study (conference reports, 2013, 2014, 2015; publ 2014) [[5365]] [[7944]] [[11035]] [[13708]] [[18400]] [[22565]] Phase: Extension phase of Phase III trial [[789]] [[3823]] [[5365]] [[18400]] Study Design: Company-sponsored extension of a trial comparing alemtuzumab with interferon beta-1a in patients who had relapsed on previous therapy [[5365]]; in the original trial, participants received alemtuzumab or subcutaneous interferon beta-1a; in the extension, those in the alemtuzumab arm received alemtuzumab re-treatment as needed ≥1 year apart or other therapy, whereas those in the crossover cohort received 2 courses of alemtuzumab 12 months apart [[18400]] Disease Stage: RRMS [[5365]] [[18400]] Enrollment/Number of Patients: 393 (93% of the eligible participants) from the core study alemtuzumab group and 146 (83%) from the interferon beta-1a group [[18400]] Duration: 2 years [[18400]] Status/Outcome: Among patients who received alemtuzumab in the original 2-year study, 55% remained relapse-free during the extension; the relapse rate for patients receiving alemtuzumab was 0.25 in the first year of the extension; 70.0% of patients had improved or stable disability over 3 years; >80% of patients who received alemtuzumab in the original trial did not receive additional treatment during year 1 of the extension (for which they were eligible if they experienced relapse or new or enlarging lesions) [[5365]]; at 3 years, 70% of individuals treated with alemtuzumab displayed Expanded Disability Status Scale scores that were stable or improved as compared with those at baseline [[7944]]; additionally, in year 3 of treatment, the rate of brain atrophy continued to slow and >70% of patients lacked MRI lesions indicating acute inflammation [[11035]]; 68% of participants who received alemtuzumab in the original trial did not receive additional alemtuzumab through year 2 of the extension (with 5% receiving another disease-modifying therapy), whereas most (90%) of those from the interferon beta-1a group who continued in the extension received 2 alemtuzumab courses [[18400]]; annualized relapse rates (ARRs) remained low (0.23 in year 4, comparable to rates in the original trial among treated participants) and disability scores remained stable or improved in 66% of participants [[13708]]; the ARR (0.27) of those participants receiving alemtuzumab in the original trial (60% of whom did not receive additional alemtuzumab during the next 4 years) remained low from years 3-5 (0.22-0.18), and 76% of such participants exhibited no worsening of disability progression confirmed over 6 months through year 5 [[22565]] Trial name: Cossburn et al., Neurology, January 2013 study [[4234]] Phase: Observational study [[4234]] Study Design: Study to test whether the observed variation in lymphocyte recovery time after alemtuzumab treatment affects disease activity [[4234]] Disease Stage: RRMS [[4234]] Enrollment/Number of Patients: 56 [[4234]] Duration: 39.5 months (median followup post alemtuzumab treatment) [[4234]] Status/Outcome: CD19+, CD8+, and CD4+ lymphocytes were reconstituted with mean times of 6, 10, and 36 months; whereas CD8+ and CD19+ reconstitution did not vary between patients in remission and those with active disease, CD4+ cells recovered more rapidly, and were present at higher counts at 24 months, in patients with active disease, indicating that differential lymphocyte recovery might serve as a biomarker for relapse [[4234]] Trial name: Fox et al., Eur. J. Neurol., February 2012 study [[4210]] Phase: Open-label study [[4210]] Study Design: Single-arm, open-label study to determine the effectiveness of alemtuzumab in patients with RRMS that is not controlled by interferon therapy (such that patients experienced ≥2 relapses in the previous 2 years); patients received 24 mg of intravenous alemtuzumab per day for 5 days at baseline and for 3 days after 12 months [[4210]] Disease Stage: Treatment-refractory RRMS [[4210]] Enrollment/Number of Patients: 45 [[4210]] Duration: 2 years [[4210]] Status/Outcome: Drug reduced the annualized relapse rate by 94% as compared with pretreatment levels (from 1.6, 2 years before treatment to 0.17, 2 years following treatment); drug also improved or stabilized scores on the Expanded Disability Status Scale in 86% of patients [[4210]] Trial name: CAMMS223 extension study (publ 2012; meeting reports 2010, 2016) [[788]] [[997]] [[29282]] Phase: Extension of Phase II study [[997]] Study Design: Open-label extension of a trial comparing the efficacy of an annual infusion of alemtuzumab (12 mg or 24 mg) to thrice-weekly subcutaneous interferon beta-1a (44 micrograms) [[788]] [[997]] Disease Stage: RRMS [[997]] Enrollment/Number of Patients: 250, with 198 on alemtuzumab and 47 on interferon beta-1a, out of original 334 randomized [[997]] Duration: 5-year total followup [[997]]; 10-year followup [[29282]] Status/Outcome: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% as compared with interferon beta-1a; the annualized relapse rate (ARR) during that time was 0.11 for alemtuzumab and 0.35 for interferon beta-1a; among participants taking alemtuzumab, 72% were estimated to be relapse-free after 5 years, compared to 41% on interferon beta-1a, but participants on alemtuzumab had more frequent serious infections, thyroid disorders, and immune thrombocytopenia than those treated with interferon beta-1a [[997]]; over 10 years, a low ARR was maintained for individuals on alemtuzumab; 76% of those participants were free of 6-month confirmed disability worsening [[29282]] Trial name: Coles et al., Clin. Neurol. Neurosurg., June 2004 trial [[458]] Phase: Observational study [[458]] Study Design: Investigator-led observational study of response to 5 daily doses of 20 mg of alemtuzumab and optional retreatment in 12-18 months in individuals with increasing disability [[458]] Disease Stage: SPMS and RRMS [[458]] Enrollment/Number of Patients: 36 (22 women) SPMS; 22 (17 women) RRMS [[458]] Duration: Individuals treated between 1991 and 2002; 280 total patient-years [[458]] Status/Outcome: Alemtuzumab was associated wtih a decrease in relapse rate (RRMS, 94%, SPMS, 97%) and lesion formation measured by MRI in both groups; individuals with SPMS showed accumulating disability, whereas individuals with RRMS remained stable, suggesting that suppressing inflammation is only effective early in disease progression [[458]]
Amiloride	Trial name: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) (Study start date, October 2013) [[12584]] Phase: Phase IIB trial [[12584]] Study Design: University-, institute-, and society-sponsored, multicenter, multi-arm, randomized, double-blind, placebo-controlled trial to compare the effects of three repurposed, candidate neuroprotective drugs [amiloride (5 mg once per day for 4 weeks, then 5 mg twice per day), riluzole (50 mg once per day for 4 weeks, then 50 mg twice per day), and ibudilast (50 mg once per day for 4 weeks, then 50 mg twice per day), each versus matched placebo] on the rate of brain volume loss as assessed by MRI (primary outcome measure) and other measures [[12584]] Disease Stage: SPMS [[12584]] Enrollment/Number of Patients: 440 (estimated) [[12584]] Duration: 96 weeks [[12584]] Status/Outcome: Not yet recruiting as of July 2013; estimated study completion date, September 2016 [[12584]] Trial name: Amiloride Clinical Trial In Optic Neuritis (ACTION) trial (recruiting as of March 2013) [[12599]] [[23629]] Phase: Phase II trial [[12599]] Study Design: University- and society-sponsored, randomized, double-blind, placebo-controlled trial to examine the neuroprotective effects of amiloride (10 mg once per day for 5 months) by comparing the retinal nerve fiber layer thickness in the affected eye (at 6 months) and in the unaffected eye (at baseline) (primary outcome measure), as well as with other measures [[12599]] [[23629]] Disease Stage: Unilateral optic neuritis (within 28 days of onset of first symptoms; can be with an existing RRMS diagnosis) [[12599]] [[23629]] Enrollment/Number of Patients: 46 (estimated) [[12599]] [[23629]] Duration: 12 months [[12599]] Status/Outcome: Estimated study completion date, February 2015 [[12599]] Trial name: Amiloride Hydrochlorothiazide as Treatment of Acute Inflammation of the Optic Nerve (recruiting as of May 2014) [[12600]] Phase: Phase IIa trial [[12600]] Study Design: University-sponsored, randomized, double-blind, placebo-controlled trial to study the effect of amiloride hydrochlorothiazide (5.68 mg amiloridhydrochloride 2H20 and 50 mg hydrochlorothiazid) on the change in the thickness of the retinal nerve fiber layer between baseline and followup (primary outcome measure) [[12600]] Disease Stage: First episode of optic neuritis [[12600]] Enrollment/Number of Patients: 78 (estimated) [[12600]] Duration: 24 weeks [[12600]] Status/Outcome: Estimated study completion date, April 2016 [[12600]]		Trial name: Arun et al., Brain, January 2013 study [[4764]] Phase: Observational/open-label study [[4764]] Study Design: Observational study to examine the effects of oral amiloride (10 mg daily) on whole-brain atrophy (primary outcome) and measures of brain tissue integrity; the study included MRI scans during a pretreatment period followed by a 1 year treatment period [[4764]] Disease Stage: PPMS [[4764]] Enrollment/Number of Patients: 14 [[4764]] Duration: 3 years [[4764]] Status/Outcome: Amiloride was associated with a reduction in the normalized annual rate of whole-brain atrophy in the treatment versus pretreatment phase [[4764]] Trial name: Pasternak et al., Pharmacoepidemiol. Drug Saf., August 2012 study [[1659]] Phase: Retrospective registry data review [[1659]] Study Design: Registry-based propensity score-matched cohort studies to examine whether amiloride use is associated with a lower risk of MS; one study compared rates of incident MS in new users of amiloride versus thiazide diuretics (an active control treatment), whereas the second study compared death and MS-related hospitalization rates between amiloride versus thiazide users in a cohort of individuals with MS [[1659]] Disease Stage: MS [[1659]] Enrollment/Number of Patients: 213,690 (36,659 amiloride users and 177,031 thiazide users) [[1659]] Duration: 92,548 person-years of followup for amiloride use and 567,599 person-years of followup for thiazide use [[1659]] Status/Outcome: Amiloride was not linked with a reduced risk of incident MS or with a reduced risk of hospitalizations or death among individuals with MS; because amiloride users are generally older, these results might not apply to younger individuals [[1659]]
ATX-MS-1467			Trial name: ATX-MS-1467 in Multiple Sclerosis (ongoing as of 2014) [[14245]] Phase: Phase IIa study [[14245]] Study Design: Industry-sponsored, multicenter, open-label, single-arm, proof-of-concept, baseline-controlled study to examine the effects of ATX-MS-1467, given using a dose-titration regimen for 4 weeks, followed by treatment for 16 weeks and then observation for 16 weeks, with the primary outcome measure the change in the average number of T1 contrast-enhanced lesions at weeks 12, 16, and 20 versus the average number at baseline (weeks -8, -4, and 0) [[14245]] Disease Stage: Relapsing MS [[14245]] Enrollment/Number of Patients: 19 (estimated) [[14245]] Duration: 36 weeks [[14245]] Status/Outcome: Study start date, February 2014; estimated study completion date, June 2016 (final date for data collection for primary outcome measure) [[14245]]; enrollment has been completed (6 August 2015) [[20798]] Trial name: ATX-MS-1467 in Patients With Relapsing Forms of Multiple Sclerosis (completed as of August, 2013; press release, September 2013) [[14244]] [[14249]] Phase: Phase I study [[14244]] Study Design: Industry-sponsored, open-label, non-randomized, single-group assignment study to evaluate the safety and activity of ATX-MS-1467, given either intradermally or subcutaneously in an upward dose titration, with the drug given 9 times, 2 weeks apart, after which there was a 22-week followup period; adverse events (primary outcome measure) and effect on brain lesions (a secondary outcome measure) were monitored [[14244]] Disease Stage: RRMS [[14244]] Enrollment/Number of Patients: 42 [[14244]] Duration: 48 weeks [[14244]] Status/Outcome: ATX-MS-1467 was well tolerated; intradermal (but not subcutaneous) delivery of the drug was associated with a decrease in the number of contrast-enhancing brain lesions [[14249]] Trial name: ATX-MS-1467 in SPMS (final results announced January, 2008; publ June, 2015) [[14248]] [[17758]] Phase: Phase I/IIa study [[14248]] Study Design: Industry-sponsored, open-label, dose-escalation study to examine the safety and tolerability of ATX-MS-1467; doses of 25, 50, 100, 400, and 800 microg, followed by another 800 microg dose, were given 7 to 14 days apart [[14248]]; participants expressed a variety of HLA-DR alleles (DRB101, DRB104, DRB107, DRB111, DRB113, DRB114, and DRB1*15) [[17758]] Disease Stage: SPMS [[14248]] Enrollment/Number of Patients: 6 [[14248]] Status/Outcome: ATX-MS-1467 was found to be safe and well tolerated and was associated with a reduction in T cell proliferation induced by myelin basic protein (whereas T cell responses to a different vaccine constitutent were unchanged); two of the six participants may have exhibited a positive clinical response to the drug (with one individual with optic neuritis resulting from MS showing improvements in vision that continued after treatment ended and another showing reductions in brain neuroinflammation as measured by MRI) [[14248]]
BGC20-0134	Trial name: A Study of Orally Administered BGC20-0134 (Structured Lipid) in Patients With Relapsing Remitting Multiple Sclerosis (RRMS) [[791]] Phase: IIa [[791]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multi-center, multinational study evaluating the cumulative number of new T1 gadolinium-enhancing lesions (primary endpoint) and safety during treatment Disease Stage: RRMS [[791]] Enrollment/Number of Patients: Estimated enrollment 166 patients [[791]] Duration: 24 weeks double-blind and placebo controlled, followed by 24 weeks open-label extension [[473]] Status/Outcome: Did not meet primary or secondary endpoints [[792]]
BIIB033	Trial name: BIIB033 In Acute Optic Neuritis (RENEW) (press releases, January, April 2015) [[16280]] [[16281]] [[18493]] Phase: Phase II trial [[16280]] Study Design: Industry-sponsored, multinational, randomized, double-blind, parallel-group, placebo-controlled trial to examine the efficacy of BIIB033 (6 doses of 100 mg per kg intravenous infusion, given once every 4 weeks for 20 weeks) in individuals experiencing their first episode of unilateral acute optic neuritis, with the primary outcome measure the change in optic nerve latency (time for a nerve signal to move from the retina to the visual cortex) at week 24 in the affected eye as compared with the baseline measure in the unaffected eye; secondary outcome measures included changes in the thickness of retinal layers and in low-contrast letter acuity at week 24 as compared with baseline [[16280]] [[16281]] Disease Stage: Acute optic neuritis (first episode) [[16280]] Enrollment/Number of Patients: 82 [[16280]] Duration: 24 weeks [[16280]] Status/Outcome: Study completion date, October 2014 [[16280]]; BIIB033 was associated with a recovery of optic nerve latency (a 34% improvement as compared with placebo) at week 24, but not with a change in the thickness of retinal layers or with improved visual function [[16281]]; at week 32, 12 weeks after the last dose, additional latency recovery was measured (a 41% improvement) [[18493]] Trial name: Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY) (recruiting as of May 2014) [[13427]] Phase: Phase II trial [[13427]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial to examine the efficacy and safety of BIIB033 (intravenous infusion of 0, 3, 10, 30, or 100 mg per kg every 4 weeks) when used together with interferon beta-1a (Avonex, given by weekly intramuscular injections); the primary outcome measure is the percentage of participants who display improved neurophysical or cognitive function [[13427]] Disease Stage: Relapsing forms of MS [[13427]] Enrollment/Number of Patients: 396 (estimated) [[13427]] Duration: 84 weeks [[13427]] Status/Outcome: Estimated study completion date, June 2016 [[13427]] Trial name: BIIB033 single ascending dose study in healthy volunteer subjects; Tran et al., Neurol. Neuroimmunol. Neuroinflammation, August 2014 trial [[485]] [[13242]] Phase: Phase I trial [[485]] [[13242]] Study Design: Company-sponsored, randomized, blinded, placebo-controlled, single-ascending dose trial to evaluate the safety and tolerability (primary outcome measures) and pharmacokinetics, serum antibody levels, and exploratory biomarkers (secondary outcome measures); single ascending doses (0.1 to 100 mg per kg) were administered by intravenous infusion or subcutaneous injection [[485]] [[13242]] Disease Stage: Healthy individuals [[485]] [[13242]] Enrollment/Number of Patients: 72 [[485]] [[13242]] Duration: Up to 4 months [[485]] Status/Outcome: The drug was well tolerated; adverse events occurred at similar frequencies in the drug and placebo groups and no serious adverse events occurred; furthermore, anti-drug antibodies were detected in only one participant [[13242]] Trial name: Safety study of BIIB033 in subjects with multiple sclerosis; Tran et al., Neurol. Neuroimmunol. Neuroinflammation, August 2014 trial [[486]] [[13242]] Phase: Phase I trial [[486]] [[13242]] Study Design: Company-sponsored, randomized, blinded, placebo-controlled, serial-cohort, multiple ascending dose trial to determine the safety and tolerability (primary outcomes) and pharmacokinetics and potential biomarkers of activity (secondary outcomes) of two doses of drug (intravenous infusion of 0.3, 1, 3, 10, 30, 60, or 100 mg per kg) administered 14 days apart [[486]] [[13242]] Disease Stage: RRMS or SPMS [[486]] [[13242]] Enrollment/Number of Patients: 47 [[13242]] Duration: 6 months [[486]] Status/Outcome: The drug was well tolerated; adverse events occurred at similar frequencies in the drug and placebo groups and no serious adverse events occurred [[13242]]
Cladribine	Trial name: Oral Cladribine in Early Multiple Sclerosis (ORACLE MS) (publ February 2014) [[795]] [[9678]] Phase: Phase III trial [[795]] [[9678]] Study Design: Company-sponsored, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of cladribine (cumulative doses of either 5.25 mg or 3.5 mg per kilogram) on reducing the time to conversion to MS after a first clinical demyelinating event (primary outcome) [[795]] [[9678]] Disease Stage: Patients who had sustained their first clinical demyelinating event ≤75 days before screening, who were at at high risk of converting to MS [[795]] [[9678]] Enrollment/Number of Patients: 616 [[9678]] Duration: 96 weeks [[9678]] Status/Outcome: Both doses were associated with a delay in the diagnosis of MS; the safety profile was comparable to that seen in individuals with RRMS [[9678]] Trial name: Phase II Cladribine Add-on to Interferon-beta (IFN-b) Therapy in MS Subjecs With Active Disease (ONWARD) (ongoing as of January 19, 2012) [[800]] Phase: Phase II trial [[800]] Study Design: Company-sponsored, multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and effectiveness of oral claribine (up to 4 cycles, of 0.875 mg per kilogram per cycle) when taken in combination with interferon-beta therapy (Rebif, Avonex, or Betaseron), in treating MS [[800]] Disease Stage: RRMS or SPMS [[800]] Enrollment/Number of Patients: 214 [[800]] Duration: 96 weeks [[800]] Status/Outcome: Final data collection for primary outcome measure is September 2011; estimated study completion date is June 2012 [[800]] Trial name: Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) (publ 2010; additional analyses publ 2011, 2012) [[559]] [[4317]] [[4465]] [[4464]] [[4463]] Phase: Phase III trial [[559]] Study Design: Company-supported, randomized, double-blind, placebo-controlled trial to test the effects of oral cladribine (a cumulative dose of either 3.5 mg or 5.25 mg per kilogram of body weight, given in several short courses) on on the rate of relapse at 96 weeks (primary outcome) and several other outcome measures [[559]] Disease Stage: RRMS [[559]] Enrollment/Number of Patients: 1326, with 1184 completing the study [[559]] Duration: 96 weeks [[559]] Status/Outcome: Drug was associated with a reduction in the annualized rate of relapse in both treatment groups [0.14 in the 3.5 mg group (a relative reduction of 57.6%) and 0.15 in the 5.25 mg group (a relative reduction of 54.5%) as compared with 0.33 in the placebo group] and a lower mean number of brain lesions per patient as compared to the placebo; lymphocytopenia and herpes zoster occurred more frequently in patients receiving cladribine than in those receiving placebo [[559]] [[4465]]; posthoc analysis of data indicated that cladribine increased the proportion of patients with sustained freedom from disease activity (no relapse, no 3-month sustained change in expanded disability status scale score, and no new MRI lesions), such that over 96 weeks, 44% of patients in the 3.5 mg group, 46% in the 5.25 mg group, and 16% in the placebo group were free from disease activity [[4463]]; additional assessment of MRI outcomes showed that, when data were stratified by baseline disease characteristics, active lesion counts were significantly reduced, and the proportions of patients without active lesions were significantly increased, by cladribine [[4317]]; analysis of economic data from this study indicated that cladribine efficacy was associated with reduced need for medical and societal support and less consumption of healthcare resources [[4464]] Trial name: CLARITY Extension Study (meeting report, April 2016) [[794]] [[29281]] Phase: Phase IIIb trial [[794]] Study Design: Company-sponsored, re-randomized, placebo-controlled, double blind, parallel assignment, multicenter extension trial involving patients from the CLARITY trial, such that participants from the placebo group were re-randomized to receive 3.5 mg/kg cladribine and participants originally receiving cladribine were re-randomized 2:1 to receive either 3.5 mg/kg cladribine or placebo [[794]] [[29281]] Disease Stage: RRMS (in original CLARITY trial) [[794]] [[559]] Enrollment/Number of Patients: 883 [[794]] Duration: 2 years [[29281]] Status/Outcome: A low annual relapse rate (ARR) was generally maintained in all arms of the study over 2.5 years; participants treated with cladribine for 4 years exhibited an ARR of 0.10 and those who switched from cladribine in the trial to placebo in the extension exhibited an ARR of 0.15, indicating the beneficial effects of the drug persist (meeting report, April 2016) [[29281]]		Trial name: Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Trials (PREMIERE) (recruiting as of July 22, 2011) [[798]] Phase: Extension trial [[798]] Study Design: Company-sponsored, observational, case-controlled, prospective study, in which patients who have participated in cladribine clinical trials will be followed to determine long-term safety, with the primary outcome an estimate of risk factors and their frequency and the secondary outcomes the occurrence of severe infections, malignancies, deaths, hematological toxicity, pregnancies, and pregnancy outcomes [[798]] Disease Stage: MS patients who have taken oral cladribine in MS clinical studies [[798]] Enrollment/Number of Patients: Estimated 1500 [[798]] Duration: Will last until 2 years of follow-up data are available for 1000 subjects after registry enrollment [[798]] Status/Outcome: Final data collection date for the primary outcome measure is Dec 2018 [[798]]
Cyclophosphamide	Trial name: Likosky et al., J. Neurol. Neurosurg. Psychiatry, December 1991 trial [[932]] Phase: Phase II trial [[932]] Study Design: Hospital-supported, randomized, single-blinded, placebo-controlled trial to study the ability of intensive immunosuppression induced by intravenous cyclophosphamide (400 to 500 mg given 5 days a week until a target leucocyte count was reached) to stabilize progressive MS [[932]] Disease Stage: Chronic progressive MS [[932]] Enrollment/Number of Patients: 42 [[932]] Duration: 2 years [[932]] Status/Outcome: Cyclophosophamide and control were associated with similar disease progression [[932]] Trial name: Canadian Cooperative Multiple Sclerosis Study Group, Lancet, February 1991 trial [[943]] Phase: Phase II trial [[943]] Study Design: Research council supported, randomized, multicenter, placebo-controlled, single-masked trial to test the safety and efficacy of (i) intravenous cyclophosphamide (1 g on alternate days until a target white blood cell count was reached or until 9 g had been given) with oral prednisone, (ii) oral cyclophosphamide (1.5 to 2.0 mg per kg daily) with alternate day prednisone for 22 weeks and weekly plasma exchange for 20 weeks, or (iii) sham plasma exchange and placebo medications; the primary analysis was a comparison of the rates of treatment failure on two consecutive 6 month assessments [[943]] Disease Stage: Progressive MS [[943]] Enrollment/Number of Patients: 168 [[943]] Duration: 3 years [[943]] Status/Outcome: Neither drug regime was associated with a reduction in the rate of treatment failure, which was statistically similar among all groups [[943]]	Trial name: Efficacy of Cyclophosphamide Versus Methylprednisolone in Patients with Secondary Progressive Multiple Sclerosis (PROMESS) (ongoing as of October 2010; meeting report, October 2013) [[926]] [[7898]] Phase: Phase III trial [[926]] Study Design: Hospital- and ministry-sponsored, double-blind, two-arm, multicenter, randomized trial to compare the effectiveness of intravenous cyclophosphamide versus intravenous methylprednisolone (each given every 4 weeks for 1 year and every 8 weeks for 1 year) on the delay to disability deterioration (primary outcome measure) and on the proportion of patients with disability deterioration and number of relapses (secondary outcome measures) [[926]] Disease Stage: Secondary MS [[926]] Enrollment/Number of Patients: 138 (72 on cyclophosphamide and 66 on methylprednisolone) [[7898]] Duration: 2 years [[926]] Status/Outcome: Estimated completion date is July 2011 (final data collection for primary outcome) [[926]]; individuals treated with cyclophosphamide were more than twice as likely to drop out of the study than those on methylprednisolone (such that 33 out of 72 on cyclophosphamide dropped out before the end of the study, 20 because of adverse events); cyclophosphamide treatment appeared to be associated with a lower risk of additional disability than was methylprednisolone treatment, such that 18.1% of those on cyclophosphamide exhibited disability deterioration (measured by the Expanded Disability Status Scale score) versus 31.8% of those on methylprednisolone, but cyclophosphamide use did not reach statistical significance as being superior to methylprednisolone in intention-to-treat analysis because of the higher dropout rate [[7898]] Trial name: Zipoli et al., J. Neurol. Sci., March 2008 study [[4494]] Phase: Open label comparative study [[4494]] Study Design: Study to compare the safety and efficacy of intravenous mitoxantrone (8 mg per square meter monthly for 3 months, then every 3 months to reach a dose of 120 mg per square meter) to that of intravenous cyclophosphamide (700 mg per square meter, monthly for 12 months and then bimonthly for another 24 months) [[4494]] Disease Stage: Active RRMS or SPMS [[4494]] Enrollment/Number of Patients: 153 [[4494]] Duration: Mean followup of 3.6 years [[4494]] Status/Outcome: No significant difference was seen between the time to first relapse in the two groups; time to disease progression was 3.8 years in the mitoxantrone group and 3.6 years in the cyclophosphamide group; discontinuation because of side effects occurred more frequently in the cyclophosphamide group, although both drug regimes were considered tolerable [[4494]] Trial name: Smith et al., Mult. Scler., October 2005 trial [[942]] Phase: Phase II trial [[942]] Study Design: Randomized, single-blind, parallel-group, multicenter trial to test the safety and efficacy of combination therapy, with methylprednisolone (1 g intravenously for 3 days at screening) and interferon beta-1a (30 mcg intramuscularly weekly for 24 months) and either (i) cyclophosphamide (800 mg per m2) and methylprednisolone (1 g intravaneously) or (ii) methylprednisolone once per month for 6 months, with the primary endpoint the change in the mean number of gadolinium-enhanding lesions and a secondary endpoint the time to treatment failure [[942]] Disease Stage: MS patients with active disease when treated with interferon beta [[942]] Enrollment/Number of Patients: 59 [[942]] Duration: 2 years [[942]] Status/Outcome: Cyclophosphamide and methylprednisolone regime was associated with fewer lesions and a lower cumulative rate of treatment failure as compared with the methylprednisolone regime [[942]] Trial name: Hauser et al., N. Engl. J. Med., January 1983 trial [[944]] Phase: Phase II trial [[944]] Study Design: Foundation- and NIH-sponsored, prospective, randomized, three-arm controlled trial to compare the effects of (i) short-term, high-dose intravenous cyclophosphamide (10 to 14 days of 400 to 500 mg per day) plus adrenocorticotropic hormone (ACTH), (ii) ACTH alone (for 21 days), or (iii) plasma exchange, ACTH (for 21 days), and low-dose oral cyclophosphamide (2 mg per kg per day for 8 weeks) [[944]] Disease Stage: Severe progressive MS [[944]] Enrollment/Number of Patients: 58 [[944]] Duration: 1 year [[944]] Status/Outcome: High-dose cyclophosphamide plus ACTH was the most effective drug combination for halting disease progression; patients in this category were more likely to be improved or stable after 1 year as compared with patients receiving ACTH alone or plasma exchange (80% versus 20% versus 50%); 11 of the 16 patients in the cyclophosphamide-ACTH group who had been improved or stable at 1 year experienced re-progression in the second or third year after treatment [[944]]	Trial name: DeZern et al., Am. J. Blood Res., January 2013 study [[4740]] Phase: Open label/observational study [[4740]] Study Design: Observational study to determine if repeat treatment with high-dose cyclophosphamide (50 mg per kg, given intravenously over one hour on 4 consecutive days) after initial cyclophosphamide-induced remission (lasting 22 to 108 months) followed by relapse could safely induce remission a second time in severe autoimmune disease [[4740]] Disease Stage: Severe MS, refractory to standard immunomodulatory therapy [[4740]] Enrollment/Number of Patients: 1 (with MS); 7 others with other autoimmune diseases [[4740]] Duration: 67 months followup for the MS patient [[4740]] Status/Outcome: The quality of the second remissions appeared to be equal to or better than the first; the MS patient was in remission 24 months after the first treatment and for at least 33 months after the second [[4740]] Trial name: Harrison et al., Mult. Scler., February 2012 study [[930]] Phase: Retrospective medical record review [[930]] Study Design: Retrospective review of population of MS patients treated with with high-dose cyclophosphamide (200 mg per kg intravenous infusion over 4 days) followed by maintenance with glatiramer acetate to determine if there is a long-term benefit [[930]] Disease Stage: RRMS [[930]] Enrollment/Number of Patients: 32 [[930]] Duration: 14 months (mean post-treatment follow-up) [[930]] Status/Outcome: Drug regime was associated with a reduction in the annualized relapse rate (as compared with the rate 2 years before treatment), disability progression, and the mean number of gadolinium-enhanced lesions [[930]] Trial name: Le Bouc et al., Mult. Scler., January 2012 study [[4493]] Phase: Historical prospective study [[4493]] Study Design: Study to examine cancer incidence after treatment with cyclophosphamide, in which demographic and medical data were collected and cancers were histologically confirmed; the incidence of cancer was compared to that in the general population [[4493]] Disease Stage: Progressive MS [[4493]] Enrollment/Number of Patients: 354 [[4493]] Duration: 5 years median followup time (with a range of 2 to 15 years) after treatment [[4493]] Status/Outcome: Evidence for an increased risk of cancer after cyclophosphamide treatment was not found [[4493]] Trial name: DeZern et al., Medicine (Baltimore), March 2011 study [[951]] Phase: Observational/open-label study [[951]] Study Design: NIH-funded, observational, retrospective study to determine the effects of high-dose intravenous cyclophosphamide (50 mg per kg per day for 4 consecutive days) without stem cell rescue on disease activity, relapse rate, and overall survival in patients who were refractory to standard treatment [[951]] Disease Stage: Active MS [[951]] Enrollment/Number of Patients: 47 (47 patients with MS; 140 total patients, with a variety of severe autoimmune diseases) [[951]] Duration: 50 months (mean follow-up time; range was 1 to 127 months) [[951]] Status/Outcome: Drug was associated with a response in 70.2% of the MS patients of at least 1 point improvement on the Expanded Disability Status Scale, with a median duration of 9 months [[951]] Trial name: Schwartzman et al., CNS Neurosci. Ther., Summer 2009 study [[4490]] Phase: Observational/open-label study [[4490]] Study Design: Study to determine if high dose (immunoablative) cyclophosphamide could stabilize RRMS, SPMS, or PPMS, as determined by monitoring extended disability status scale scores, lesion load, brain volume, and relapse frequency [[4490]] Disease Stage: RRMS (9 patients), SPMS (11 patients), and PPMS (3 patients) [[4490]] Enrollment/Number of Patients: 23 [[4490]] Duration: 3.5 years [[4490]] Status/Outcome: Cyclophosphamide use in RRMS showed effectiveness (4 of the 9 RRMS patients showed no clinical progression up to 3.5 years after treatment and 7 of 9 had reduced flare frequencies), but use was generally not effective in SPMS and failed in 2 PPMS patients [[4490]] Trial name: Makhani et al., Neurology, June 2009 study [[4511]] Phase: Retrospective medical record review [[4511]] Study Design: Review to examine the effects of cyclophosphamide in pediatric MS patients with severe relapses or who are not responsive to conventional therapies; children had received (i) induction therapy only (5 doses given over 8 days, with the dosing determined by white blood cell count); (ii) induction therapy followed by monthly pulse maintenance therapy; or (iii) pulse maintenance therapy alone [[4511]] Disease Stage: RRMS or SPMS [[4511]] Enrollment/Number of Patients: 17 [[4511]] Duration: N/A [[4511]] Status/Outcome: Cyclophosphamide resulted in a reduced relapse rate and disability score stabilization 1 year after treatment began for most patients and was well-tolerated by most, but some side effects occurred (vomiting, transient alopecia, osteoporosis, and amenorrhea) [[4511]] Trial name: Krishnan et al., Arch Neurol., Aug 2008 study [[946]] Phase: Observational/open-label study [[946]] Study Design: University and foundation-supported, open-label study to explore the safety and effectiveness of high-dose (immunoablative) cyclophosphamide (50 mg per kg per day for 4 consecutive days) without subsequent bone marrow transplantation or immunomodulatory therapy unless the patient required rescue therapy, with the primary outcome safety and tolerability and secondary outcome measures a change in gadolinium-enhancing lesions in MRI and a change in disability measures [[946]] Disease Stage: Aggressive RRMS [[946]] Enrollment/Number of Patients: 9 [[946]] Duration: 2 years [[946]] Status/Outcome: Treatment was well-tolerated and was associated with a reduction in disability and in the mean number of gadolinium-enhancing lesions (81.4% reduction), indicating that cyclophosphamide may be an alternative to bone marrow transplantation [[946]] Trial name: La Mantia et al., Cochrane Database Syst. Rev., January 2007 study [[950]] Phase: Retrospective trial review [[950]] Study Design: Systematic review of relevant randomized controlled trials (which involved cyclophosphamide alone or cyclophosphamide with adrenocorticotropic hormone or steroids) to evaluate whether the drug slows MS progression [[950]] Disease Stage: Progressive MS [[950]] Enrollment/Number of Patients: 152 [[950]] Duration: N/A [[950]] Status/Outcome: Drug regimes did not prevent long-term progression of disability [[950]] Trial name: Gladstone et al., Arch. Neurol., October 2006 study [[4569]] Phase: Observational/open-label study [[4569]] Study Design: Study to evaluate the effects of high-dose cyclophosphamide (200 mg per kg over 4 days) in patients with an Expanded Disability Status Scale (EDSS) score ≥3.5 after evaluation of 2 or more approved disease-modifying therapy regimens [[4569]] Disease Stage: Severe refractory MS [[4569]] Enrollment/Number of Patients: 12 [[4569]] Duration: Median followup, 15 months; range, 6 to 24 months [[4569]] Status/Outcome: Treatment was associated with minimal morbidity and improved clinical outcomes, such that the EDSS score never increased by >1.0 and decreased by ≥1.0 in 5 patients; patients described improvement in all quality-of-life issues measured [[4569]] Trial name: Reggio et al., J. Neurol., October 2005 study [[4508]] Phase: Observational/open label study [[4508]] Study Design: Study to determine the effects of cyclophosphamide [given in monthly intravenous pulses (dose ranging from 500 mg to 1500 mg per square meter) to obtain chronic reduction of lymphocytes] in combination with interferon beta-1a or interferon beta-1b for 24 months in patients who had already been treated with interferon beta alone for at least 12 months and had apparently failed to receive benefit, with the primary endpoint the yearly relapse rate [[4508]] Disease Stage: RRMS [[4508]] Enrollment/Number of Patients: 30 patients who experienced failure of interferon beta therapy [[4508]] Duration: 24 months (patients were examined one year before cyclophosphamide began and during the 24 months of combination therapy) [[4508]] Status/Outcome: Cyclophosphamide treatment was associated with a significant improvement in the yearly relapse rate, such that the relapse rate was 1.4 12 months before the combination therapy began, 0.4 at 12 months, and 0.17 at 24 months [[4508]] Trial name: Patti et al., J. Neurol. Sci., December 2004 study [[4489]] Phase: Observational/open-label study [[4489]] Study Design: Study to examine the long-term effects of 18 months of combination therapy [monthly intravenous cyclophosphamide pulses (500 mg to 1500 mg per square meter) for 12 months to obtain lasting reduction of lymphocytes followed by bimonthly cyclophosphamide for 6 months] combined with standard doses of interferon beta-1a or interferon beta-1b, after which interferon beta alone was continued at standard doses [[4489]] Disease Stage: Rapidly transitional MS, refractory to interferon beta therapy [[4489]] Enrollment/Number of Patients: 10 [[4489]] Duration: 4.5 years (18 months of combination therapy plus followup for 36 months) [[4489]] Status/Outcome: The addition of cyclophosphamide significantly reduced the number of relapses, extended disability status scale score, and lesion burden, and these reductions were maintained for 36 months after cyclophosphamide was discontinued [[4489]] Trial name: Zephir et al., J. Neurol. Sci., March 2004 study [[4567]] Phase: Retrospective medical record review [[4567]] Study Design: Cohort study to determine which clinical patterns might predict a good response to monthly cyclophosphamide pulses in patients in whom the Expanded Disability Status Scale (EDSS) score had worsened by ≥1 point in the previous year; the EDSS score was determined at baseline and at 6 months and 12 months of treatment [[4567]] Disease Stage: Progressive MS (SPMS or PPMS) [[4567]] Enrollment/Number of Patients: 490 (data from 490 patients were collected; 476 had been treated for ≥1 year with cyclophosphamide and methylprednisolone) [[4567]] Duration: 1 year of treatment [[4567]] Status/Outcome: Response to treatment did not significantly differ between SPMS and PPMS patients; after 12 months, 78.6% of SPMS and 73.5% of PPMS patients exhibited an improved or stabilized EDSS score [those who improved had a shorter mean progressive time course (5.1 years) than those who remained stable or became worse (7.1 years)] and the treatment was generally well tolerated [[4567]]

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