Multiple Sclerosis Discovery Forum

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Displaying 28 drugs.

Name	Class	Target	Status for MS	Administration	Commercial
Alemtuzumab	IS NP	CD52 [[435]]	Used on a research basis in MS since 1991 [[783]] Fast tracked by the US Food and Drug Administration in June, 2010 [[784]] Phase III trials showed that alemtuzumab caused a reduction in relapse rate as compared to interferon beta1-a (results announced July 2011, publ October 2012) [[784]] [[789]] [[3822]] [[3823]]	Intravenous [[781]] Subcutaneous administration was effective and well tolerated in two patients with highly active relapsing MS [[4208]]	Discovered by researchers at Cambridge University, UK [[435]] 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Medicines Agency by Genzyme, to seek approval for use of alemtuzumab in the treatment of RRMS (12 June 2012) [[2738]] Withdrawn as a cancer drug (known as Campath/MabCampath) in the US and EU by Sanofi's Genzyme, so that this company can concentrate on marketing the drug for MS (as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 Lemtrade 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 Lemtrade 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]]
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 (two studies are described as completed as of June and November, 2012) [[485]] [[486]]	Intravenous infusions used in Phase I trial [[486]]	Discovered by Biogen Idec [[377]] Clinical trials are sponsored by Biogen Idec [[485]] [[486]]
Cladribine	IS	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 FDA in March 2011 [[552]] 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]]
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) [[432]] T cell expansion [[431]] Innate immune system [[2700]]	In Phase III trials for RRMS [[432]]	Subcutaneous [[801]] Intravenous [[431]]	Initially marketed by Hoffman-La Roche, withdrawn in EU in 2008 and in US in 2009 for commercial reasons [[806]] [[807]] Current trials for MS sponsored by Biogen Idec and Abbott [[801]]
Dalfampridine	IM	Voltage-gated potassium channels [[348]] [[384]] Degenerin/epithelial sodium channels [[4942]]	Approved in US (2010) to improve walking in patients with all forms of MS [[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 FDA [[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 FDA (23 July 2012) [[2649]]	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]] 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]]
Dimethyl fumarate	IM NP	Cytokine secretion [[341]] CD62E [[341]] Inflammation [[341]] Nrf2 transcriptional pathway [[341]]	Results from Phase III trials have been published (September 2012) and reported in Biogen Idec press releases (October 2011 and April 2011) [[583]] [[1793]] [[3222]] [[3221]] Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]	Oral [[583]]	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 have been sponsored by Biogen Idec [[583]] Marketing applications from Biogen Idec have been accepted by US and EU regulatory authorities for review (May 2012) [[1792]] Review time for the New Drug Application 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) has been granted patent protection by the US Patent and Trademark Office (19 March 2013) [[5317]] 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]] Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]
Estriol	IM NP	Estrogen receptor beta [[443]] T cells [[461]] Dendritic cells [[423]]	In Phase II trials [[864]] [[865]]	Oral [[864]]	Early studies were conducted by Rhonda Voskuhl 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]]
Fingolimod	IM NP	Sphingosine 1-phosphate receptors [[301]] Immune cell migration [[301]]	Approved in US, EU, and other countries for RRMS [[466]] [[467]] [[468]] [[469]]	First oral treatment for RRMS available in US [[307]] 0.5 mg orally once daily (information provided by the manufacturer) [[470]] Label has been updated to say that all patients should have an electrocardiogram before the first dose, according to information from the manufacturer (Apr 2012) [[1795]] Contraindicated in the presence of specific cardiac conditions, according to information from the manufacturer [[1795]] Drug-drug interactions are not observed with a combined oral contraceptive (ethinylestradiol/levonorgestrel) [[2271]] 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]]	Clinical trials sponsored by Novartis Pharma [[303]] [[302]] [[304]] Marketed by Novartis [[307]] Licensed from Mitsubishi Tanabe Pharma Corporation [[468]]
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]]	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]]	Involves daily subcutaneous injection, according to information from the FDA [[492]] Prefilled syringes contain 20 mg glatiramer acetate in solution [[489]] [[492]] 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 approval for a three-times weekly dose of Copaxone has been filed by Teva (March, 2013) [[5913]] 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]]
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]] Rebif Rebidose (a single-use auto-injector for interferon beta-1a) was approved by the US Food and Drug Administration (3 January 2013) [[4437]]	Avonex was developed and is manufactured and marketed by Biogen Idec [[1063]] Rebif is manufactured by EMD Serono and co-marketed by Pfizer in the US [[1064]] CinnoVex is manufactured and marketed by CinnaGen [[1065]]
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 FDA 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]]	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]]
Laquinimod	IM NP	NFkB-mediated inflammatory pathways [[567]] T helper cell response [[567]] B cells [[2675]] Dendritic cells [[5351]]	Phase III trial for treating RRMS has been completed (press release 2011; publ 2012) [[809]] [[883]] Granted fast-track review status by the US Food and Drug Administration in 2009 [[818]] [[348]] 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]]	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]] 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]]
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]]
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 FDA [[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]]
Natalizumab	IM	α4 integrins [[300]] Leukocyte trafficking [[379]]	Approved in US for treating relapsing forms of MS and in the EU for treating RRMS [[300]] [[593]]	300 mg via intravenous infusion every four weeks (this information was provided by the manufacturer) [[592]]	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-JCV 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]]
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]]
Ofatumumab	IS	B cells [[432]] CD20 [[432]]	Phase I/II study ongoing [[432]] [[648]] [[649]] Phase II study planned [[645]] [[651]]	Intravenous [[648]] Subcutaneous as of September, 2010 [[645]]	Development sponsored by GlaxoSmithKline [[432]]
ONO-4641	IM	Sphingosine 1-phosphate (S1P) receptor [[626]][[428]]	Phase II [[626]]	Oral [[626]][[428]]	Discovered and developed by Ono Pharmaceutical Co. for commercialization in Japan, Korea and Taiwan [[626]] Licensed to Merck Serono for development and commercialization outside of in Japan, Korea and Taiwan [[626]]
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]]	Discovered by Biogen Idec [[484]] Co-marketed by Genentech and Biogen Idec in the US [[484]] 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]]
RPC1063		Sphingosine-1-phosphate receptors [[3777]]	Phase II trial is underway (22 October 2012) [[3775]]	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 clinical trial sponsored by Receptos [[3777]]
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]]
Teriflunomide	IS IM	Dihydroortate dehydrogenase [[411]] [[410]] Pyrimidine synthesis [[410]] Lymphocyte proliferation [[401]]	Approved in the US, Australia, and Argentina for RRMS [[3139]] [[4011]] [[5779]]	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]]
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 sponsored by Centocor (owned by Johnson&Johnson) [[452]] [[625]] Marketed by Centocor in US and Janssen-Ortho, Inc outside the US [[619]] [[437]]

Name	Trade name	Synonyms	Systematic name
Alemtuzumab	Lemtrada [[779]]	Alemtuzumab [[465]] Campath [[465]] Campath 1H [[465]] Campath 1H/LDP03 [[465]] 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]]
BGC20-0134	Pleneva [[473]]
BIIB033		Anti-LINGO-1 antibody [[485]]
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	Zenapax [[801]]	Dacliximab [[465]] Daclizumab [[465]] Ro 24-7375 [[465]] UNII-CUJ2MVI71Y [[465]] Zenapax [[465]] Anti-Tac [[454]] DAC [[432]] Zenapax [[801]]	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]] 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]] 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]]
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]]	2-Amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol [[465]] FTY-720 [[465]] FTY270 [[465]] Fingolimod [[465]] Gilenia [[465]] Gilenya [[465]] 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]]	COP-1 [[465]] Copaxone [[490]] Copolymer-1 [[465]] GA [[343]] L-Glutamic acid peptide with L-alanine, L-lysine and L-tyrosine, acetate (salt) [[465]] UNII-5M691HL4BO [[465]]	L-Glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt) [[465]]
Interferon beta-1a	Avonex [[1063]] Rebif [[1064]] CinnoVex (generic) [[1065]] PLEGRIDY (peginterferon beta-1a) [[5316]]	Avonex [[465]] Interferon beta-1a [[465]] Neoferon [[465]] Recombinant human interferon beta 1a [[465]] UNII-XRO4566Q4R [[465]] Rebif [[1064]] CinnoVex [[1065]]	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	N/A	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]]
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]]
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	N/A	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	n/a	n/a	n/a
Rituximab	Rituxan [[481]] MabThera [[484]] 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]]
RPC1063
RTL1000	n/a	n/a	Human recombinant T cell receptor ligand (RTL1000) consisting of DR2 α1 and β1 domains linked covalently to MOG-35-55 peptide [[427]]
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]] 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	Target	Properties	Mechanism/Effects (Human)	Mechanism/Effects (Animal)
Alemtuzumab	IS NP	CD52 [[435]]	Molecular weight ~150kDa [[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 24kDa light polypeptide chains and two 55kDa heavy polypeptide chains [[436]] Half life approximately 288 hours / 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 tissues 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]] 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 [[787]] May trigger neuroprotective autoimmunity, based on long-term follow-up 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]] Improves contrast sensitivity in vision tests in patients with early, untreated RRMS [[5147]]	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]]
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]]	Monoclonal antibody [[377]]		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]]
Cladribine	IS	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]]	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]] 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]]	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]]
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]]	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) [[432]] 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 ~150kDa [[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]]	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]] May inhibit CD40L expression [[440]] Reduces Treg frequency and function, based on blood and cerebrospinal fluid samples in 15 patients [[444]] 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]]
Dalfampridine	IM	Voltage-gated potassium channels [[348]] [[384]] Degenerin/epithelial sodium channels [[4942]]	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]]	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]] Improved upper limb tremor in one progressive MS patient [[3605]]	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]]
Dimethyl fumarate	IM NP	Cytokine secretion [[341]] CD62E [[341]] Inflammation [[341]] Nrf2 transcriptional pathway [[341]]	After ingestion, is rapidly hydrolyzed to its primary metabolite, monomethylfumarate, which is in turn further metabolized in the citric acid cycle [[341]] Half-life of dimethyl fumarate is 12 minutes [[341]] Half-life of metabolite monomethylfumarate is 36 hours [[341]]	Exact mechanism unknown [[341]] Shifts T-helper response from Th1 to Th2 in cultured human cells [[341]] 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]]	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]] 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]]
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 non-pregnant state, increases progressively during pregnancy [[460]] [[443]]	Induces an immune shift from Th1 to Th2 in cultured T cells [[461]] In a pilot clinical study, estriol-treated patients had increased levels of IL-5 and IL-10 and decreased levels of TNF-alpha in stimulated peripheral blood mononuclear cells isolated during treatment [[460]] Might reduce MS relapse rate, 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 severity of EAE in mice [[443]] Generates tolerogenic dendritic cells, which protect against EAE 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 EAE [[443]] Prevents changes in hippocampal synaptic transmission in mice with EAE [[1565]]
Fingolimod	IM NP	Sphingosine 1-phosphate receptors [[301]] Immune cell migration [[301]]	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]] 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]]	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 degration 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]] 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]] 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]] Associated with an increase in macular volume within 5 months in a longitudinal observational study [[4171]] Comparison of a Markov transition model approach and survival analysis methods for quantifying the effects of fingolimod on disability progression has been published [[4975]] 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]] 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]]	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]] Active phosphorylated form induces apoptosis in cultured rat Schwann cells [[2328]] 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]] 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]] 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]] 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]] Attenuates learning and memory impairment induced by intrahippocampus injection of beta-amyloid peptide in rats [[5052]]
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]]	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 MW 6.4 kDa [[343]] Binds to class II MHC molecules on antigen-presenting cells [[343]] Polar [[343]] Not likely to cross blood-brain barrier [[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]] 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 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 alpha production increases [[5605]] 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]] 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]] Probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients [[4420]] Not an immunosuppressor [[343]]	Augments B cell activity in mice, suppressing experimental autoimmune encephalomyelitis (EAE), as shown by the finding that B cells from glatiramer acetate (GA)-treated mice suppress EAE in recipient mice [[343]] Induces production of anti-GA antibodies that might enhance remyelination in EAE mice [[343]] Developed to induce EAE, 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 EAE 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 EAE mice [[3892]] Enhances production of interleukin 10 by dendritic cells in EAE mice [[3892]] Reduces the expression of pro-inflammatory, brain-specific chemokines that might attract antigen promoting cells to the central nervous system in EAE mice [[3892]] Induces a strong neuroprotective response in mice who received a crush injury to the optic nerve after Copaxone treatment, but this response is absent if the mice are exposed to chronic mild stress before receiving Copaxone (and the response is regained if Copaxone is combined with Prozac) [[4478]] Has a neuroprotective role against glutamate toxicity in EAE mice [[4802]] Reverses the changes in striatal glutamate-mediated excitatory postsynaptic currents (which are induced by tumor necrosis factor-alpha) that occur in EAE mice [[4802]] Reduces microglial activation and expression of tumor necrosis factor-alpha in EAE mice [[4802]] 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]] Promotes maturation of oligodendrocytes in an animal model (involving cuprizone-induced demyelination) [[5788]]
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]] Glycoprotein [[1063]] [[1064]] Cytokine [[1063]] [[1064]] Produced in genetically engineered Chinese Hamster Ovary cells expressing a human beta interferon gene [[1063]] [[1064]] Specific activity for Avonex: 200 million international units of antiviral activity per mg [[1063]] Specific activity for Rebif: 270 million international units of antiviral activity per mg [[1064]] Pharmacokinetic and pharmacodynamic properties have been described in healthy volunteers [[1066]] [[1067]] [[1068]] 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]]	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]] 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]] Causes upregulation of Toll-like receptor 7 when applied to cultured dendritic cells [[1071]] [[1072]] May decrease T cells’ ability to cross the blood brain barrier by lowering levels of trophic chemokines that draw Th1 cells to the blood vessel wall [[1070]] 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]] 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]] 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]] Interferon beta probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients [[4420]] 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]]	Promotes neuronal growth and survival in cultured mouse cells [[1070]] [[1075]] Promotes the release of nerve growth factor in cultured astrocyte cells [[1070]] [[1091]]
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]]	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]] 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]] 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]] 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 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]] 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]] 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]] 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]] Interferon beta probably does not play a large role in regulating Fcγ receptors on immune cells in RRMS patients [[4420]] 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]] 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]]	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]]
Laquinimod	IM NP	NFkB-mediated inflammatory pathways [[567]] T helper cell response [[567]] B cells [[2675]] Dendritic cells [[5351]]	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]] 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]] Most of what is known comes from experiments in rodents, because studies in patients are lacking [[560]]	Inhibits the development of experimental autoimmune encephalomyelitis (EAE) [[562]] [[563]] [[566]] Inhibits the infiltration of CD4+ T cells and macrophages into the spinal cord, preventing relapse after EAE initiates [[566]] Reduces demyelination, inflammation, and axonal damage in EAE rodents [[571]] Reduces astrogliosis, demyelination, and axonal damage in EAE 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 EAE [[566]] Reduces proinflammatory cytokines, such as interleukin 17, in EAE 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 EAE rodents [[562]] Restores brain derived neurotrophic factor expression to healthy levels in EAE mice [[2341]] 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 EAE mice [[4179]] Preserves the sensitivity of cannabinoid CB1 receptors, which is normally lost during EAE, in EAE mice [[4179]] Increases inhibitory post-synpatic currents and reduces excitatory post-synaptic currents in EAE mice [[4179]]
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]] Does not damage chromosomes or affect mitosis in mouse cells [[1334]]
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]]	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]] 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]] 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 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]]	Can impair dendritic cell maturation and function in mice [[874]]
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]] 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]] 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]] Reduces levels of soluble vascular cell adhesion molecule 1, a ligand for α4β1 integrin that is upregulated in MS, in MS patients [[350]] 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]] 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]] 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]] 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]] 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]] 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]] Does not appear to affect anti-JC virus antibody prevalence, as shown by a cross-sectional study of a multinational MS cohort [[5143]] Lowers serum IgM and IgG levels in MS patients, as shown in both cross-sectional and longitudinal analyses [[5076]] Increases total natural killer cells, as well as the subset of CD56(bright) (immature) natural killer cells, in peripheral blood of MS patients [[5263]]	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]]
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]]	Molecular Weight: 149 kD [[429]] Immunoglobulin G1 (IgG1) kappa human monoclonal antibody [[429]] Generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line [[429]] Pharmacokinetic data has 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 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 (S1P) receptor [[626]][[428]]	In monkeys, lymphocyte counts reached lowest point at 4-8 hrs post-administration [[428]] PK/PD response in humans has been modeled in monkey studies, but needs refinement with human data when available [[428]]	Like other S1P receptor modulators, thought to reduce circulating levels of lymphocytes [[428]] Keeping lymphocytes in lymph nodes presumably stops them from infiltrating lesions [[626]]	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 numbers but did not affect number of regulatory T cells in the lamina propria, a key pathogenic site in colitis [[418]]
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]] 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]] 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]]
RPC1063		Sphingosine-1-phosphate receptors [[3777]]	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]]
RTL1000	IM NP	T cell receptors [[427]] T cell proliferation [[430]] Cytokine secretion [[430]]	Consists of the beta1 and alpha1 domains of HLA DR2 (HLA DRB1*1501) linked to the myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide [[427]] Half-life in human plasma < 5 min [[427]] Design and engineering properties have been described [[447]]	Exact mechanism unknown [[427]][[625]] Causes a transient increase in dose-dependent cytokines similar to that seen in HLA-DR2 transgenic mice with EAE receiving 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 (RTLs) tested can prevent or treat EAE in numerous mouse and rat EAE models [[427]] In mice with EAE, RTL1000 binds preferentially to antigen presenting cells such as B cells, macrophages and dendritic cells, but not T cells [[426]] Treatment with various human recombinant T cell receptors (RTLs) related to RTL1000 induces interleukin 10 production by T-cells [[625]] Mice with EAE treated with different human recombinant T cell receptors (RTLs) related to RTL1000 experience remyelination and axonal repair [[427]][[625]] Several human recombinant T cell receptors (RTLs) related to RTL1000 downregulate interleukin 17 and tumor necrosis factor alpha secretion in mice with EAE [[625]][[430]] Human recombinant T cell receptors (RTLs) related to RTL1000 can suppress T cells in addition to cognate T cells to which they are targeted [[430]] Human recombinant T cell receptors (RTLs) related to RTL1000 treatment decrease infiltration of encephalitogenic cells into the CNS and increase the numbers of those already present [[625]] Human recombinant T cell receptors (RTLs) related to RTL1000 treatment in EAE mice downregulate chemokines and chemokine receptors [[625]] Proposed two-pronged mechanism: a) binds to T cell receptors on pathogenic (autoreactive) T cells in an antigen-specific manner, reducing CXCL1/2 production and thereby inflammatory damage, and b) binds to astrocytes or other parenchymal cells in an antigen peptide-independent manner, reducing CXCL1/2 production, oligodendrocyte repopulation, and thereby remyelination [[427]]
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]] >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]] 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]]	Reduces inflammation, demyelination, and axonal loss in the Dark Agouti rat model of experimental autoimmune encephalomyelitis [[368]] Leflunomide (the prodrug from which the active metabolite teriflunomide is derived) inhibits murine B cell proliferation [[409]]
Ustekinumab	IM	Subunit P40 on cytokines interleukin 12 and interleukin 23 [[437]]	Fully human IgG1 antibody that binds to shared subunit P40 on interleukin 12 and interleukin 23 [[620]] Molecular weight: 148.6 kD [[620]] Metabolism of the drug has not been characterized [[621]] Mean half-life ranged from 15-46 days in 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	Used on a research basis in MS since 1991 [[783]] Fast tracked by the US Food and Drug Administration in June, 2010 [[784]] Phase III trials showed that alemtuzumab caused a reduction in relapse rate as compared to interferon beta1-a (results announced July 2011, publ October 2012) [[784]] [[789]] [[3822]] [[3823]]	Approved [[785]] [[786]]	Approved by FDA for B cell chronic lymphocytic leukemia in 2001 [[785]] Approved by EMEA for B cell chronic lymphocytic leukemia in 2001 [[786]] Used extensively to induce immunosuppression after organ transplantation [[449]] 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]]	Intravenous [[781]] Subcutaneous administration was effective and well tolerated in two patients with highly active relapsing MS [[4208]]	Autoimmune hemolytic anemia [[432]] Autoimmune neutropenia [[432]] Burkitt’s lymphoma and other cancers, though relationship to treatment unclear [[790]] Goodpasture syndrome [[435]] Immune thrombocytopenic purpura [[435]] Infections [[435]] Infusion reactions, which can be reduced by pre-treatment with corticosteroids [[436]] Thyroid autoimmunity, such as Graves disease [[435]]	Discovered by researchers at Cambridge University, UK [[435]] 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 Sanofi's Genzyme, 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 Lemtrade 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 Lemtrade 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]]
BGC20-0134	Phase IIa [[473]] [[791]]	Phase IIa [[473]] [[792]]		Oral [[473]] [[791]]		Developed by BTG plc [[473]]
BIIB033	Phase I (two studies are described as completed as of June and November, 2012) [[485]] [[486]]	Phase I [[485]] [[486]]		Intravenous infusions used in Phase I trial [[486]]		Discovered by Biogen Idec [[377]] Clinical trials are sponsored by Biogen Idec [[485]] [[486]]
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]] Lymphocyclophosphamidetopenia [[793]] Malignancies (melanoma, pancreas carcinoma, and ovarian carcinoma) [[793]] 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 FDA in March 2011 [[552]] 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]]
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]] 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]]	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	In Phase III trials for RRMS [[432]]	Approved by FDA 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]]	Autoimmune attacks (hepatic and renal) [[3771]] Cardiotoxicity[[432]] Central nervous system vasculitis developed in one treated MS patient [[4520]] Chest discomfort [[431]] Fatigue [[432]] Fever [[431]] Gastrointestinal symptoms [[432]] Generalized weakness [[432]] Hypersensitivity (4) Infusion reaction [[432]] Lymphadenopathy [[431]] Mouth ulcers [[432]] Psoriasis in patient with a positive family history [[432]] Rash [[431]] Severe infections [[433]] Transient formation of autoantibodies requiring corticosteroid therapy [[432]] Viral meningitis [[432]]	Initially marketed by Hoffman-La Roche, withdrawn in EU in 2008 and in US in 2009 for commercial reasons [[806]] [[807]] Current trials for MS sponsored by Biogen Idec and Abbott [[801]]
Dalfampridine	Approved in US (2010) to improve walking in patients with all forms of MS [[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 FDA approval for use in MS, 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]] 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]]	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 FDA [[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 FDA (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]] Back pain [[494]] Balance problems [[494]] Constipation [[495]] Diarrhea [[495]] Dizziness [[494]] Headache [[494]] 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]] Urinary tract infection [[494]] Weakness [[494]]	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]] 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]]
Dimethyl fumarate	Results from Phase III trials have been published (September 2012) and reported in Biogen Idec press releases (October 2011 and April 2011) [[583]] [[1793]] [[3222]] [[3221]] Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]	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]]	Oral [[583]]	Abdominal pain [[370]] Diarrhea [[5512]] Fatigue [[370]] Flushing [[370]] Hot flush [[370]] Headache [[370]] Nausea [[5512]]	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 have been sponsored by Biogen Idec [[583]] Marketing applications from Biogen Idec have been accepted by US and EU regulatory authorities for review (May 2012) [[1792]] Review time for the New Drug Application 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) has been granted patent protection by the US Patent and Trademark Office (19 March 2013) [[5317]] 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]] Approved by the US Food and Drug Administration as a first-line treatment for relapsing forms of MS (27 March 2013) [[5512]]
Estriol	In Phase II trials [[864]] [[865]]	Approved in Europe and Asia [[866]]	Post-menopausal hot flashes [[443]]	Oral [[864]]	Cannot be used in men [[443]]	Early studies were conducted by Rhonda Voskuhl 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]]
Fingolimod	Approved in US, EU, and other countries for RRMS [[466]] [[467]] [[468]] [[469]]	Approved [[466]]	Initially tested in preclinical trials for ability to prevent rejection of allografts [[301]] Prolongs survival of allografts [[301]] May 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]] May be useful for treating autoimmune optic neuritis, based on experiments in mice [[5731]] Inhibits neuroinflammation and decreases the length, frequency, and severity of spontaneous convulsions in a rat model of epilepsy [[3078]] May 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]] May be useful for treating colitis-associated colon cancer, based on experiments in mice [[4730]] 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]]	First oral treatment for RRMS available in US [[307]] 0.5 mg orally once daily (information provided by the manufacturer) [[470]] Label has been updated to say that all patients should have an electrocardiogram before the first dose, according to information from the manufacturer (Apr 2012) [[1795]] Contraindicated in the presence of specific cardiac conditions, according to information from the manufacturer [[1795]] Drug-drug interactions are not observed with a combined oral contraceptive (ethinylestradiol/levonorgestrel) [[2271]] 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]]	Bradycardia [[307]] Bradyarrhythmia [[307]] Breathing problems [[307]] Cancers (?) [[302]] Infections (particularly herpes virus infections) [[307]] [[302]] Liver problems [[307]] 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]] Cystoid macular edema [[4539]] Bilateral cystoid macular edema has been associated with fingolimid in one patient [[3421]] Varicella-zoster virus encephalitis and vasculopathy have been reported in one patient receiving fingolimod [[3346]] Severe varicella-zoster virus reactivation has been reported in one patient receiving fingolimod [[3345]]	Clinical trials sponsored by Novartis Pharma [[303]] [[302]] [[304]] Marketed by Novartis [[307]] Licensed from Mitsubishi Tanabe Pharma Corporation [[468]]
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]]	Approved [[488]]	Had positive effects in a mouse model of Alzheimer disease [[383]] 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 for controlling epileptic seizures, based on experiments in rats [[5763]] Inhibits graft rejection in mice [[399]] Reduces inflammation and neurodegeneration in a mouse model of HIV1 encephalomyelitis [[378]] Had positive effects in mouse models of inflammatory bowel disease [[387]] [[3236]] Weekly vaccination with GA decreased symptoms of dry age-related macular degeneration in a small human trial [[369]]	Involves daily subcutaneous injection, according to information from the FDA [[492]] Prefilled syringes contain 20 mg glatiramer acetate in solution [[489]] [[492]] Nasal administration appears effective in experimental autoimmune encephalomyelitis mice [[5357]]	Dyspnea (shortness of breath) [[354]] May have contributed to the development of Guillain-Barré syndrome in one patient [[1747]] Has been associated with severe acute hepatitis in one patient [[2752]] 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]] Urticaria (hives) [[354]] Vasodilatation [[354]] 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]]	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 approval for a three-times weekly dose of Copaxone has been filed by Teva (March, 2013) [[5913]] 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]]
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]] Rebif Rebidose (a single-use auto-injector for interferon beta-1a) was approved by the US Food and Drug Administration (3 January 2013) [[4437]]	Abdominal pain [[1064]] Asthenia (weakness) [[1063]] Autoimmune disorders [[1063]] Cardiovascular events [[1063]] Chills [[1063]] Depression [[1063]] [[1064]] Elevated liver enzymes [[1064]] Fever [[1063]] Flu syndrome [[1063]] [[1064]] Headache [[1063]] [[1064]] Injection site reactions [[1063]] [[1064]] Leukopenia [[1064]] Myalgia [[1063]] [[1064]] Seizures [[1063]] Severe liver injury [[1063]] [[1078]] 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]] 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]] Exposure to interferon beta during pregnancy does not seem to be a major teratogenic risk, based on an analysis of 78 pregnancies [[3117]]	Avonex was developed and is manufactured and marketed by Biogen Idec [[1063]] Rebif is manufactured by EMD Serono and co-marketed by Pfizer in the US [[1064]] CinnoVex is manufactured and marketed by CinnaGen [[1065]]
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 FDA 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]]	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]] 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]] 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]] 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]] Exposure to interferon beta during pregnancy does not seem to be a major teratogenic risk, based on an analysis of 78 pregnancies [[3117]]	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]]
Laquinimod	Phase III trial for treating RRMS has been completed (press release 2011; publ 2012) [[809]] [[883]] Granted fast-track review status by the US Food and Drug Administration in 2009 [[818]] [[348]] 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]]	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]] 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]] Studied to examine neuroprotective effects in animal models of rheumatoid arthritis, insulin-dependent diabetes mellitus, and Guillain Barre Syndrome [[813]]	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]] 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]]
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]] Pancreatic cancer (investigational) [[1378]] Gastrointestinal stromal tumors (investigational) [[1378]] Multiple myeloma (investigational) [[1378]] Metastatic solid tumors (investigational) [[1378]] Mastocytosis (investigational) [[1378]] Rheumatoid arthritis (investigational) [[1378]] Asthma (investigational) [[1378]] Alzheimer disease (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]]
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 FDA [[920]] Cumulative lifetime dose should be limited [[511]]	Alopecia [[505]] Amenorrhea [[505]] Bilirubin [[505]] Birth defects [[507]] Cardiotoxicity [[505]][[526]] 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]] Leukopenia [[505]] Nausea and vomiting [[505]] Phlebitis [[505]] Respiratory tract infections [[505]] Thrombocyclophosphamidetopenia [[505]] Urinary tract infections [[505]]	Marketed by EMD Serono, Inc. [[917]]
Mycophenolate Mofetil	Phase II [[425]] [[599]]	Approved [[600]]	Approved for prevention of transplant organ rejection [[597]] Neuromyelitis optica [[439]] Systemic lupus erythematosus [[439]] Autoimmune hepatitis [[439]] Psoriasis [[439]] Blistering dermopathies [[439]] Vasculitides [[439]] Myasthenia gravis [[439]] Multifocal motor neuropathy [[439]] Inflammatory myopathies [[439]] Chronic inflammatory demyelinating polyradiculoneuropathy [[439]] Autonomic ganglionopathy [[439]] Vasculitic neuropathies [[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]]
Natalizumab	Approved in US for treating relapsing forms of MS and in the EU for treating RRMS [[300]] [[593]]	Approved [[300]]	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]]	300 mg via intravenous infusion every four weeks (this information was provided by the manufacturer) [[592]]	Allergic reactions [[589]] Anaphylaxis [[589]] Arm and leg pain [[589]] Breathing problems [[589]] Chest pain [[589]] Chills [[589]] Depression [[589]] Diarrhea [[589]] Dizziness [[589]] Feeling tired [[589]] Flushing skin [[589]] Headache [[589]] Natalizumab-induced autoimmune hepatitis has been observed in one MS patient [[3607]] Herpes zoster has been reported in three cases [[5006]] Varicella-zoster virus myelitis has been reported in one patient [[5769]] Hives [[589]] Infections [[589]] Itching [[589]] Joint pain [[589]] Liver damage [[589]] Low blood pressure [[589]] Nausea [[589]] Fatal neuroinflammation occurred in one patient with anti-natalizumab antibodies [[4881]] Progressive multifocal leucoencaphalopathy [[391]] 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]] 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]] Aggravated psoriasis in one patient [[3715]] Rash [[589]] Reversible leukoencephalopathy syndrome (which can mimic progressive multifocal leukoencephalopathy) [[1831]] Stomach pain [[589]] Urinary tract infection [[589]] Vaginitis [[589]] 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]] Withdrawal led to a lethal MS relapse in one patient [[3734]]	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-JCV 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]]
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]]
Ofatumumab	Phase I/II study ongoing [[432]] [[648]] [[649]] Phase II study planned [[645]] [[651]]	Approved [[647]]	Approved for chronic lympocytic 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 [[432]]	Intravenous [[648]] Subcutaneous as of September, 2010 [[645]]	Anemia [[429]] Bronchitis [[429]] Cough [[429]] Diarrhea [[429]] Dyspnea (4) Fatigue [[429]] Infections (most commonly upper respiratory tract infections) [[429]] Infusion reactions [[429]] Nausea [[429]] Neutropenia [[429]] Pneumonia [[429]] Pyrexia [[429]] Rash [[429]]	Development sponsored by GlaxoSmithKline [[432]]
ONO-4641	Phase II [[626]]	Phase II [[626]]	Preclinical study in colitis [[418]]	Oral [[626]][[428]]	Slower heartbeat at the beginning of treatment [[2754]] Liver enzyme elevations [[2754]] Grade 4 lymphopenia [[2754]]	Discovered and developed by Ono Pharmaceutical Co. for commercialization in Japan, Korea and Taiwan [[626]] Licensed to Merck Serono for development and commercialization outside of in Japan, Korea and Taiwan [[626]]
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 FDA in Nov 1997 for treating CD20-positive, B-cell, non-Hodgkins lymphoma [[480]] [[481]] Approved in June 1998 in European Union, under tradename MabThera, for treating non-Hodgkin's lymphoma [[484]] Approved by FDA in Feb 2006 for treating rheumatoid arthritis [[481]] [[484]] Approved by FDA for treating additional non-Hodgkins lymphomas in 2006 [[484]] Prescribed off-label for treating certain other diseases, such as systemic lupus erythematosus [[481]] 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, and neuromyelitis optica [[373]]	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]]	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]] Viral reactivation [[484]]	Discovered by Biogen Idec [[484]] Co-marketed by Genentech and Biogen Idec in the US [[484]] 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]]
RPC1063	Phase II trial is underway (22 October 2012) [[3775]]	Phase II trial is underway (22 October 2012) [[3775]] 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]]	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 clinical trial sponsored by Receptos [[3777]]
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]]
Teriflunomide	Approved in the US, Australia, and Argentina for RRMS [[3139]] [[4011]] [[5779]]	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 FDA for treatment of rheumatoid arthritis [[404]] [[582]]	Oral [[341]]	Diarrhea [[339]] Hair thinning [[339]] Headache [[579]] Nausea [[579]] [[339]]	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]]
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]]	In trials for psoriatic arthritis and 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]]	Fatigue [[625]] Headache [[625]] Injection site reactions [[625]] Infections [[625]] Could reactivate latent tuberculosis [[621]] Could increase incidence of malignant tumors [[621]]	Clinical trials sponsored by Centocor (owned by Johnson&Johnson) [[452]] [[625]] Marketed by Centocor in US and Janssen-Ortho, Inc outside the US [[619]] [[437]]

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 July 2011, publ October 2012) [[784]] [[3822]] 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]] Trial name: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) (reported November 2011, publ October 2012) [[789]] [[3823]] 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]] Trial name: International Campath-1H in Multiple Sclerosis CAMMS223 (publ 2008) [[448]] 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: RRMS [[448]] Enrollment/Number of Patients: 334 (with 333 completing the study) [[448]] Duration: 36 months [[448]] Status/Outcome: Drug was associated with a 71% reduction in the relative risk of sustained disability and a 74% relative reduction in relapse rate (primary endpoints). Drug was also associated with a more marked reduction in lesions (T2-weighted MRI) than interferon beta-1a and an increase in brain volume (compared to a decrease with interferon beta-1a); proportion of patients relapse-free after 3 years on drug was 80%, vs 52% for interferon beta-1a (secondary endpoints) [[448]]	Trial name: CARE-MS I extension study (conference report, March 2013) [[5365]] Phase: Extension phase of Phase III trial [[784]] [[3822]] [[5365]] Study Design: Company-sponsored extension of a trial comparing alemtuzumab with interferon beta-1a in patients new to treatment [[5365]] Disease Stage: RRMS [[5365]] Enrollment/Number of Patients: >90% of patients in original trial [[5365]] Duration: Results from 1 year extension described in March 2013 [[5365]] 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 patients who received alemtuzumab in the original trial did not receive additional treatment during year 1 of the extension [[5365]] Trial name: CARE-MS II extension study (conference report, March 2013) [[5365]] Phase: Extension phase of Phase III trial [[789]] [[3823]] [[5365]] Study Design: Company-sponsored extension of a trial comparing alemtuzumab with interferon beta-1a in patients who had relapsed on previous therapy [[5365]] Disease Stage: RRMS [[5365]] Enrollment/Number of Patients: >90% of patients in original trial [[5365]] Duration: Results from 1 year extension described in March 2013 [[5365]] 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 [[5365]] 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 post-hoc and subset analysis (publ 2011) [[448]] [[422]] Phase: Additional data analysis for Phase II study [[422]] Study Design: Post-hoc and subset analysis 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) [[448]] [[422]] Disease Stage: RRMS [[422]] Enrollment/Number of Patients: 334 [[422]] Duration: 2 years [[422]] Status/Outcome: The drug 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 EDSS [[422]] Trial name: CAMMS223 5-year follow-up (published 2012) [[997]] Phase: Extension of Phase II study [[997]] Study Design: Open-label 2-year 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) [[422]][[788]][[997]] Disease Stage: RRMS [[997]] Enrollment/Number of Patients: 198 on alemtuzumab and 47 on interferon beta1-a, out of original 334 randomized [[997]] Duration: Five year follow-up [[997]] Status/Outcome: Alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with interferon beta-1a over 5 years. The annualized relapse rate during that time was 0.11 for alemtuzumab and 0.35 for interferon beta-1a Among patients taking alemtuzumab, 72% were estimated to be relapse-free after 5 years, compared to 41% on interferon beta-1a. Patients on alemtuzumab had more frequent serious infections, thyroid disorders and immune thrombocytopenia than those treated with interferon beta-1a [[997]] 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 patients with increasing disability [[458]] Disease Stage: SPMS and RRMS [[458]] Enrollment/Number of Patients: 36 (22 women) SPMS; 22 (17 women) RRMS [[458]] Duration: Patients treated between 1991 and 2002; 280 total patient-years [[458]] Status/Outcome: Drug was associated wtih decrease in relapse rate (RRMS, 94%, SPMS, 97%) and lesion formation measured by MRI in both groups; SPMS patients showed accumulating disability, while RRMS patients remained stable, suggesting that suppressing inflammation is only effective early in disease progression [[458]]
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 single ascending dose study in healthy volunteer subjects (completed as of June 2012) [[485]] Phase: Phase I [[485]] Study Design: Randomized, blinded, placebo-controlled, single-ascending dose study to evaluate safety and tolerability (primary outcome measures) and pharmacokinetics, serum antibody levels, and exploratory biomarkers (secondary outcome measures) [[485]] Disease Stage: Healthy individuals [[485]] Enrollment/Number of Patients: 72 [[485]] Duration: Up to 4 months [[485]] Status/Outcome: Completed (as of June 2012) [[485]] Trial name: Safety study of BIIB033 in subjects with multiple sclerosis (completed as of November 2012) [[486]] Phase: Phase I [[486]] Study Design: Randomized, blinded, placebo-controlled, serial-cohort, multiple ascending dose study 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/kg) administered two weeks apart [[486]] Disease Stage: RRMS or SPMS [[486]] Enrollment/Number of Patients: Approximately 42 [[486]] Duration: 6 months [[486]] Status/Outcome: Completed (as of November 2012) [[486]]
Cladribine	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: Oral Cladribine in Early Multiple Sclerosis (ORACLE MS) (ongoing as of September 28, 2011) [[795]] Phase: Phase III trial [[795]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of cladribine (either 1.75 mg or 3.5 mg per kilogram per year, with the dose given once per week for 4 weeks at the beginning of a cycle) on delaying the conversion to MS after CIS (primary outcome) [[795]] Disease Stage: Patients who have sustained their first CIS, who are at at high risk of converting to MS [[795]] Enrollment/Number of Patients: 617 [[795]] Duration: 2 years [[795]] Status/Outcome: Final data collection date for the primary outcome is July 2011; estimated study completion date is July 2013 [[795]] 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]]; post-hoc 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 (ongoing as of January 23, 2012) [[794]] 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 patients from the placebo group were re-randomized to receive 3.5 mg cladribine and patients receiving cladribine were re-randomized to receive either 3.5 mg cladribine or placebo [[794]] Disease Stage: RRMS (in original CLARITY trial) [[794]] [[559]] Enrollment/Number of Patients: 883 [[794]] Duration: 2 years [[794]] Status/Outcome: Final data collection date is September 2011 [[794]]		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 12, 2010) [[926]] 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: 360 (estimated) [[926]] Duration: 2 years [[926]] Status/Outcome: Estimated completion date is July 2011 (final data collection for primary outcome) [[926]] 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]] Trial name: Portaccio et al., Mult. Scler., October 2003 study [[4492]] Phase: Medical record review [[4492]] Study Design: Review to determine the frequency and severity of side effects and drug tolerability in patients who received intravenous cyclophosphamide each month for 12 months (700 mg per square meter of body surface), then once every two months for another 12 months [[4492]] Disease Stage: Progressive or very active MS [[4492]] Enrollment/Number of Patients: 112 [[4492]] Duration: 24 months of active treatment with prospective followup [[4492]] Status/Outcome: 81.8% of patients felt that the treatment regimen was at least relatively tolerable and acceptable, whereas 18% discontinued therapy because of side effects; serious side effects, which were seen in 21.4% of patients, included definitive amenorrhea (33.3% of fertile women), hypogammaglobulinemia (5.4%), hemorrhagic cystitis (4.5%), and malignancies (3.6%, 75% of whom had been previously treated with azathioprine) [[4492]] Trial name: Perini and Gallo, J. Neurol., July 2003 study [[4491]] Phase: Controlled open-label study [[4491]] Study Design: Controlled, open-label study to examine the safety and efficacy of pulse cyclophosphamide therapy, in which patients received high dose (tailored to the white blood cell response and ranging from 800 to 1200 mg per square meter of body surface) intravenous cyclophosphamide every 4 weeks for 1 year and every 8 weeks for an additional year [[4491]] Disease Stage: Very active SPMS [[4491]] Enrollment/Number of Patients: 24, with 16 receiving treatment [[4491]] Duration: 2 years [[4491]] Status/Outcome: Cyclophosphamide was associated with a decrease in the expanded disability status scale score (from a mean of 5.6+/-1.0 at the time the study began to 4.3+/-1.6 at year 1 and 4.1+/-1.6 at year 2) and a decrease in the mean relapse rate (from 3.0+/-1.4 in the 2 years before therapy to 0.25+/-0.45 during therapy) [[4491]] Trial name: Patti et al., J. Neurol. Neurosurg. Psychiatry, September 2001 study [[4509]] Phase: Observational/open label study [[4509]] 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) for 12 months to obtain chronic lymphocytopenia and then given every 60 days for another 6 months] in combination with interferon beta-1a or interferon beta-1b, in patients who were already receiving interferon beta treatment, but who did not benefit from it [[4509]] Disease Stage: Rapidly transitional MS [[4509]] Enrollment/Number of Patients: 10 [[4509]] Duration: 18 months [[4509]] Status/Outcome: The combination of cyclophosphamide and interferon beta was associated with a reduction in the number of relapses, previously accumulated disability, and T2 lesion burden, such that disease progression appeared to be halted [[4509]] Trial name: Khan et al., Mult. Scler., June 2001 study [[4533]] Phase: Observational/open label study [[4533]] Study Design: Study to determine the effects of monthly intravenous cyclophosphamide, given for 6 months, in patients who had undergone severe deterioration during the previous 12 months despite receiving conventional immunomodulating drugs and intravenous methylprednisolone [[4533]] Disease Stage: RRMS [[4533]] Enrollment/Number of Patients: 14 [[4533]] Duration: 18 months [[4533]] Status/Outcome: Patients treated with cyclophosphamide improved and displayed neurological stability within 6 months, and these changes were sustained for at least 18 months after the initiation of cyclophosphamide treatment [[4533]] Trial name: Hohol et al., Mult. Scler., December 1999 study [[4532]] Phase: Observational/open label study [[4532]] Study Design: Study to determine what factors are associated with a response to cyclophosphamide/methylprednisolone therapy (given at 4 to 8 week intervals) [[4532]] Disease Stage: Progressive MS [[4532]] Enrollment/Number of Patients: 95 [[4532]] Duration: 12 months [[4532]] Status/Outcome: The length of time the patient had been in the progressive phase was found to be the most significant variable that correlated with response to the drug regime, such that patients who had improved at 12 months had progressive disease for an average of 2.1 years before therapy, but those whose disease remained stable or became more severe had progressive disease for 5.0 or 4.1 years, respectively; age, gender, age at onset, and age at treatment did not correlate with response [[4532]] Trial name: Gobbini et al., J. Neuroimmunol., September 1999 study [[933]] Phase: Observational/open-label study [[933]] Study Design: Open-label study to determine the effect of intravenous cyclophosphamide (monthly pulses of 1 g per kg2) on disease activity as monitored by MRI [[933]] Disease Stage: RRMS [[933]] Enrollment/Number of Patients: 5 [[933]] Duration: 28 months [[933]] Status/Outcome: Drug was associated with a reduction in the frequency of contrast-enhancing lesions in all patients and a decrease in the T2 lesion load in 3 patients in the first 5 months of therapy [[933]] Trial name: La Mantia et al., Ital. J. Neurol. Sci., February 1998 study [[4568]] Phase: Observational/open-label study [[4568]] Study Design: Study to compare the safety and efficacy of different cyclophosphamide treatment schedules [(i) induction and then bimonthly boosters for 1 year; (ii) bimonthly boosters for 1 year; or (iii) monthly boosters for 1 year] [[4568]] Disease Stage: Progressive MS [[4568]] Enrollment/Number of Patients: 53 [[4568]] Duration: 1 year [[4568]] Status/Outcome: Treatment schedules (i) and (iii) were associated with a higher percentage of stable patients, as shown by survival analysis; side effects included myelotoxicity in group (i) and broncopneumonia in group (ii); response was limited to SPMS patients [[4568]] Trial name: Weiner et al., Neurology, May 1993 trial [[941]] Phase: Phase II trial [[941]] Study Design: Randomized, single-blinded, non-treatment control trial to test whether booster intravenous cyclophosphamide therapy (700 mg per m2 every other month for 2 years or nothing) after induction therapy (2- to 3- week course of intravenous cyclophosphamide plus adrenocorticotropic hormone) affects reprogression, and to test two different cyclophosphamide induction regimens (a fixed dose of cyclophosphamide versus a dose that was adjusted depending on the white blood cell count, as in previous studies) [[928]] [[941]] Disease Stage: Progressive MS [[941]] Enrollment/Number of Patients: 256 [[941]] Duration: 30 months [[941]] Status/Outcome: Booster therapy was associated with slower disease progression at 24 and 30 months and prolonged the time to treatment failure after 1 year (with better response in patients under 40 years of age); the two induction regimes had equivalent effects on initial stabilization and subsequent progression (with 56% of patients stable at 1 year) [[928]] [[941]] Trial name: Lamers et al., J. Neurol. Neurosurg. Psychiatry, October 1988 study [[945]] Phase: Observational/open-label study [[945]] Study Design: Study to determine the effects of cyclophosphamide (daily dose of 400 mg, for a total dose of 8 g) and prednisone (100 mg) on the levels of myelin basic protein in cerebrospinal fluid [[945]] Disease Stage: Chronic progressive MS [[945]] Enrollment/Number of Patients: 11 [[945]] Duration: 3 to 10 weeks [[945]] Status/Outcome: Drugs were associated with a decrease in the levels of myelin basic protein in cerebrospinal fluid (which are elevated in MS patients as compared with a reference group of patients without MS) [[945]] Trial name: Carter et al., Neurology, July 1988 study [[940]] Phase: Observational/open-label study [[940]] Study Design: Open label, uncontrolled, retrospective study to determine safety, dosage required for efficacy, factors that might predict a response to therapy, and disease course after treatment in patients who had received high-dose intravenous cyclophosphamide and adrenocorticotropic hormone over the previous 6 years [[940]] Disease Stage: Chronic progressive MS [[940]] Enrollment/Number of Patients: 164 [[940]] Duration: 6 years (cumulative experience) [[940]] Status/Outcome: Drug was associated with improved stability among 81% of patients after 1 year, but reprogression later occurred in 69% of patients (with the average time to reprogression 1.5 years); second treatment was given to 58 patients who re-progressed, and 70% of them were improved or stabilized one year after retreatment [[928]] [[940]] Trial name: Gonsette et al., in Progress in Multiple Sclerosis Research, 1980 study [[928]] Phase: Observational/open-label study [[928]] Study Design: Uncontrolled, open label trial to test the effects of immunosuppression induced by intravenous cyclophosphamide [using the same protocol as in [[939]]] [[928]] Disease Stage: RRMS [[928]] Enrollment/Number of Patients: 134 [[928]] Duration: 2 to 10 years [[928]] Status/Outcome: Drug stabilized the annual relapse rate in 76% of patients; in 70% of patients, the annual relapse rate decreased by 75% (as compared to the rate 1 to 2 years before treatment), whereas in 30% of patients, there was no response; effects were most pronounced in patients with the shortest course of disease [[928]] Trial name: Gonsette et al., J. Neurol., February 1977 study [[939]] Phase: Observational/open-label study [[939]] Study Design: Open-label, uncontrolled study to test the safety and efficacy of a single, intensive immunosuppression induced by intravenous cyclophosphamide (1 to 12 g over 2 weeks to reach immunosuppression, maintaining a leukopenia of 2000 and a lymphopenia of 1000 for 2 to 3 weeks) on the annual relapse rate and neurological signs [[928]] [[939]] Disease Stage: RRMS [[928]] [[939]] Enrollment/Number of Patients: 140, with 110 followed for 2 to 6 years [[939]] Duration: 2 to 6 years [[939]] Status/Outcome: Drug decreased the annual relapse rate after 2 years and 4 years (62% of patients were stabilized between the 2 and 4 year marks), but only stabilized 5% of patients after 4 years; drug stabilized and improved neurological signs in 60% of patients [[939]] Trial name: Hommes et al., Clin. Neurol. Neurosurg., 1975 study [[4531]] Phase: Observational/open-label study [[4531]] Study Design: Study to evaluate the efficacy and safety of cyclophosphamide and prednisone treatment (given over 20 days) to induce immunosuppression [[4531]] Disease Stage: Chronic progressive MS [[4531]] Enrollment/Number of Patients: 32 [[4531]] Duration: 33 months [[4531]] Status/Outcome: Most patients improved just after treatment, and in 15 of 25 patients who were scored 6 to 33 months after treatment, the improvement continued [[4531]] Trial name: Girard et al., Presse Med., April 1967 study [[928]] [[938]] Phase: Observational/open-label study [[928]] [[938]] Study Design: Open-label, uncontrolled study to assess safety and efficacy of cyclophosphamide (200 mg per day, given intravenously for 4 to 6 weeks to total 4 to 9 g) [[928]] Disease Stage: Progressive MS [[928]] Enrollment/Number of Patients: 30 [[928]] Duration: 2 years [[928]] Status/Outcome: Drug stabilized or improved symptoms in 50% of the patients [[928]]
Daclizumab	Trial name: Safety and Efficacy Study of Daclizumab HYP to Treat Relapsing-Remitting Multiple Sclerosis (SELECT) (results reported August 2011, publ 3 April 2013) [[803]] [[5545]] Phase: Phase IIb trial [[803]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multinational, multicenter trial to evaluate the efficacy of two doses (150 mg or 300 mg) of daclizumab high-yield process (HYP), given subcutaneously every 4 weeks for 52 weeks, on the annualized relapse rate (primary endpoint) [[803]] [[5545]] Disease Stage: RRMS [[803]] [[5545]] Enrollment/Number of Patients: 621, with over 90% completing the study [[5545]] Duration: 1 year [[803]] [[5545]] Status/Outcome: Compared to placebo, daclizumab HYP was associated with a lower annualized relapse rate (0.21 for the 150 mg dose and 0.23 for the 300 mg dose versus 0.46 for placebo, representing 54% and 50% reductions for the two doses, respectively), and a reduction in cumulative number of gadolinium-enhancing lesions between weeks 8 and 24, a reduction in number of newly enlarging T2 hyperintense lesions at one year, and reduction in proportion of patients who relapsed [[803]] [[5545]]; three cases of autoimmune attacks (hepatic and renal) occurred [[3771]] Trial name: CHOICE trial (Daclizumab in active, relapsing multiple sclerosis) (publ 2010) [[433]] Phase: Phase II trial [[433]] Study Design: Company-sponsored randomized, placebo controlled, multinational, multicenter study to evaluate the efficacy of daclizumab (two doses) combined with interferon beta therapy on number of new or enlarged gadolinium-enhancing lesions (primary endpoint) [[433]] Disease Stage: RRMS patients taking interferon beta [[433]] Enrollment/Number of Patients: 230 patients enrolled; all completed the study [[433]] Duration: 24 weeks [[433]] Status/Outcome: The drug was associated with fewer gadolinium-enhancing lesions at high dose (2mg/kg every 2 weeks) plus interferon beta and at low dose (1mg/kg every 4 weeks) plus interferon beta, compared to placebo and interferon beta [[433]]	Trial name: DECIDE [[804]] Phase: Phase III trial [[804]] Study Design: Company-sponsored, randomized, double-blind, multinational, multicenter trial comparing efficacy of daclizumab to interferon beta-1a [[804]] Disease Stage: RRMS [[804]] Enrollment/Number of Patients: Expected enrollment, 1500 patients [[804]] Duration: 96 to 144 weeks [[804]] Status/Outcome: Enrollment began May 2011; completion is expected in January 2014 [[804]]	Trial name: Borges et al., Mult. Scler. Relat. Disord., April 2013 study [[5594]] Phase: Retrospective medical record review [[5594]] Study Design: Analysis of MRI results (a total of 1332 scans from a single center) to determine whether daclizumab reduces the rate of brain atrophy [[5594]] Disease Stage: RRMS [[5594]] Enrollment/Number of Patients: 70 MS cases; 26 were treated with daclizumab and 44 were not treated with this drug [[5594]] Duration: 4.3 years (median treatment time with daclizumab) [[5594]] Status/Outcome: Daclizumab decreased the rate of brain atrophy relative to other disease-modifying therapies, probably because of a reduction in the atrophy rate of gray matter [[5594]] Trial name: Safety and Efficacy Extension Study of Daclizumab High Yield Process (DAC HYP) to Treat Relapsing Remitting Multiple Sclerosis (SELECTION) (meeting report, 15 October 2012) [[3771]] [[5777]] Phase: Extension of Phase IIb trial (SELECT) [[5545]] [[5777]] Study Design: Company-sponsored, multicenter, open-label extension study to examine the safety and efficacy of continued treatment with daclizumab high-yield process (HYP), given subcutaneously every 4 weeks, such that patients originally given placebo were re-randomized to either the 150 mg or the 300 mg dose and patients originally given daclizumab HYP were re-randomized to either continue the same dose or to undergo a 24-week washout, after which the original dose was continued for 24 weeks; another primary aim was to monitor the long-term immunogenicity of the drug [[3771]] [[5777]] Disease Stage: RRMS [[3771]] Enrollment/Number of Patients: 517, with 92% participating for the full year [[3771]] Duration: 1 year [[3771]] Status/Outcome: In patients who originally received placebo, the mean annualized relapse rate fell from 0.434 to 0.179 (59% reduction) after they switched to drug treatment and in patients who continuously received treatment, the reduced annualized relapse rates were maintained (meeting report, 15 October 2012) [[3771]]; estimated completion date, September 2015 [[5777]] Trial name: Bielekova et al., Arch Neurol., April 2009 study [[444]] Phase: Phase II study [[444]] Study Design: Investigator-led, open-label, single-center study to determine whether daclizumab efficacy (measured as the reduction of contrast-enhancing lesions; primary endpoint) was dependent on combination with interferon beta or dose [[444]] Disease Stage: RRMS and SPMS [[444]] Enrollment/Number of Patients: 12 RRMS and 3 SPMS patients enrolled; 13 completed the study [[444]] Duration: 3 months interferon beta alone, 5.5 months interferon beta plus daclizumab, then 10 months daclizumab alone [[444]] Status/Outcome: Daclizumab monotherapy was associated with a stabilization of MRI disease activity in 9 of 13 patients, with four requiring additional interferon treatment [[444]] Trial name: Rose et al., Neurol., August 2007 study [[451]] Phase: Phase II study [[451]] Study Design: Investigator-led, open-label, single-center study to evaluate the effect of daclizumab on lesion size (primary endpoint) [[451]] Disease Stage: RRMS patients treated with interferon but with continuing relapses [[451]] Enrollment/Number of Patients: 9 patients enrolled in and completed study [[451]] Duration: 27.5 months [[451]] Status/Outcome: Drug was associated with a reduction in contrast enhancing lesions and improved clinical scores that were not controlled by interferon [[451]]
Dalfampridine	Trial name: Horton et al., Neurology, April 2013 study [[5770]] Phase: Phase II trial [[5770]] Study Design: Randomized, placebo-controlled, double-blind, crossover trial to study the effect of 4-aminopyridine on vision in MS patients with demyelinating optic neuropathy; patients received either placebo or drug for 5 weeks and then crossed to the other treatment for 5 weeks [[5770]] Disease Stage: MS patients with optic neuropathy [[5770]] Enrollment/Number of Patients: Not stated in abstract [[5770]] Duration: 10 weeks [[5770]] Status/Outcome: 4-Aminopyridine improved visual acuity in a subset of patients; the highest response rates occurred in eyes with a retinal nerve fiber layer that measured between 60 and 80 microns [[5770]] Trial name: Goodman et al., Ann. Neurol., Oct 2010 trial [[347]] Phase: Phase III trial [[347]] Study Design: Randomized, 39-center, double-blind, placebo-controlled trial to test the effects of oral dalfampridine (10 mg twice daily) on walking ability, as measured by a timed 25-foot walk (primary outcome, percentage of timed walk responders) [[347]] Disease Stage: Any stage of MS [[347]] Enrollment/Number of Patients: 239, with 237 in final analysis [[347]] Duration: 9 weeks [[347]] Status/Outcome: Drug improved walking ability in some MS patients (42.9% timed walk responders with drug versus 9.3% with placebo), such that the effect is continued between doses and the average improvement in speed among responders was 24.7% [[347]] Trial name: Goodman et al., Lancet, Feb 2009 trial [[367]] Phase: Phase III trial [[367]] Study Design: Randomized, multicenter, double-blind, placebo-controlled trial to test the effects of sustained-release oral fampridine (10 mg twice daily) on walking ability, as measured by a timed 25-foot walk (primary outcome, percentage of timed walk responders) [[367]] Disease Stage: Any stage of MS [[367]] Enrollment/Number of Patients: 301, with efficacy analyses based on 296 [[367]] Duration: 14 weeks [[367]] Status/Outcome: Drug improved walking ability (25.2% increase in speed versus 4.7% with placebo) in some MS patients (35% versus 8% for placebo) [[367]] Trial name: Goodman et al., Neurology, Oct 2008 trial [[374]] Phase: Phase II trial [[374]] Study Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to test the effects of fampridine (10, 15, or 20 mg twice daily) on walking speed (primary efficacy variable, percent change in speed in a timed 25-foot walk) [[374]] Disease Stage: People with MS [[374]] Enrollment/Number of Patients: 206 [[374]] Duration: 2 weeks of placebo for all participants, followed by 15 weeks of drug or placebo [[374]] Status/Outcome: Drug was associated with a non-significant trend toward increased walking speed in prospective analysis, but in post hoc analysis, subsets of patients in each dose group consistently showed increased walking speeds during the treatment versus the nontreatment period (36.7% were consistent responders in treatment groups versus 8.5% in placebo group) [[374]]		Trial name: Two-year safety data for AMPYRA® (press release, 10 October 2012) [[3587]] Phase: Post-marketing [[3587]] Study Design: Safety data from MS patients taking AMPYRA [extended release tablets (10 mg)] during the two years it has been available in the US were analyzed, such that all adverse events reported to Acorda and the US Food and Drug Administration from March 2012 through March 2012 were examined [[3587]] Disease Stage: MS [[3587]] Enrollment/Number of Patients: >62,400 [[3587]] Duration: 2 years [[3587]] Status/Outcome: Safety profile is consistent with that observed in clinical trials; specifically, 160 seizures (4.6 per 1000 patient-years of use) were reported, which is comparable to the seizure rate in the general MS population [[3587]] Trial name: Postmarketing commitment study exploring 5 mg dose of extended release dalfampridine (press release, 13 August 2012) [[3018]] Phase: Postmarketing study required by the US Food and Drug Administration [[3019]] Study Design: Company-sponsored, randomized, placebo-controlled trial to compare the effects of 5 mg and 10 mg (the currently marketed dose) of extended release dalfampridine, twice daily, on the change in walking speed on a timed 25-foot walk test (primary outcome measure) [[3018]] Disease Stage: MS [[3018]] Enrollment/Number of Patients: 430 [[3018]] Duration: 4 weeks [[3018]] Status/Outcome: Neither the 10 mg nor the 5 mg dose met the primary endpoint; however, Accorda Therapeutics reported that when different analyses, similar to those used in the pivotal studies that led to the approval of Ampyra, were performed, the 10 mg dose improved walking speed as compared to placebo (0.443 versus 0.303 feet per second) but the 5 mg dose did not (0.366 versus 0.303 feet per second) [[3018]] [[3019]] Trial name: Fampridine - Benefit assesment according to § 35a Social Code Book V (2012) [[3015]] Phase: Retrospective review [[3015]] [[3016]] Study Design: German Institute for Quality and Efficiency in Health Care (IQWiG) assessed the added benefit of fampridine for adult MS patients with a higher grade walking disability (grades 4 to 7 on the Expanded Disability Status Scale) [[3015]] [[3016]] Disease Stage: MS [[3015]] [[3016]] Enrollment/Number of Patients: N/A [[3015]] [[3016]] Duration: N/A [[3015]] [[3016]] Status/Outcome: Because (i) there are no studies that directly compare fampridine with physiotherapy, which was previously specified as the appropriate comparator therapy; (ii) the specific methodological conditions for indirect comparisons were not met; and (iii) the physiotherapy studies included patients with lower grade walking disability, the IQWiG determined that there is no proof of fampridine conferring an added benefit [[3015]] [[3016]]
Dimethyl fumarate	Trial name: COmparator and aN oral Fumarate In RRMS (CONFIRM) (publ September 2012, press releases April 2012 and October 2012, meeting report March 2013) [[1793]] [[3222]] [[3590]] [[5513]] Phase: Phase III trial [[1793]] [[3222]] Study Design: Company-sponsored, global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the safety and efficacy of oral BG-12 (240 mg given either twice a day or three times a day) or glatiramer acetate (20 mg subcutaneous injection each day) in reducing the annualized relapse rate (ARR) (primary endpoint) and the proportion of patients who relapse at two years and the number of T2-hyperintense lesions (secondary endpoints); study was not designed to test whether BG-12 is superior or noninferior to glatiramer acetate [[1793]] [[3222]] Disease Stage: RRMS [[1793]] [[3222]] Enrollment/Number of Patients: 1430 [[1793]] [[3222]] Duration: 2 years [[1793]] [[3222]] Status/Outcome: BG-12 reduced the ARR by 44% (twice a day dose; ARR=0.22) or 51% (three times a day dose; ARR=0.20) and glatiramer acetate reduced this rate by 29% (ARR=0.29) as compared to placebo (ARR=0.40); BG-12 reduced the proportion of patients who relapsed at two years by 34% (twice a day dose) or 45% (three times a day dose) and glatiramer acetate reduced this rate by 29% as compared to placebo; BG-12 also had a significant effect on brain lesions [[1793]] [[3222]]; pooled analysis from >2,300 patients in the CONFIRM and DEFINE studies indicated that both doses decreased the ARR by 49%; the drug decreased the proportion of patients who relapsed by 43% (twice a day dose) and 47% (three times a day dose) and reduced the risk of 12-week confirmed disability progression by 32% (twice a day dose) and 30% (three times a day dose) (press release, 12 October 2012) [[3590]]; secondary analysis showed that the twice a day dose led to a reduction in relapse rate within 10 weeks [[5513]] Trial name: Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS (DEFINE) (publ September 2012, press releases October 2011 and October 2012, meeting report March 2013) [[583]] [[3221]] [[3590]] [[5513]] Phase: Phase III trial [[583]] [[3221]] Study Design: Global, randomized, double-blind, placebo-controlled, dose-comparison trial to determine the safety and efficacy of BG-12 (240 mg, 2 or 3 times per day) at reducing the proportion of relapsing patients at two years (primary endpoint) and at reducing the annualized relapse rate (ARR), the risk of disability progression, and the number of lesions as measured by brain MRI (secondary endpoints) [[583]] [[3221]] Disease Stage: RRMS [[583]] [[3221]] Enrollment/Number of Patients: 1237, with 952 completing the study [[583]] [[3221]] Duration: 2 years [[583]] [[3221]] Status/Outcome: Drug reduced the risk of relapse by 49% (2 times per day dose; 27% of these patients, versus 46% in the placebo group, had at least one relapse by 2 years) or 50% (3 times per day; 26% had at least one relapse by 2 years), the ARR by 53% (2 times a day; ARR=0.17 versus 0.36 for the placebo group) or 48% (3 times per day; ARR=0.19), and the risk of disability progression by 38% (2 times per day) or 34% (3 times per day), as well as reducing the mean number of several types of brain lesions [[583]] [[3221]]; pooled analysis from >2,300 patients in the CONFIRM and DEFINE studies indicated that both doses decreased the ARR by 49%; the drug decreased the proportion of patients who relapsed by 43% (twice a day dose) and 47% (three times a day dose) and reduced the risk of 12-week confirmed disability progression by 32% (twice a day dose) and 30% (three times a day dose) (press release, 12 October 2012) [[3590]]; secondary analysis showed that the twice a day dose led to a reduction in relapse rate within 10 weeks [[5513]] Trial name: Kappos et al., Lancet, Oct 2008 trial [[370]] Phase: Phase IIb trial [[370]] Study Design: Multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of BG00012 (120 mg, 1 time per day; 120 mg, 3 times per day; or 240 mg, 3 times per day) at reducing the number of new gadolinium enhancing lesions (primary endpoint) and at reducing other types of brain lesions and the annualized relapse rate (secondary endpoints) [[370]] Disease Stage: RRMS [[370]] Enrollment/Number of Patients: 257 [[370]] Duration: 24 weeks, with a 24 week extension period [[370]] Status/Outcome: 240 mg drug (3 times a day) reduced the mean total number of new gadolinium enhancing lesions by 69% from week 12 to 24 as compared to placebo and reduced the annualized relapse rate by 32% [[370]]; additional analysis showed that the 240 mg, 3 times a day dose reduced the number of new gadolinium-enhanced lesions in a range of patient subgroups (which were based on demographics and baseline disease characteristics), and the reduction varied depending on the subgroup [[2193]] Trial name: Schimrigk et al., Eur. J. Neurol., Jun 2006 trial [[385]] Phase: Pilot study [[385]] Study Design: Exploratory, prospective, baseline-controlled, open-label study to examine the effects of Fumaderm (which contains dimethyl fumarate and and salts of monoethylfumarate) [6 weeks baseline, 18 weeks treatment (target dose of 720 mg per day), 4 weeks washout, 48 weeks treatment (target dose of 360 mg per day)] on number and volume of gadolinium enhancing lesions (primary outcome) [[385]] Disease Stage: RRMS [[385]] Enrollment/Number of Patients: 10, with 3 withdrawing [[385]] Duration: 76 weeks [[385]] Status/Outcome: Drug was associated with reductions from baseline in the number and volume of gadolinium enhancing lesions [[385]]		Trial name: ENDORSE (press release, 12 October 2012) [[3590]] Phase: Phase III extension study [[3590]] Study Design: Industry-sponsored, dose-blind, multicenter extension study to evaluate the long-term safety and efficacy of dimethyl fumarate (240 mg, two times a day or three times a day); patients from the 2-year DEFINE or CONFIRM trials who had received dimethyl fumarate continued on the same dose, whereas those who had received placebo or glatiramer acetate (CONFIRM trial) were randomized to the twice a day or three times a day dimethyl fumarate doses [[3590]] Disease Stage: RRMS [[3590]] Enrollment/Number of Patients: 1736 [[3590]] Duration: >1 year [[3590]] Status/Outcome: Overall safety profile was similar to those from the DEFINE and CONFIRM trials as of October 2012 [[3590]]
Estriol	Trial name: Estriol Treatment in Multiple Sclerosis: Effect on Cognition [[865]] [[867]] Phase: Phase II [[867]] Study Design: Company-sponsored, randomized, double-blind placebo-controlled, single-site, parallel-assignment study examining efficacy of estriol on cognitive function as assessed by Paced Serial Addition Test (primary endpoint) [[867]] Disease Stage: RRMS and SPMS [[867]] Enrollment/Number of Patients: Expected enrollment 64 female patients [[867]] Duration: 1 year [[867]] Status/Outcome: Expected completion date April 2013 [[867]] Trial name: A combination trial of Copaxone plus Estriol in Relapsing Remitting Multiple Sclerosis [[864]] [[868]] Phase: Phase II [[868]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multi-center, US-based trial comparing relapse rate (primary endpoint) of estriol and Copaxone (glatiramer acetate) to Copaxone alone [[868]] Disease Stage: RRMS [[868]] Enrollment/Number of Patients: Enrolled 150 patients [[864]] [[868]] Duration: 2 years [[868]] Status/Outcome: Expected completion date September 2013 [[868]]		Trial name: Sicotte et al., Ann Neurol, October 2002 trial [[461]] Phase: Pilot study [[461]] Study Design: Investigator-run crossover study evaluating efficacy of pregnancy-level doses of estriol in controlling MS lesions [[461]] Disease Stage: RRMS and SPMS [[461]] Enrollment/Number of Patients: 12 female patients – 6 with RRMS and 6 with PPMS enrolled; 10 completed study [[461]] Duration: 22 months [[461]] Status/Outcome: No effect in SPMS patients [[461]] ; Lesion number and volume decreased significantly in RRMS group, and returned to pre-treatment levels after treatment ended [[461]]; Significantly increased cognitive function in the RRMS group [[461]] ; Further analysis showed increased levels of interleukin 5 and interleukin 10 and decreased levels of tumor necrosis factor alpha in stimulated peripheral blood mononuclear cells isolated during treatment [[460]] Trial name: PRIMS (Pregnancy in Multiple Sclerosis Study) [[464]] Phase: Not applicable [[464]] Study Design: Multicenter, prospective, observational European study to determine the effects of pregnancy, postpartum state, breast-feeding, and epidural analgesia on rate of relapse [[464]] Disease Stage: Any [[464]] Enrollment/Number of Patients: 254 pregnant women diagnosed with MS before pregnancy [[464]] Status/Outcome: Rate of relapse declined by nearly 80% during pregnancy and increased during three months post-partum, returning to pre-pregnancy levels [[464]]
Fingolimod	Trial name: Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting Multiple Sclerosis (FREEDOMS II) (press release, 12 October 2012; conference report, March 2013) [[3592]] [[3591]] [[5361]] Phase: Phase III trial [[3592]] [[3591]] Study Design: Industry-sponsored, double-blind, randomized, multicenter, placebo-controlled, parallel-group study to compare the efficacy and safety of fingolimod at two doses (0.5 mg or 1.25 mg oral dose, once per day), with the primary outcome measure the aggregate annualized relapse rate (ARR) up to month 24 [[3592]] [[3591]] Disease Stage: RRMS [[3592]] [[3591]] Enrollment/Number of Patients: 1083 [[3592]] Duration: 24 months [[3591]] Status/Outcome: Drug was associated with an aggregate ARR estimate up to month 24 of 0.203 (1.25 mg dose) or 0.208 (0.5 mg dose) versus 0.403 for placebo [[3591]]; post hoc analysis indicated that the 0.5 dose resulted in significant relapse-related benefits within the first three months and brain volume-related benefits by six months [mean percent volume change of -0.23 (fingolimod) versus -0.38 (placebo) at six months] [[3592]]; over 2 years, fingolimod decreased the rate of brain volume loss by 33% as compared to placebo [[5361]]; fingolimod-associated reductions in ARR occurred across baseline disease activity, previous treatment, age, and gender [[5361]] Trial name: FTY720 in Patients With Primary Progressive Multiple Sclerosis (INFORMS) (active as of Aug 2011) [[471]] Phase: Phase III trial [[471]] Study Design: Double-blind, randomized, multicenter, placebo-controlled, parallel-group trial to evaluate the effect of FTY720 (0.5 mg daily) on delaying time to sustained disability progression (primary endpoint) [[471]] Disease Stage: PPMS [[471]] Enrollment/Number of Patients: 951 (estimated) [[471]] Duration: 36 months [[471]] Status/Outcome: Final data collection date (primary outcome measure) is Aug 2014 [[471]] Trial name: FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) (publ 2010; additional analyses publ 2012; conference report, March 2013) [[303]] [[2331]] [[3592]] [[5361]] Phase: Phase III trial [[303]] Study Design: Industry-supported, double-blind, placebo-controlled, multicenter, multinational trial to test the effects of daily oral fingolimod (0.5 mg or 1.25 mg dose) on the annualized relapse rate (primary endpoint) and the time to disability progression and the number of gadolinium-enhancing lesions (secondary endpoints) [[303]]; MRI scans were obtained at 0, 6, 12, and 24 months [[2331]] Disease Stage: RRMS [[303]] Enrollment/Number of Patients: 1272 (with 1033 completing study) [[303]] Duration: 24 months [[303]] Status/Outcome: Drug caused a relative reduction in the annualized relapse rate of 54% (daily oral 0.5 mg dose) or 60% (1.25 mg dose), an increase in the time to disability, and a reduction in the number of gadolinium-enhancing lesions; drug was also associated with less reduction in brain volume [[303]]; both doses reduced inflammatory lesions (gadolinium-enhancing and new/newly enlarged T2 lesions) in a rapid and sustained manner and slowed the rate of brain volume loss [[2331]]; post hoc analysis indicated that the 0.5 dose resulted in significant relapse-related benefits within the first three months and brain volume-related benefits by six months [mean percent volume change of -0.22 (fingolimod) versus -0.34 (placebo) at six months] [[3592]]; over 2 years, fingolimod decreased the rate of brain volume loss by 35% as compared to placebo [[5361]] Trial name: Efficacy and Safety of FTY720 in Patients With Relapsing Multiple Sclerosis (publ 2006) [[478]] Phase: Phase II trial [[304]] Study Design: Double-blind placebo-controlled, proof-of-concept trial to test the effects of daily oral fingolimod (0.5 mg or 1.25 mg dose) on the number of gadolinium-enhanced lesions [[304]] Disease Stage: RRMS [[304]] Enrollment/Number of Patients: 281 (with 255 completing core study and 227 completing extension study) [[304]] Duration: 6-month core study and 6-month extension study [[304]] Status/Outcome: Drug caused a reduction in the number of gadolinium-enhanced lesions [[304]] Trial name: Kahan <em>et al., N. Engl. J. Med.</em>, Oct 2003 trial [[304]] Phase: Phase I trial [[304]] Study Design: Randomized, multicenter, double-blind, placebo-controlled trial to examine safety, pharmacodynamics, and pharmacokinetics of daily oral dose (0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg) [[330]] Disease Stage: Not MS; stable renal transplant patients [[330]] Enrollment/Number of Patients: 65 [[330]] Duration: 28 days [[330]] Status/Outcome: Drug doses greater or equal to 1.0 mg caused a reversible reduction in the number of peripheral blood lymphocytes, with no major increase in adverse events [[330]]	Trial name: Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) (publ 2010, conference report March 2013, additional analyses publ April 2013) [[302]] [[5361]] [[5862]] Phase: Phase III trial [[302]] Study Design: Multicenter, randomized, double-blind, double-dummy, parallel group trial to compare the efficacy of a daily oral dose of fingolimod (1.25 mg or 0.5 mg) versus a weekly intramuscular dose of interferon beta-1a (30 micrograms) [[302]] Disease Stage: RRMS [[302]] Enrollment/Number of Patients: 1292 (with 1153 completing study) [[302]] Duration: 12 months [[302]] Status/Outcome: Fingolimod was associated with a lower annualized relapse rate (ARR) than interferon beta-1a [0.20 (1.25 mg dose) or 0.16 (0.5 mg dose) for fingolimod versus 0.33 for interferon beta-1a] and with significantly fewer lesions in MRI scans at 12 months than interferon beta-1a, whereas no differences in time to confirmed progression of disability were seen [[302]]; over 1 year, fingolimod decreased the rate of brain volume loss by -32% as compared to interferon beta-1a [[5361]]; when specific subgroups (defined on the basis of demographics, baseline disease characteristics, and previous responses to therapy) were analyzed, fingolimod reduced the ARR over 1 year by 32 to 59% relative to interferon beta-1a in all subgroups based on demographics or baseline disease characteristics; in patients with high levels of disease activity during interferon beta treatment in the previous year (before the study), fingolimod reduced the ARR by 61% as compared to interferon beta-1a [[5862]]	Trial name: FREEDOMS II extension study (conference report, March 2013) [[5361]] Phase: Extension of Phase III trial [[3591]] [[5361]] Study Design: Company-sponsored extension study to examine efficacy and safety of fingolimod [[5361]] Disease Stage: Relapsing MS [[5361]] Enrollment/Number of Patients: 632 [[5361]] Duration: Up to 4 years [[5361]] Status/Outcome: 83% of patients completed the extension study, which did not reveal unexpected safety concerns [[5361]] Trial name: Brandes et al., J. Med. Econ., February 2013 study [[4902]] Phase: Observational study [[4902]] Study Design: Analysis to assess the effect of real-world adherence (estimated from a study of a single claims database of a national pharmacy benefit manager) on the cost-effectiveness (the cost per avoided relapse) of fingolimod, subcutaneous interferon beta-1b (Extavia or Betaseron) and interferon beta-1a, glatiramer acetate, and intramuscular interferon beta-1a [[4902]] Disease Stage: MS [[4902]] Enrollment/Number of Patients: N/A [[4902]] Duration: N/A [[4902]] Status/Outcome: Costs per relapse avoided were estimated at $90,566 (fingolimod), $127,024 (Extavia), $137,492 (Betaseron), $144,016 (subcutaneous inferferon beta-1a), $160,314 (glatiramer acetate), and $312,629 (intramuscular interferon beta-1a) [[4902]] Trial name: Sempere et al., Acta Neurol. Scand., January 2013 trial [[4662]] Phase: Observational/open-label study [[4662]] Study Design: Observational study to examine the effects of switching from natalizumab (after treatment of more than 1 year) to fingolimod in JC virus-positive patients; after natalizumab withdrawal, patients received methylprednisolone for 3 months followed by oral fingolimod (0.5 mg) daily [[4662]] Disease Stage: RRMS [[4662]] Enrollment/Number of Patients: 8 JC virus-positive patients who switched drugs and 9 JC virus-negative patients who did not switch [[4662]] Duration: Patients received fingolimod for 4 to 12 months (mean, 9 months); patients who continued receiving natalizumab had a mean followup time of 13 months [[4662]] Status/Outcome: Disease reactivation occurred in patients who switched drugs, with 63% having clinical relapses and 75% showing MRI activity, whereas neither activity was observed in patients who remained on natalizumab [[4662]] Trial name: Havla et al., J. Neurol., December 2012 study [[4336]] Phase: Observational study [[4336]] Study Design: Study to examine the effect of switching to fingolimod, within 24 weeks, on patients who had discontinued natalizumab (which often leads to recurrence of MS symptoms) [[4336]] Disease Stage: RRMS [[4336]] Enrollment/Number of Patients: 36; 26 switched to fingolimod and 10 did not receive any disease-modifying therapy [[4336]] Duration: 55.1 weeks mean follow-up post natalizumab discontinuation [[4336]] Status/Outcome: Initiation of fingolimod after discontinuation of natalizumab was associated with a reduction in disease activity recurrence, such that 42% (11 patients) in the fingolimod group had one or more relapses during followup, as compared to 70% (7 patients) in the therapy-free group; starting fingolimod earlier tended to reduce the annual relapse rate [[4336]] Trial name: Rinaldi et al., Mult. Scler., November 2012 study [[3731]] Phase: Observational study [[3731]] Study Design: Study to determine the efficacy of switching patients (with JC virus antibodies) from natalizumab to fingolimod after a 3-month washout period [[3731]] Disease Stage: RRMS [[3731]] Enrollment/Number of Patients: 22 [[3731]] Duration: 9 months (mean follow-up period) [[3731]] Status/Outcome: 50% of patients experienced disease reactivation (6 patients experienced clinical relapses and 5 displayed MRI activity); thus, fingolimod does not appear to act quickly enough to prevent MS reactivation after termination of natalizumab treatment [[3731]] Trial name: TRANSFORMS extension study (press release, June 2012) [[2105]] Phase: Phase III trial [[2105]] Study Design: Company-sponsored, open-label extension trial to study the efficacy and safety of fingolimod versus interferon beta-1a; patients who received fingolimod (0.5 mg, once daily oral dose) during the original study continued receiving this drug and patients who had originally received interferon beta-1a switched to fingolimod [[2105]] Disease Stage: RRMS [[2105]] Enrollment/Number of Patients: 356 patients received continuous treatment with fingolimod in the original trial and extension; 167 patients switched to fingolimod during the extension [[2105]] Duration: Up to 3.5 years extending beyond the original 12 month study [[2105]] Status/Outcome: Among patients who received fingolimod during the original trial and the extension, the annualized relapse rate remained steady (0.16); among patients who switched to fingolimod during the extension, the annualized relapse rate decreased from 0.33 (core study, treated with interferon beta-1a) to 0.20 (extension); fingolimod was generally well tolerated [[2105]] Trial name: Roskell et al., Curr. Med. Res. Opin., May 2012 study [[3359]] Phase: Retrospective trial review [[3359]] Study Design: Meta-analysis of placebo-controlled and head-to-head trials, which evaluated the effects of one or more drugs (fingolimod, interferon beta-1a, interferon beta-1b, and/or glatiramer acetate), to compare the effects of fingolimod versus the other treatments on the annualized relapse rate (ARR) [[3359]] Disease Stage: RRMS [[3359]] Enrollment/Number of Patients: N/A [[3359]] Duration: N/A [[3359]] Status/Outcome: Meta-analyses indicated that fingolimod significantly reduced the ARR as compared to the other drugs; the relative ARRs for each drug versus fingolimod were 1.43 (glatiramer acetate, 20 mg dose), 1.51 (interferon beta-1b, 250 microg dose), 1.55 (interferon beta-1a, 44 microg dose), 1.67 (interferon beta-1a, 22 microg dose), 1.93 (interferon beta-1a, 30 microg dose), and 2.32 (placebo) [[3359]] Trial name: FREEDOMS extension study (press release, April 2012) [[1794]] Phase: Phase III trial [[1794]] Study Design: Company-sponsored, open-label trial to study the safety and efficacy of fingolimod [[1794]] Disease Stage: RRMS [[1794]] Enrollment/Number of Patients: 1033 completed the original FREEDOMS study; 90% completed 3 years of additional observation and 45% completed 4 years [[1794]] Duration: 4 years [[1794]] Status/Outcome: Drug was associated with a 55% decrease in the annualized relapse rate in patients who switched from placebo (taken during the original FREEDOMS trial) to drug (during the extension); patients who received continuous drug treatment (during the original trial and the extension) were more likely to remain relapse free than those who received placebo during the original trial (59% versus 37%) [[1794]] Trial name: Del Santo et al., Eur. J. Clin. Pharmacol., April 2012 study [[2482]] Phase: Retrospective trial review [[2482]] Study Design: Review of 10 randomized trials that tested interferon, glatiramer acetate, natalizumab, or fingolimod in RRMS, such that the relapse-free rates at 12 months were compared, either directly or through network meta-analysis [[2482]] Disease Stage: RRMS [[2482]] Enrollment/Number of Patients: N/A [[2482]] Duration: N/A [[2482]] Status/Outcome: Fingolimod was determined to have the most favorable profile with respect to relapse-free rate at the follow-up assessment at 1 year [[2482]]
Firategrast	Trial name: Miller et al., Lancet Neurol 2012 trial [[1338]] Phase: Phase II [[1338]] Study Design: Company-sponsored, multicenter, multinational, randomized, double-blind, placebo-controlled dose-ranging study examining efficacy at four doses (150mg, 600mg, 900mg, 1200mg) as measured by cumulative number of new gadolinium-enhancing lesions (primary endpoint) [[1338]] Disease Stage: RRMS [[1338]] Enrollment/Number of Patients: 343 patients with RRMS who had not previously received immunosuppressant or immunomodulatory therapies enrolled; 286 completed trial [[1338]] Duration: 24 weeks treatment and 12 weeks core follow-up, plus 12 months extended follow-up [[1338]] Status/Outcome: Reduction in lesion number (49%; 2.69, compared to 5.31 with placebo) in patients given 900mg and 1200mg drug; no effect at lower doses [[1338]]
Flupirtine	Trial name: Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS) [[1500]] Phase: Phase II [[1500]] Study Design: Investigator-run, multicenter, double-blind, randomized, placebo controlled pilot study assessing effect of flupirtine, added to interferon beta therapy, on neurodegeneration (primary endpoint: cumulative number of new T2 hypertensive lesions with MRI) [[1500]] Disease Stage: RRMS [[1500]] Enrollment/Number of Patients: Estimated enrollment 80 patients [[1500]] Duration: 12 months [[1500]] Status/Outcome: Results expected in early 2013 (Jan Dorr, personal communication, February 13, 2012)		Trial name: Effect of the Kv7-channel Opener Flupirtine on the Excitability of Human Peripheral Myelinated Axons in Vivo [[1501]] Phase: Phase I [[1501]] Study Design: Investigator-run, randomized, double-blind trial investigating effect on excitability of peripheral myelinated axons in vivo and in vitro [[1501]] Disease Stage: Healthy volunteers [[1501]] Enrollment/Number of Patients: 20 healthy volunteers [[1501]] Duration: Two hours [[1501]] Status/Outcome: Study completed, results not yet released [[1501]]
Glatiramer acetate	Trial name: Glatiramer Acetate Low-Frequency Administration (GALA) (press releases, June 2012 and October 2012) [[2158]] [[3588]] Phase: Phase III trial [[2158]] Study Design: Company-sponsored, multinational, randomized, double-blind, placebo-controlled trial to study the safety and effect of glatiramer acetate injection (40 mg/1 ml, administered 3 times weekly) on reducing the number of confirmed relapses (primary endpoint) [the dose in this study is higher but less frequent than the marketed dose (20 mg/1 ml daily) at the time of this press release] [[2158]] Disease Stage: RRMS [[2158]] Enrollment/Number of Patients: >1400 [[2158]] Duration: 12 months [[2158]] Status/Outcome: Drug at the 40 mg/1 ml dose reduced the annualized relapse rate by 34.4% as compared with placebo [[2158]]; additionally, the drug at this dose reduced the cumulative number of new and enlarging T2 lesions by 34.4% and the cumulative number of gadolinium-enhancing lesions by 44.8% as compared with placebo, but the drug did not affect the percent change of brain volume at 12 months [[3588]] Trial name: Comparator and aN oral Fumarate In RRMS (CONFIRM) (publ September 2012, press release April 2012) [[1793]] [[3222]] Phase: Phase III trial [[1793]] [[3222]] Study Design: Company-sponsored, global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the safety and efficacy of oral BG-12 (dimethyl fumarate) (240 mg given either twice a day or three times a day) or glatiramer acetate (20 mg subcutaneous injection each day) in reducing the annualized relapse rate (ARR) (primary endpoint) and the proportion of patients who relapse at two years and the number of T2-hyperintense lesions (secondary endpoints); study was not designed to test whether BG-12 is superior or noninferior to glatiramer acetate [[1793]] [[3222]] Disease Stage: RRMS [[1793]] [[3222]] Enrollment/Number of Patients: 1430 [[1793]] [[3222]] Duration: 2 years [[1793]] [[3222]] Status/Outcome: BG-12 reduced the ARR by 44% (twice a day dose; ARR=0.22) or 51% (three times a day dose; ARR=0.20) and glatiramer acetate reduced this rate by 29% (ARR=0.29) as compared to placebo (ARR=0.40); BG-12 reduced the proportion of patients who relapsed at two years by 34% (twice a day dose) or 45% (three times a day dose) and glatiramer acetate reduced this rate by 29% as compared to placebo; BG-12 also had a significant effect on brain lesions [[1793]] [[3222]] Trial name: Early GA Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis in Subjects Presenting With a Clinically Isolated Syndrome (CIS) (PreCISe) (publ 2009; further analyses publ 2013) [[343]] [[360]] [[5629]] Phase: Phase III trial [[491]] Study Design: Randomized, double-blind, multicenter trial to study the effect of early glatiramer acetate (20 mg per day) on the time to clinically definite MS from clinically isolated syndrome (primary outcome measure) [[360]] Disease Stage: CIS [[360]] Enrollment/Number of Patients: 481 [[360]] Duration: Up to 36 months [[360]] Status/Outcome: Drug reduced the risk of CIS converting to clinically definite MS by 45% as compared to placebo [[360]]; in a substudy (involving 34 patients, 20 of whom did not relapse and were in the study through 12 months of followup), the drug (versus placebo) appeared to exert a neuroprotective effect in a large central brain volume, based on measurements of the ratio of a marker of neuronal integrity (N-acetylaspartate) relative to creatine [[5629]] Trial name: Metz et al., Mult. Scler., Oct 2009 trial [[361]] Phase: Phase II trial [[361]] Study Design: Double-blind, placebo-controlled study to compare the effects of glatiramer acetate plus minocycline (100 mg twice daily) vs. glatiramer acetate plus placebo on the total number of T1 gadolinium-enhanced lesions [[361]] Disease Stage: RRMS (28) Enrollment/Number of Patients: 44, with 40 completing study [[361]] Duration: 9 months [[361]] Status/Outcome: Glatiramer acetate plus minocycline reduced the number of T1 gadolinium-enhanced lesions by 63% as compared to glatiramer acetate alone [[361]] Trial name: PROMiSe Trial [[381]] Phase: Phase III trial [[955]] Study Design: Multinational, multicenter, double-blind, placebo-controlled trial to test whether glatiramer acetate (20 mg per day) results in a delay in time to sustained progression of accumulated disability in PPMS (primary outcome) [[381]] Disease Stage: PPMS [[381]] Enrollment/Number of Patients: 943 [[381]] Duration: 3 years [[381]] Status/Outcome: Study was stopped prematurely when an interim analysis (at which time 757 patients had completed 2 or more years of the study or had ended participation prematurely) showed that there was no discernible effect of glatiramer acetate on the primary outcome [[381]] Trial name: Comi et al., Ann. Neurol., Mar 2001 trial [[400]] Phase: Phase of trial not stated in article [[400]] Study Design: Multicenter, double-blind, randomized, placebo-controlled European/Canadian trial to study the effects of glatiramer acetate (20 mg per day) on disease activity (primary outcome, the number of enhancing lesions on T1-weighted images), as measured with monthly MRI scans and clinical assessments [[400]] Disease Stage: RRMS [[400]] Enrollment/Number of Patients: 239 [[400]] Duration: 9 months [[400]] Status/Outcome: Drug was associated with a reduction in the total number of enhancing lesions (-10.8) as compared to placebo (primary outcome), as well as a reduction in the relapse rate (33%) in the treatment vs. placebo group [[400]] Trial name: Johnson et al., Neurology, July 1995 trial [[412]] Phase: Phase III trial [[412]] Study Design: Multicenter, double-blind, randomized, placebo-controlled trial to determine whether glatiramer acetate (20 mg per day) caused a difference in the relapse rate (primary end point) [[412]] Disease Stage: RRMS [[412]] Enrollment/Number of Patients: 251 [[412]] Duration: 2 years [[412]] Status/Outcome: Drug was associated with a reduction in the relapse rate (primary outcome measure) (1.19 vs. 1.68 over 2 years in the treatment vs. placebo group) [[412]] Trial name: Bornstein et al., N. Engl. J. Med., Aug 1987 trial [[414]] Phase: Pilot trial; phase II trial [[414]] Study Design: Single-center, double-blind, randomized, placebo-controlled trial to test the effects of glatiramer acetate (20 mg per day) on the number of exacerbations [[414]] Disease Stage: Exacerbating-remitting MS [[414]] Enrollment/Number of Patients: 50 [[414]] Duration: 2 years (2) Status/Outcome: Drug was associated with a reduction in the number of exacerbations (0.6 vs 2.7 average per patient in treatment vs. placebo group over 2 years) [[414]]	Trial name: Calabrese et al., Mult. Scler., April 2012 trial [[3009]] Phase: Postmarketing [[3009]] Study Design: Randomized study to compare the effects of subcutaneous (sc) interferon beta-1a (44 mcg three times weekly), intramuscular (im) interferon beta-1a (30 mcg weekly), and glatiramer acetate (20 mg daily) on the development of cortical lesions and cortical atrophy [[3009]] Disease Stage: RRMS [[3009]] Enrollment/Number of Patients: 165 treated patients and 50 untreated patients, with 141 treated patients completing the study [[3009]] Duration: 24 months [[3009]] Status/Outcome: Interferon beta-1a and glatiramer acetate significantly decreased the development of new cortical lesions and the progression of cortical atrophy, with the most pronounced effects seen with sc interferon beta-1a, such that at 12 months, one or more new cortical lesions were seen in 26% of patients receiving sc interferon beta-1a, 64% of patients receiving im interferon beta-1a, 50% of patients receiving glatiramer acetate, and 74% of untreated patient [[3009]] Trial name: Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (results described at meeting, July 2012, publ February 2013) [[2567]] [[2566]] [[5011]] Phase: Phase III trial [[2567]] [[2566]] Study Design: NIH-funded, randomized, double-blind, controlled study to examine whether a combination of interferon beta-1a (30 microg, intramuscularly, per week) and glatiramer acetate (20 mg per day) is more effective than either treatment alone plus placebo, with a reduction in the annualized relapse rate (ARR) the primary endpoint; time to confirmed disability, the Multiple Sclerosis Functional Composite (MSFC) score, and MRI measures were among the secondary endpoints [[2567]] [[2566]] [[5011]] [[5364]] Disease Stage: RRMS [[2567]] [[2566]] [[5011]] Enrollment/Number of Patients: 1008 [[2567]] [[2566]] [[5011]] Duration: 3 years [[2567]] [[2566]] [[5011]] Status/Outcome: Combination therapy did not reduce the risk of relapse as compared to glatiramer acetate alone, but both of those treatments were superior to interferon beta-1a in this regard; combination therapy did not reduce confirmed progression of the Extended Disability Status Scale or MSFC score as compared to either therapy alone, but combination therapy was better than either therapy alone in reducing the accumulation of lesions and new lesion activity [[5011]]; the combination therapy resulted in a half-point benefit on the 22-point scale measuring bladder control [[2567]] [[2566]] Trial name: Rinaldi et al., Mult. Scler., May 2012 trial [[1697]] Phase: Postmarketing [[1697]] Study Design: Prospective study to determine the efficacy of natalizumab versus interferon beta-1a or glatiramer acetate in reducing the accumulation of new cortical lesions [[1697]] Disease Stage: RRMS [[1697]] Enrollment/Number of Patients: 120 [[1697]] Duration: 2 years [[1697]] Status/Outcome: Natalizumab reduced the accumulation of new cortical lesions and the progression of cortical atrophy as compared to interferon beta-1a, glatiramer acetate, or no treatment [[1697]] Trial name: BECOME (BEtaseron vs COpaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints) (publ 2009) [[365]] Phase: Phase IV [[956]] Study Design: Trial to compare the ability of interferon beta-1b and glatiramer acetate to suppress signs of disease activity (primary outcome, number of combined active lesions per patient per scan in first year) as measured by monthly brain MRI [[365]] Disease Stage: CIS or RRMS [[365]] Enrollment/Number of Patients: 75 [[365]] Duration: Up to 2 years [[365]] Status/Outcome: Patients taking either interferon beta-1b and glatiramer acetate showed similar numbers of combined active lesions per patient for first year (primary outcome) and similar numbers of relapses for 2 years [[365]] Trial name: BEYOND (Betaferon Efficiency Yielding Outcomes of a New Dose) (publ 2009) [[362]] Phase: Phase III trial [[957]] Study Design: Multicenter, randomised, prospective study to compare the efficacy, safety, and tolerability of interferon beta-1b (250 or 500 microg every other day) and glatiramer acetate (20 mg per day) (primary outcome, relapse risk) [[362]] Disease Stage: RRMS [[362]] Enrollment/Number of Patients: 2447 [[362]] Duration: 2.0 to 3.5 years [[362]] Status/Outcome: Relapse risk, expanded disability status scale progression, and T1-hypointense lesion volume were similar among all treatment groups [[362]] Trial name: REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) (publ 2008) [[371]] Phase: Phase IV trial [[958]] Study Design: Multicenter, randomised, comparative, parallel-group, open-label study to compare effect of interferon beta-1a (44 microg 3 times a week) and glatiramer acetate (20 mg per day) on time to first relapse (primary outcome) or brain lesions (secondary outcomes) [[371]] Disease Stage: RRMS [[371]] Enrollment/Number of Patients: 764 [[371]] Duration: 96 weeks [[371]] Status/Outcome: Study showed no significant difference between interferon beta-1a and glatiramer acetate on the primary outcome or secondary outcomes, except that interferon beta-1a was associated with fewer gadolinium-enhanding lesions per patient per scan [[371]]	Trial name: Jokubaitis et al., PLoS One, March 2013 study [[5370]] Phase: Prospective cohort study [[5370]] Study Design: Multicenter Australian cohort study using the MSBase platform to characterize use of disease-modifying therapies (DMTs, which included interferon beta, glatiramer acetate, and natalizumab); specifically, treatment persistence, factors that predict treatment discontinuation, and rates of switching between DMTs were studied [[5370]] Disease Stage: RRMS [[5370]] Enrollment/Number of Patients: 1113 [[5370]] Duration: 4.2 years (median time patients were followed) [[5370]] Status/Outcome: Treatment persistence in this study was short, such that patients remained on their first DMT for 2.5 years (median) and on their next DMT for 2.3 years; annualized switch or cessation rates were 9.5 to 12.5% (interferon beta), 11.6% (glatiramer acetate), and 4.4% (natalizumab); younger age and higher disability scores predicted DMT discontinuation [[5370]] Trial name: CombiRx extension study (conference report, March 2013) [[5364]] Phase: Extension phase of Phase III trial [[5011]] [[5364]] Study Design: Extension of the CombiRx trial, comparing effectiveness of combination therapy (interferon beta-1a and glatiramer acetate) with either therapy alone in reducing the annualized relapse rate (primary endpoint) [[5364]] Disease Stage: RRMS (in original study) [[5011]] [[5364]] Enrollment/Number of Patients: 687 [[5364]] Duration: 90 months [[5364]] Status/Outcome: Combination therapy did not reduce the risk of relapsing or confirmed disability progression as compared to glatiramer acetate, and glatiramer acetate reduced the risk of relapse more than interferon beta-1a, over 90 months; combination therapy was associated with a higher proportion of patients who were free of disease activity (driven by results from MRI) as compared with either therapy alone, but this effect is reduced over time [[5364]] Trial name: Comparison of Patients Treated with Natalizumab and Interferon-Beta/Glatiramer Using Propensity-Matched Multiple Sclerosis Registry Data (press release, 18 March 2013) [[5315]] Phase: Retrospective medical record review [[5315]] Study Design: Data from two MS patient registries [TYSABRI Observational Program (TOP) and MSCOMET] were used in a propensity-matched analysis to compare the effects of natalizumab, interferon beta, and glatiramer acetate on relapses [[5315]] Disease Stage: MS [[5315]] Enrollment/Number of Patients: N/A [[5315]] Duration: N/A [[5315]] Status/Outcome: Natalizumab was associated with a lower rate of first relapse as compared to interferon beta and glatiramer acetate; relapses in patients treated with natalizumab also occurred more slowly than in those treated with the other drugs [[5315]] Trial name: Romeo et al., Eur. J. Neurol., February 2013 study [[5033]] Phase: Observational/open-label study [[5033]] Study Design: Observational study to determine clinical- and MRI-based predictors of response to glatiramer acetate and interferon beta; patients were considered "responders" if clinical and MRI activity were absent during treatment and "non-responders" in the presence of MRI activity or if the reduction in annualized relapse rate (ARR) was <50% of the ARR in the 2 previous years [[5033]] Disease Stage: RRMS [[5033]] Enrollment/Number of Patients: 594 [[5033]] Duration: 2 years [[5033]] Status/Outcome: Later age at disease onset, a lower level of disability, and a lower number of gadolinium-enhancing lesions at baseline were predictors of response, on the basis of a multivariate analysis [[5033]] Trial name: Brandes et al., J. Med. Econ., February 2013 study [[4902]] Phase: Observational study [[4902]] Study Design: Analysis to assess the effect of real-world adherence (estimated from a study of a single claims database of a national pharmacy benefit manager) on the cost-effectiveness (the cost per avoided relapse) of fingolimod, subcutaneous interferon beta-1b (Extavia or Betaseron) and interferon beta-1a, glatiramer acetate, and intramuscular interferon beta-1a [[4902]] Disease Stage: MS [[4902]] Enrollment/Number of Patients: N/A [[4902]] Duration: N/A [[4902]] Status/Outcome: Costs per relapse avoided were estimated at $90,566 (fingolimod), $127,024 (Extavia), $137,492 (Betaseron), $144,016 (subcutaneous inferferon beta-1a), $160,314 (glatiramer acetate), and $312,629 (intramuscular interferon beta-1a) [[4902]] Trial name: Comi et al., Mult. Scler., December 2012 study (analyses of results obtained during open-label phase of the PreCISe trial) [[360]] [[4203]] Phase: Open-label extension study [[4203]] Study Design: Industry-sponsored, open-label extension study to compare the effects of early treatment (at randomization during the placebo-controlled phase of the PreCISe trial; 20 mg daily subcutaneous dose) versus delayed treatment (in patients originally randomized to placebo and then switched to glatiramer acetate in the open-label phase) in CIS patients [[4203]] Disease Stage: CIS [[4203]] Enrollment/Number of Patients: 409 (in open-label phase), with 289 completing the study [[4203]] Duration: Median time on drug was 1709 days (early-treatment group) versus 1260 days (delayed-treatment group) [[4203]] Status/Outcome: Early treatment reduced the risk of conversion to clinically definite MS by 41% versus delayed treatment; early treatment was associated with a 972-day delay in conversion [[4203]] Trial name: Lu et al., Neurology, August 2012 study [[2959]] Phase: Retrospective literature review [[2959]] Study Design: Systematic review of the literature for information about the effects of interferon beta, glatiramer acetate, or natalizumab on the offspring of MS patients who used these disease-modifying drugs (DMDs) during pregnancy [[2959]] Disease Stage: MS [[2959]] Enrollment/Number of Patients: 97 glatiramer acetate-exposed pregnancies were identified [[2959]] Duration: N/A [[2959]] Status/Outcome: Glatiramer acetate exposure during pregnancy was not associated with preterm birth, spontaneous abortion, congenital anomalies, or lower mean birth weight, but discontinuing DMD use before conception continues to be recommended [[2959]] Trial name: Rossi et al., Eur. J. Neurol., June 2012 study [[2319]] Phase: Observational/open-label study [[2319]] Study Design: Multicenter, open-label, non-randomized, prospective, pilot study to determine if glatiramer acetate is effective and safe in patients who have discontinued natalizumab; glatiramer acetate treatment was initiated 4 weeks after natalizumab was discontinued [[2319]] Disease Stage: RRMS [[2319]] Enrollment/Number of Patients: 40 [[2319]] Duration: 12 months [[2319]] Status/Outcome: Twelve months after beginning glatiramer acetate treatment, 62.5% of patients were relapse-free; the annualized relapse rate and time to relapse were both lower than before natalizumab treatment, indicating that glatiramer acetate can reduce the possibility of MS rebound or early reactivation after natalizumab is discontinued [[2319]] Trial name: Roskell et al., Curr. Med. Res. Opin., May 2012 study [[3359]] Phase: Retrospective trial review [[3359]] Study Design: Meta-analysis of placebo-controlled and head-to-head trials, which evaluated the effects of one or more drugs (fingolimod, interferon beta-1a, interferon beta-1b, and/or glatiramer acetate), to compare the effects of fingolimod versus the other treatments on the annualized relapse rate (ARR) [[3359]] Disease Stage: RRMS [[3359]] Enrollment/Number of Patients: N/A [[3359]] Duration: N/A [[3359]] Status/Outcome: Meta-analyses indicated that fingolimod significantly reduced the ARR as compared to the other drugs; the relative ARRs for each drug versus fingolimod were 1.43 (glatiramer acetate, 20 mg dose), 1.51 (interferon beta-1b, 250 microg dose), 1.55 (interferon beta-1a, 44 microg dose), 1.67 (interferon beta-1a, 22 microg dose), 1.93 (interferon beta-1a, 30 microg dose), and 2.32 (placebo) [[3359]] Trial name: Del Santo et al., Eur. J. Clin. Pharmacol., April 2012 study [[2482]] Phase: Retrospective trial review [[2482]] Study Design: Review of 10 randomized trials that tested interferon, glatiramer acetate, natalizumab, or fingolimod in RRMS, such that the relapse-free rates at 12 months were compared, either directly or through network meta-analysis [[2482]] Disease Stage: RRMS [[2482]] Enrollment/Number of Patients: N/A [[2482]] Duration: N/A [[2482]] Status/Outcome: Fingolimod was determined to have the most favorable profile with respect to relapse-free rate at the follow-up assessment at 1 year [[2482]] Trial name: Meca-Lallana et al., J. Neurol. Sci., April 2012 study [[4248]] Phase: Observational study [[4248]] Study Design: Observational, multicenter study to evaluate changes in spasticity after a switch from interferon beta to glatiramer acetate treatment, with the primary endpoint made up of changes in the Penn Spasm Frequency Scale, Modified Ashworth Scale, Adductor Tone Rating Scale, and Global Pain Score at 3 and 6 months after the switch [[4248]] Disease Stage: RMMS, with spasticity [[4248]] Enrollment/Number of Patients: 68 [[4248]] Duration: 6 months [[4248]] Status/Outcome: Switching to glatiramer acetate led to statistically significant improvement in spasm frequence, muscle tone, and pain after 3 and 6 months [[4248]] Trial name: Khan et al., J. Neurol. Sci., January 2012 study [[3065]] Phase: Retrospective medical record review [[3065]] Study Design: Study to measure the effects of glatiramer acetate (20 mg, injected subcuraneously once a day; 121 patients), interferon beta-1a (30 mcg, injected intramuscularly once a week; 53 patients), and interferon beta-1b (250 mcg, injected subcutaneously every other day; 101 patients), with treatments given for five years, on the loss of brain volume in previously treatment-naïve patients with relatively early RRMS (of less than or equal to five years duration when the study began); patients received brain MRI scans on the same scanner with the same protocol at baseline and year 5 [[3065]] Disease Stage: RRMS [[3065]] Enrollment/Number of Patients: 275 [[3065]] Duration: 5 years [[3065]] Status/Outcome: The disease-modifying therapies were associated with an adjusted (for pseudoatrophy in the first year) percentage change in brain volume (PCBV) over five years of -2.27% (glatiramer acetate), -2.62% (interferon beta-1a), and -3.21% (interferon beta-1b), which were all significantly reduced as compared to the PCBV (-4.75%) for 34 patients who were untreated for 8 to 24 months [[3065]] Trial name: Jongen et al., Health Qual. Life Outcomes, November 2010 study [[4981]] Phase: Observational/open-label study [[4981]] Study Design: Investigator-initiated, prospective, observational, international, multicenter study to determine whether glatiramer acetate increases the health-related quality of life (HR-QoL), reduces fatigue, and/or reduces depression during the first 12 months of treatment [[4981]] Disease Stage: RRMS [[4981]] Enrollment/Number of Patients: 197 (91 with previous immunomodulatory or immunosuppressive treatment and 106 without such treatment) [[4981]] Duration: 12 months [[4981]] Status/Outcome: In the previously untreated group, glatiramer acetate increased the HR-QoL score (such that 43% of the patients had improved scores at 12 months) and decreased fatigue at 6 and 12 months, whereas these improvements did not occur in the previously treated group; neither group experienced changes in depression [[4981]] Trial name: US Glatiramer Acetate Trial (publ 2010) [[355]] Phase: Extension study [[355]] Study Design: Ongoing open-label trial to study up to 15 years of continuous glatiramer acetate as only disease-modifying therapy [[355]] Disease Stage: RRMS [[355]] Enrollment/Number of Patients: 232 enrolled when study began in 1991 and 100 were continuing as of Feb 2008 [[355]] Duration: Beginning 20th year as of 2011 (K. Johnson, ECTRIMS, Oct 2011) Status/Outcome: Drug is associated with reduced relapse rates and decreased progression to disability and SPMS, with no long-term safety issues [[355]]
Interferon beta-1a	Trial name: ADVANCE (press releases, 24 January 2013 and 20 March 2013) [[4731]] [[5316]] Phase: Phase III trial [[4731]] Study Design: Company-sponsored, global, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial to test the safety and efficacy of peginterferon beta-1a, a form of interferon beta-1a that is pegylated to increase its half-life, given subcutaneously at a dose of 125 microg either once every two weeks or once every four weeks; the primary endpoint is the annualized relapse rate (ARR) at one year [[4731]] Disease Stage: RRMS [[4731]] Enrollment/Number of Patients: 1516 [[4731]] Duration: Two years [[4731]] Status/Outcome: Peginterferon beta-1a was associated with a significant reduction in ARR at one year (35.6% for the two-week dosing and 27.5% for the four-week dosing) as compared to placebo [[4731]]; also at one year, peginterferon beta-1a decreased the percentage of patients who relapsed (by 39%), the number of new T2-hyperintense lesions (by 67%), and the risk of 12-week confirmed disability progression (by 38%) as compared to placebo [[5316]] Trial name: Leary et al., Neurol., Jan 2003 trial [[1079]] Phase: Phase II trial [[1079]] Study Design: Randomized, controlled, open-label, single-center exploratory trial of safety and efficacy (primary endpoint: sustained progression in disability) of two doses (30 micrograms and 60 micrograms) of interferon beta-1a in patients with PPMS [[1079]] Disease Stage: PPMS [[1079]] Enrollment/Number of Patients: 50 (49 completed) [[1079]] Duration: Two years [[1079]] Status/Outcome: Drug was well-tolerated at low dose but caused severe flu-like syndrome at high dose; no evidence of efficacy [[1079]] Trial name: Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon Beta-1a in MS (SPECTRIMS) study (publ 2001) [[1080]] [[1081]] Phase: Phase III trial [[1080]] Study Design: Randomized, placebo-controlled, multicenter parallel-group study to determine whether interferon beta-1a (subcutaneous, 22 or 44 micrograms 3x weekly) increased time to confirmed progression of disability (primary endpoint) [[1080]] Disease Stage: SPMS [[1080]] Enrollment/Number of Patients: 618 [[1080]] Duration: Three years [[1080]] Status/Outcome: No significant effect on disability progression, although there appeared to be greater benefit in women; caused significant improvement on MRI measures, particularly in patients who had experienced relapses in the past two years [[1080]] [[1081]] Trial name: Controlled High Risk Avonex Multiple Sclerosis (CHAMPS) study (publ 2001) [[1082]] Phase: Phase III trial [[1082]] Study Design: A randomized, double-blind, placebo-controlled, multicenter trial to determine whether weekly injections of drug (intramuscular) in patients experiencing a single demyelinating event lowered the incidence of MS (primary endpoint) [[1082]] Disease Stage: Clinically isolated syndrome [[1082]] Enrollment/Number of Patients: 383 patients who had experienced a first demyelinating event and showed MRI evidence of two or more clinically silent lesions of the brain [[1082]] Duration: Three years ([[1082]] Status/Outcome: After 3 years of treatment, the probability that patients had developed clinically defined MS was 35% for the interferon group and 50% for the placebo group; patients on interferon also showed a relative reduction in the volume of brain lesions, fewer new or enlarging lesions, and fewer gadolinium-enhancing lesions [[1082]] Trial name: Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial (publ 1998) [[1083]] Phase: Phase III [[1083]] Study Design: Randomized, double-blind, placebo-controlled, multicenter study to test the efficacy of two doses (22 micrograms and 44 micrograms) of subcutaneous interferon beta-1a therapy (primary endpont: relapse rate) [[1083]] Disease Stage: RRMS [[1083]] Enrollment/Number of Patients: 560 patients [[1083]] Duration: Two years [[1083]] Status/Outcome: Treatment significantly reduced relapse rate (mean number per patient: 1.82 at 22 micrograms; 1.73 at 44 micrograms; 2.56 for placebo); time to first relapse was extended by 3 (22 micrograms) and 5 (44 micrograms) months [[1083]] Trial name: Multiple Sclerosis Collaborative Research Group, Ann. Neurol., March 1996 trial [[1084]] Phase: Phase III trial [[1084]] Study Design: Randomized, placebo-controlled, multicenter trial examining whether interferon beta-1a (30 micrograms/week, intramuscularly) could delay time to sustained sustained disability progression of at least one point on the Kurtzke Expanded Disability Status Scale (primary endpoint) [[1084]] Disease Stage: RRMS [[1084]] Enrollment/Number of Patients: 301 patients enrolled; because the study was stopped prematurely, just 282 completed 1 year, 172 completed 2 years [[1084]] [[1063]] Duration: Two years [[1084]] Status/Outcome: 34.9% of patients progressed on placebo, whereas 21.9% progressed on drug; annual exacerbation rate was 0.90 with placebo and 0.61 with drug [[1084]]	Trial name: Calabrese et al., Mult. Scler., April 2012 trial [[3009]] Phase: Postmarketing [[3009]] Study Design: Randomized study to compare the effects of subcutaneous (sc) interferon beta-1a (44 mcg three times weekly), intramuscular (im) interferon beta-1a (30 mcg weekly), and glatiramer acetate (20 mg daily) on the development of cortical lesions and cortical atrophy [[3009]] Disease Stage: RRMS [[3009]] Enrollment/Number of Patients: 165 treated patients and 50 untreated patients, with 141 treated patients completing the study [[3009]] Duration: 24 months [[3009]] Status/Outcome: Interferon beta-1a and glatiramer acetate significantly decreased the development of new cortical lesions and the progression of cortical atrophy, with the most pronounced effects seen with sc interferon beta-1a, such that at 12 months, one or more new cortical lesions were seen in 26% of patients receiving sc interferon beta-1a, 64% of patients receiving im interferon beta-1a, 50% of patients receiving glatiramer acetate, and 74% of untreated patients [[3009]] Trial name: Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (results described at meeting, July 2012, publ February 2013) [[2567]] [[2566]] [[5011]] Phase: Phase III trial [[2567]] [[2566]] Study Design: NIH-funded, randomized, double-blind, controlled study to examine whether a combination of interferon beta-1a (30 microg, intramuscularly, per week) and glatiramer acetate (20 mg per day) is more effective than either treatment alone plus placebo, with a reduction in the annualized relapse rate (ARR) the primary endpoint; time to confirmed disability, the Multiple Sclerosis Functional Composite (MSFC) score, and MRI measures were among the secondary endpoints [[2567]] [[2566]] [[5011]] [[5364]] Disease Stage: RRMS [[2567]] [[2566]] [[5011]] Enrollment/Number of Patients: 1008 [[2567]] [[2566]] [[5011]] Duration: 3 years [[2567]] [[2566]] [[5011]] Status/Outcome: Combination therapy did not reduce the risk of relapse as compared to glatiramer acetate alone, but both of those treatments were superior to interferon beta-1a in this regard; combination therapy did not reduce confirmed progression of the Extended Disability Status Scale or MSFC score as compared to either therapy alone, but combination therapy was better than either therapy alone in reducing the accumulation of lesions and new lesion activity [[5011]]; combination therapy resulted in a half-point benefit on the 22-point scale measuring bladder control [[2567]] [[2566]] Trial name: Rinaldi et al., Mult. Scler., May 2012 trial [[1697]] Phase: Postmarketing [[1697]] Study Design: Prospective study to determine the efficacy of natalizumab versus interferon beta-1a or glatiramer acetate in reducing the accumulation of new cortical lesions [[1697]] Disease Stage: RRMS [[1697]] Enrollment/Number of Patients: 120 [[1697]] Duration: 2 years [[1697]] Status/Outcome: Natalizumab reduced the accumulation of new cortical lesions and the progression of cortical atrophy as compared to interferon beta-1a, glatiramer acetate, or no treatment [[1697]] Trial name: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I) (reported July 2011, publ October 2012) [[784]] [[3822]] 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]] Trial name: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) (reported November 2011, publ October 2012) [[789]] [[3823]] 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]] Trial name: Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) (publ 2010, conference report March 2013, additional analyses publ April 2013) [[5361]] [[302]] [[5862]] Phase: Phase III trial [[302]] Study Design: Multicenter, randomized, double-blind, double-dummy, parallel group trial to compare the efficacy of a daily oral dose of fingolimod (1.25 mg or 0.5 mg) versus a weekly intramuscular dose of interferon beta-1a (30 micrograms) [[302]] Disease Stage: RRMS [[302]] Enrollment/Number of Patients: 1292 (with 1153 completing study) [[302]] Duration: 12 months [[302]] Status/Outcome: Fingolimod was associated with a lower annualized relapse rate (ARR) than interferon beta-1a [0.20 (1.25 mg dose) or 0.16 (0.5 mg dose) for fingolimod versus 0.33 for interferon beta-1a] and with significantly fewer lesions in MRI scans at 12 months than interferon beta-1a, whereas no differences in time to confirmed progression of disability were seen [[302]]; over 1 year, fingolimod decreased the rate of brain volume loss by -32% as compared to interferon beta-1a [[5361]]; when specific subgroups (defined on the basis of demographics, baseline disease characteristics, and previous responses to therapy) were analyzed, fingolimod reduced the ARR over 1 year by 32 to 59% relative to interferon beta-1a in all subgroups based on demographics or baseline disease characteristics; in patients with high levels of disease activity during interferon beta treatment in the previous year (before the study), fingolimod reduced the ARR by 61% as compared to interferon beta-1a [[5862]] Trial name: International Campath-1H in Multiple Sclerosis CAMMS223 (publ 2008) [[448]] 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: RRMS [[448]] Enrollment/Number of Patients: 334 (with 333 completing the study) [[448]] Duration: 36 months [[448]] Status/Outcome: Drug was associated with a 71% reduction in the relative risk of sustained disability and a 74% relative reduction in relapse rate (primary endpoints). Drug was also associated with a more marked reduction in lesions (T2-weighted MRI) than interferon beta-1a and an increase in brain volume (compared to a decrease with interferon beta-1a); proportion of patients relapse-free after 3 years on drug was 80%, vs 52% for interferon beta-1a (secondary endpoints) [[448]] Trial name: Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study (publ 2007) [[1085]] [[1480]] [[1481]] Phase: Phase IV/Postmarketing trial [[1085]] [[1480]] [[1481]] Study Design: Multicenter, randomized roll-over comparison of efficacy (primary endpoint: proportion of patients remaining free from relapses) of two doses (44 micrograms subcutaneously, 3x week vs 30 micrograms intramuscularly 1x week) of interferon beta-1a [[1085]] [[1480]] [[1481]] Disease Stage: RRMS [[1085]] [[1480]] [[1481]] Enrollment/Number of Patients: 677 patients enrolled; 605 patients completed the comparative phase and 439 completed the roll-over phase [[1085]] [[1480]] [[1481]] Duration: 1-2 years [[1085]] [[1480]] [[1481]] Status/Outcome: High-dose subcutaneous treatment showed a stronger reduction of clinical and imaging measures [[1085]] [[1480]] [[1481]] Trial name: Koch-Henriksen et al., Neurol., April 2006 trial [[1086]] Phase: Phase IV/Postmarketing trial [[1086]] Study Design: Open-label, multi-center, randomized, head-to-head trial comparing annualized relapse rate, time to first relapse, and neutralizing antibody formation (primary endpoints) in patients taking interferon beta-1a (22 micrograms weekly) versus interferon beta-1b (250 micrograms every other day) [[1086]] Disease Stage: RRMS [[1086]] Enrollment/Number of Patients: 421 [[1086]] Duration: Two years [[1086]] Status/Outcome: No clinical difference between the two treatments [[1086]]	Trial name: Jokubaitis et al., PLoS One, March 2013 study [[5370]] Phase: Prospective cohort study [[5370]] Study Design: Multicenter Australian cohort study using the MSBase platform to characterize use of disease-modifying therapies (DMTs, which included interferon beta, glatiramer acetate, and natalizumab); specifically, treatment persistence, factors that predict treatment discontinuation, and rates of switching between DMTs were studied [[5370]] Disease Stage: RRMS [[5370]] Enrollment/Number of Patients: 1113 [[5370]] Duration: 4.2 years (median time patients were followed) [[5370]] Status/Outcome: Treatment persistence in this study was short, such that patients remained on their first DMT for 2.5 years (median) and on their next DMT for 2.3 years; annualized switch or cessation rates were 9.5 to 12.5% (interferon beta), 11.6% (glatiramer acetate), and 4.4% (natalizumab); younger age and higher disability scores predicted DMT discontinuation [[5370]] Trial name: CombiRx extension study (conference report, March 2013) [[5364]] Phase: Extension phase of Phase III trial [[5011]] [[5364]] Study Design: Extension of the CombiRx trial, comparing effectiveness of combination therapy (interferon beta-1a and glatiramer acetate) with either therapy alone in reducing the annualized relapse rate (primary endpoint) [[5364]] Disease Stage: RRMS (in original study) [[5011]] [[5364]] Enrollment/Number of Patients: 687 [[5364]] Duration: 90 months [[5364]] Status/Outcome: Combination therapy did not reduce the risk of relapsing or confirmed disability progression as compared to glatiramer acetate, and glatiramer acetate reduced the risk of relapse more than interferon beta-1a, over 90 months; combination therapy was associated with a higher proportion of patients who were free of disease activity (driven by results from MRI) as compared with either therapy alone, but this effect is reduced over time [[5364]] Trial name: Comparison of Patients Treated with Natalizumab and Interferon-Beta/Glatiramer Using Propensity-Matched Multiple Sclerosis Registry Data (press release, 18 March 2013) [[5315]] Phase: Retrospective medical record review [[5315]] Study Design: Data from two MS patient registries [TYSABRI Observational Program (TOP) and MSCOMET] were used in a propensity-matched analysis to compare the effects of natalizumab, interferon beta, and glatiramer acetate on relapses [[5315]] Disease Stage: MS [[5315]] Enrollment/Number of Patients: N/A [[5315]] Duration: N/A [[5315]] Status/Outcome: Natalizumab was associated with a lower rate of first relapse as compared to interferon beta and glatiramer acetate; relapses in patients treated with natalizumab also occurred more slowly than in those treated with the other drugs [[5315]] Trial name: Romeo et al., Eur. J. Neurol., February 2013 study [[5033]] Phase: Observational/open-label study [[5033]] Study Design: Observational study to determine clinical- and MRI-based predictors of response to glatiramer acetate and interferon beta; patients were considered "responders" if clinical and MRI activity were absent during treatment and "non-responders" in the presence of MRI activity or if the reduction in annualized relapse rate (ARR) was <50% of the ARR in the 2 previous years [[5033]] Disease Stage: RRMS [[5033]] Enrollment/Number of Patients: 594 [[5033]] Duration: 2 years [[5033]] Status/Outcome: Later age at disease onset, a lower level of disability, and a lower number of gadolinium-enhancing lesions at baseline were predictors of response, on the basis of a multivariate analysis [[5033]] Trial name: Brandes et al., J. Med. Econ., February 2013 study [[4902]] Phase: Observational study [[4902]] Study Design: Analysis to assess the effect of real-world adherence (estimated from a study of a single claims database of a national pharmacy benefit manager) on the cost-effectiveness (the cost per avoided relapse) of fingolimod, subcutaneous interferon beta-1b (Extavia or Betaseron) and interferon beta-1a, glatiramer acetate, and intramuscular interferon beta-1a [[4902]] Disease Stage: MS [[4902]] Enrollment/Number of Patients: N/A [[4902]] Duration: N/A [[4902]] Status/Outcome: Costs per relapse avoided were estimated at $90,566 (fingolimod), $127,024 (Extavia), $137,492 (Betaseron), $144,016 (subcutaneous inferferon beta-1a), $160,314 (glatiramer acetate), and $312,629 (intramuscular interferon beta-1a) [[4902]] Trial name: Cadavid et al., PLoS One, January 2013 study [[4535]] Phase: Retrospective trial review [[4535]] Study Design: Company-sponsored retrospective review of clinical trial results to determine the effects of natalizumab or interferon beta-1a on ambulatory function, as measured by a timed 25-foot walk, in subjects with an Expanded Disability Status Scale score ≥3.5; a response was defined as a faster walking time relative to the predose walking time over different treatment periods (6-9 months or 24-30 months) [[4535]] Disease Stage: RRMS and SPMS [[4535]] Enrollment/Number of Patients: N/A [[4535]] Duration: N/A [[4535]] Status/Outcome: More (2-4 times as many) disabled patients showed a response in the timed 25-foot walk in the natalizumab groups than in the placebo or interferon beta-1a groups; responders were 24%-45% faster than those who did not respond [[4535]] Trial name: Rebif Rebidose study (press release 3 January 2013) [[4437]] Phase: Phase IIIb, open-label study [[4437]] Study Design: Company-sponsored, multicenter, open-label, single-arm study to evaluate the ease of use of Rebif Rebidose, a single-use auto-injector for the self-administration of interferon beta-1a, in patients who had received Rebif therapy (44 microg, 3 times per week) for at least 12 weeks and who continued such therapy using Rebif Redidose for the duration of the study, with the primary endpoint the proportion of patients who rated Rebif Rebidose as "easy to use" or "very easy to use" [[4437]] Disease Stage: Relapsing MS [[4437]] Enrollment/Number of Patients: 109 [[4437]] Duration: 12 weeks [[4437]] Status/Outcome: The majority of patients reported that this formulation was easy to use [[4437]] Trial name: Zivadinov et al., Neurol. Res., October 2012 study [[3132]] Phase: Observational study [[3132]] Study Design: Longitudinal study to prospectively evaluate the associations between baseline serum anti-phospholipid antibody (APLA) and the evolution of MS in patients who had received intramuscular interferon beta-1a for at least three years and remained on this treatment during the course of the study [[3132]] Disease Stage: RRMS [[3132]] Enrollment/Number of Patients: 47, with 26 APLA-positive and 21 APLA-negative [[3132]] Duration: 3 years [[3132]] Status/Outcome: APLA-positive patients who are treated with interferon beta-1a appear to display more clinical deterioration than APLA-negative patients who are treated with interferon beta-1a [[3132]] Trial name: Portaccio et al., Eur. J. Neurol., October 2012 study [[3453]] Phase: Pilot study [[3453]] Study Design: Prospective, non-randomized, pilot study to examine the possible benefits of natalizumab versus interferon beta on cognitive changes [[3453]] Disease Stage: RRMS [[3453]] Enrollment/Number of Patients: 26; 12 were treated with natalizumab and 14 with interferon beta [[3453]] Duration: 1.5 years (mean follow-up time) [[3453]] Status/Outcome: Natalizumab treatment was associated with a significantly lower mean number of neuropsychological tests that indicated deteriorating performance, and a significantly lower percentage brain volume change, than was interferon beta treatment, suggesting that natalizumab might help cognitive function by reducing brain atrophy [[3453]] Trial name: Lu et al., Neurology, Aug 2012 study [[2959]] Phase: Retrospective literature review [[2959]] Study Design: Systematic review of the literature for information about the effects of interferon beta, glatiramer acetate, or natalizumab on the offspring of MS patients who used these disease-modifying drugs (DMDs) during pregnancy [[2959]] Disease Stage: MS [[2959]] Enrollment/Number of Patients: 761 interferon beta-exposed pregnancies were identified [[2959]] Duration: N/A Status/Outcome: Interferon beta exposure during pregnancy was associated with preterm birth and lower mean birth weight and length, but not with low birth weight (<2500 g), cesarean delivery, spontaneous abortion, or congenital anomalies; discontinuing DMD use before conception continues to be recommended [[2959]] Trial name: Shirani et al., JAMA, July 2012 study [[2485]] Phase: Retrospective cohort study [[2485]] Study Design: Retrospective cohort study, based on prospectively collected data, to compare the effects of interferon beta (-1a or -1b) versus placebo on the progression to disability, such that the main outcome measure was time from eligibility for treatment with interferon beta to a confirmed sustained score of 6 on the Expanded Disability Status Scale (EDSS) [[2485]] Disease Stage: RRMS Enrollment/Number of Patients: 2656 [868 treated with interferon beta (from 1995 to 2004), 829 untreated (who met criteria to receive interferon beta in that time period), 959 from historical cohorts (who met the same criteria before interferon beta therapies were available)] [[2485]] Duration: N/A [[2485]] Status/Outcome: Interferon beta was not associated with a reduction in the progression of disability, such that 10.8% of patients in the treated group, 5.3% in the contemporary untreated group, and 23.1% in the historical untreated group reached an EDSS score of 6 [[2485]] Trial name: Roskell et al., Curr. Med. Res. Opin., May 2012 study [[3359]] Phase: Retrospective trial review [[3359]] Study Design: Meta-analysis of placebo-controlled and head-to-head trials, which evaluated the effects of one or more drugs (fingolimod, interferon beta-1a, interferon beta-1b, and/or glatiramer acetate), to compare the effects of fingolimod versus the other treatments on the annualized relapse rate (ARR) [[3359]] Disease Stage: RRMS [[3359]] Enrollment/Number of Patients: N/A [[3359]] Duration: N/A [[3359]] Status/Outcome: Meta-analyses indicated that fingolimod significantly reduced the ARR as compared to the other drugs; the relative ARRs for each drug versus fingolimod were 1.43 (glatiramer acetate, 20 mg dose), 1.51 (interferon beta-1b, 250 microg dose), 1.55 (interferon beta-1a, 44 microg dose), 1.67 (interferon beta-1a, 22 microg dose), 1.93 (interferon beta-1a, 30 microg dose), and 2.32 (placebo) [[3359]] Trial name: Del Santo et al., Eur. J. Clin. Pharmacol., April 2012 study [[2482]] Phase: Retrospective trial review [[2482]] Study Design: Review of 10 randomized trials that tested interferon, glatiramer acetate, natalizumab, or fingolimod in RRMS, such that the relapse-free rates at 12 months were compared, either directly or through network meta-analysis [[2482]] Disease Stage: RRMS [[2482]] Enrollment/Number of Patients: N/A [[2482]] Duration: N/A [[2482]] Status/Outcome: Fingolimod was determined to have the most favorable profile with respect to relapse-free rate at the follow-up assessment at 1 year [[2482]] Trial name: Meca-Lallana et al., J. Neurol. Sci., April 2012 study [[4248]] Phase: Observational study [[4248]] Study Design: Observational, multicenter study to evaluate changes in spasticity after a switch from interferon beta to glatiramer acetate treatment, with the primary endpoint made up of changes in the Penn Spasm Frequency Scale, Modified Ashworth Scale, Adductor Tone Rating Scale, and Global Pain Score at 3 and 6 months after the switch [[4248]] Disease Stage: RMMS, with spasticity [[4248]] Enrollment/Number of Patients: 68 [[4248]] Duration: 6 months [[4248]] Status/Outcome: Switching to glatiramer acetate led to statistically significant improvement in spasm frequence, muscle tone, and pain after 3 and 6 months [[4248]] Trial name: La Mantia et al., Cochrane Database Syst. Rev., January 2012 study [[2320]]; similar analysis publ April 2013 [[3036]] Phase: Retrospective trial review [[2320]] Study Design: Results from five randomized, placebo-controlled trials (RTCs) were selected for further analysis after assessment of all RTCs that evaluated the efficacy of interferon beta-1a and -1b in SPMS; the goal was to determine whether interferon beta can safely reverse or slow SPMS [[2320]] Disease Stage: SPMS [[2320]] Enrollment/Number of Patients: 3122 patients contributed to the studies involved in the analysis [[2320]] Duration: Analyzed 3 years of treatment [[3036]] Status/Outcome: In SPMS, interferon beta was not observed to stop the development of permanent physical disability, but significantly reduced the risk of relapse and of short-term disability related to relapse [[2320]] Trial name: Khan et al., J. Neurol. Sci., January 2012 study [[3065]] Phase: Retrospective medical record review [[3065]] Study Design: Study to measure the effects of glatiramer acetate (20 mg, injected subcuraneously once a day; 121 patients), interferon beta-1a (30 mcg, injected intramuscularly once a week; 53 patients), and interferon beta-1b (250 mcg, injected subcutaneously every other day; 101 patients), with treatments given for five years, on the loss of brain volume in previously treatment-naïve patients with relatively early RRMS (of less than or equal to five years duration when the study began); patients received brain MRI scans on the same scanner with the same protocol at baseline and year 5 [[3065]] Disease Stage: RRMS [[3065]] Enrollment/Number of Patients: 275 [[3065]] Duration: 5 years [[3065]] Status/Outcome: The disease-modifying therapies were associated with an adjusted (for pseudoatrophy in the first year) percentage change in brain volume (PCBV) over five years of -2.27% (glatiramer acetate), -2.62% (interferon beta-1a), and -3.21% (interferon beta-1b), which were all significantly reduced as compared to the PCBV (-4.75%) for 34 patients who were untreated for 8 to 24 months [[3065]] Trial name: CAMMS223 post-hoc and subset analysis (publ 2011) [[448]] [[422]] Phase: Additional data analysis for Phase II study [[422]] Study Design: Post-hoc and subset analysis 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) [[448]] [[422]] Disease Stage: RRMS [[422]] Enrollment/Number of Patients: 334 [[422]] Duration: 2 years [[422]] Status/Outcome: The drug 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 EDSS [[422]] Trial name: CAMMS223 extension study (reported 2010) [[788]] Phase: Extension of phase II study [[788]] Study Design: Open-label 2-year 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) [[422]] [[788]] Disease Stage: RRMS [[788]] Enrollment/Number of Patients: Not noted [[788]] Duration: Four year follow-up [[788]] Status/Outcome: 71% of treated patients remained disease-free up to three years after last treatment, compared to 35% on interferon beta-1a; 91% of treated patients had no sustained accumulation of disease, compared to 68% on interferon beta-1a; 77% of treated patients were relapse-free, compared to 49% on interferon beta-1a [[788]] Trial name: Bermel et al., Mult. Scler., Feb 2010 study [[1076]] [[1084]] Phase: Extension study [[1076]] Study Design: Open-label, 15-year follow-up of interferon beta-1a use (intramuscular) to determine long-term tolerability and efficacy using patient self-report questionnaires [[1076]] Disease Stage: RRMS [[1076]] Enrollment/Number of Patients: 136 out of 172 eligible patients [[1076]] Duration: 15 years [[1076]] Status/Outcome: Patients on long-term therapy had less disability and a better quality of life as compared with patients who stopped using the therapy after the original trial [[1076]] Trial name: Long-term follow-up for PRISMS study (publ 2006) [[1077]] [[1083]] Phase: Extension study [[1077]] Study Design: Open-label eight-year follow-up of interferon beta-1a (subcutaneous) use to determine the long-term tolerability and efficacy on the basis of Expanded Disability Status Scale, relapse rate, and T2 lesion burden [[1077]] Disease Stage: RRMS [[1077]] Enrollment/Number of Patients: 382 out of the 560 originally-enrolled patients [[1077]] Duration: 8 years [[1077]] Status/Outcome: Results supported long-term use; a stronger effect was observed at higher dose; 19.7 % of patients progressed to secondary progressive MS [[1077]]
Interferon beta-1b	Trial name: Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) (publ 2006) [[1131]] [[1137]] Phase: Phase III trial [[1131]] [[1137]] Study Design: Multicenter, randomized, double-blind, placebo-controlled trial to determine the effects of interferon beta-1b (250 microg, given subcutaneously every other day) on delaying conversion to clinically definite MS [[1137]] Disease Stage: CIS [[1137]] Enrollment/Number of Patients: 468 [[1137]] Duration: 2 years, or until MS was diagnosed [[1137]] Status/Outcome: Drug reduced the risk of conversion to clinically definite MS (from 45% in the placebo group to 28% in the interferon beta-1b group) [[1131]] [[1137]] Trial name: Barkhof et al., Arch. Neurol., September 2007 trial [[1142]] Phase: Phase III trial [[1142]] Study Design: Industry-sponsored, double-blind, placebo-controlled, randomized, parallel-group, multicenter study to examine detailed MRI findings from participants in the BENEFIT trial, in which patients received interferon beta-1b (250 microg, given subcutaneously every other day) or placebo [[1137]] [[1142]] Disease Stage: CIS [[1142]] Enrollment/Number of Patients: 404 [[1142]] Duration: 2 years, or until MS was diagnosed [[1142]] Status/Outcome: Drug was associated with a 60% relative reduction in the median cumulative number of newly active lesions (2 versus 5), with lower cumulative numbers of new T2 lesions (1 versus 3) and new gadolinium-enhancing lesions (0 versus 1) [[1131]] [[1142]] Trial name: Panitch et al., Neurology, November 2004 (North American SPMS) trial [[1141]] Phase: Phase III trial [[1141]] Study Design: Multicenter, double-blind, placebo-controlled, randomized trial to test the effects of interferon beta-1b (250 microg or 160 microg per m2 of body surface area, given subcutaneously every other day) on time to progression [at least 1.0 point increase on the Expanded Disability Status Scale (EDSS), or 0.5 point increase if the baseline was 6.0 or 6.5] (primary outcome) and on mean change in EDSS score, measures related to relapse, MRI activity, and results of a neuropsychological test (secondary outcomes) [[1141]] Disease Stage: SPMS [[1141]] Enrollment/Number of Patients: 939 [[1141]] Duration: 3 years [[1141]] Status/Outcome: Drug (at either dose) was not associated with a significant change in the time to confirmed progression of EDSS scores, but both doses were associated with benefits to relapse- and MRI-related measures [[1141]]; retrospective combined analyses of the results of the European SPMS trial (1998) and the North American SPMS trial (2004) to determine reasons for the discrepancy in outcomes determined that the the European SPMS trial included patients with an earlier stage of SPMS and with more active disease, which might be relevant to the different results of the two studies [[1140]] [[1141]] [[1192]] Trial name: European Study Group, Lancet, November 1998 (European SPMS) trial [[1140]] Phase: Phase III trial [[1140]] Study Design: Multicenter, double-masked, randomized, placebo-controlled trial to test the effects of interferon beta-1b [8 million IU (250 microg), given subcutaneously every other day] on the time to confirmed progression of disability [1.0 point increase on the Expanded Disability Status Scale (EDSS), or a 0.5 point increase if the baseline was 6.0 or 6.5] [[1131]] [[1140]] Disease Stage: SPMS [[1140]] Enrollment/Number of Patients: 718, with 661 undergoing followup [[1140]] Duration: 2 to 3 years [[1140]] Status/Outcome: Drug was associated with a reduced time to confirmed progression of disability, such that disability was delayed by 9 to 12 months during the study period of 2 to 3 years [[1140]]; retrospective combined analyses of the results of the European SPMS trial (1998) and the North American SPMS trial (2004) to determine reasons for the discrepancy in outcomes determined that the the European SPMS trial included patients with an earlier stage of SPMS and with more active disease, which might be relevant to the different results of the two studies [[1140]] [[1141]] [[1192]] Trial name: The IFNB Multiple Sclerosis Study Group, Neurology, April 1993 trial [[1136]] Phase: Phase II trial [[1136]] Study Design: Multicenter, randomized, double-blind, placebo-controlled trial to test the effects of interferon beta-1b (50 microg or 250 microg, administered subcutaneously every other day) on the annual exacerbation rate and on the proportion of exacerbation-free patients (primary endpoints) [[1131]] [[1136]] Disease Stage: RRMS [[1136]] Enrollment/Number of Patients: 372, with efficacy analysis based on data from 338 [[1131]] [[1136]] Duration: 2 years [[1136]] Status/Outcome: 250 microg interferon beta-1b was associated with a lower annual exacerbation rate (0.84) than was 50 microg interferon beta-1b (1.17) or placebo (1.27); a larger fraction of patients in the 250 microg group (31%) were exacerbation free at 2 years as compared to those in the 50 microg group (21%) or placebo group (16%); the 250 microg dose significantly reduced the median time to first relapse; the 250 microg dose also reduced the number of new lesions per year and MRI-detected burden of disease (in a cohort of 52 patients undergoing frequent MRIs) [[1131]] [[1136]] [[1156]] Trial name: The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, Neurology, July 1995 trial (extension of IFNB 1993 trial) [[1136]] [[1157]] Phase: Phase II trial [[1157]] Study Design: Double-blind extension of a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of interferon beta-1b (50 microg or 250 microg, administered subcutaneously every other day) on the exacerbation rate and the MRI burden of disease [[1136]] [[1157]] Disease Stage: RRMS [[1136]] [[1157]] Enrollment/Number of Patients: 372 in original study, with 218 completing this study [[1157]] Duration: 5 years [[1157]] Status/Outcome: 250 microg interferon beta-1b caused a one-third reduction in the annual exacerbation rate compared to placebo in each of 5 years, but the difference was not statistically significant after the second year [[1136]] [[1157]] Trial name: Knobler et al., J. Interferon Res., October 1993 study [[1159]] Phase: Pilot study [[1159]] Study Design: Placebo-controlled pilot study to test the safety and determine the side effects of recombinant human interferon beta-1b, in which patients were treated with interferon beta-1b [0.8, 4, 8, or 16 million units (mU), given subcutaneously 3 times per week] or placebo [[1159]] Disease Stage: RRMS [[1159]] Enrollment/Number of Patients: 30 enrolled; 15 patients remained in the study for over 6 years [[1159]] Duration: 6 years [[1159]] Status/Outcome: Dose-related trend in reduction of the exacerbation frequency was seen and the 8 mU dose was selected for further study at 24 weeks (such that 15 patients received the 8 mU dose for over 6 years); side effects decreased over time [[1159]]	Trial name: BEtaseron vs COpaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints (BECOME) (publ 2009) [[365]] Phase: Phase IV trial [[956]] Study Design: Trial to compare the ability of interferon beta-1b and glatiramer acetate to suppress signs of disease activity (primary outcome, number of combined active lesions per patient per scan in first year) as measured by monthly brain MRI [[365]] Disease Stage: CIS or RRMS [[365]] Enrollment/Number of Patients: 75 [[365]] Duration: Up to 2 years [[365]] Status/Outcome: Patients taking either interferon beta-1b or glatiramer acetate showed similar numbers of combined active lesions per patient for first year (primary outcome) and similar numbers of relapses for 2 years [[365]] Trial name: Betaferon Efficiency Yielding Outcomes of a New Dose (BEYOND) (publ 2009) [[362]] Phase: Phase III trial [[957]] Study Design: Multicenter, randomized, prospective study to compare the efficacy, safety, and tolerability of interferon beta-1b (250 or 500 microg every other day) and glatiramer acetate (20 mg per day) (primary outcome, relapse risk) [[362]] Disease Stage: RRMS [[362]] Enrollment/Number of Patients: 2447 [[362]] Duration: 2.0 to 3.5 years [[362]] Status/Outcome: Relapse risk, expanded disability status scale progression, and T1-hypointense lesion volume were similar among all treatment groups [[362]] Trial name: Etemadifar et al., Acta Neurol. Scand., May 2006 trial [[1158]] Phase: Phase IV/Postmarketing trial [[1158]] Study Design: Randomized, single-blind trial to compare the effects of interferon beta-1b (subcutaneous injection), interferon beta-1a (intramuscular injection), and interferon beta-1a (subcutaneous injection) [[1179]] [[1158]] Disease Stage: RRMS [[1158]] Enrollment/Number of Patients: 90 [[1158]] Duration: 2 years [[1158]] Status/Outcome: In the interferon beta-1b group, 43.3% of the patients remained relapse-free, as compared to 56.7% in the interferon beta-1a (subcutaneous) and 20% in the interferon beta-1a (intramuscular) groups; the Expanded Disability Status Scale score decreased in the interferon beta-1b and interferon beta-1a (subcutaneous) groups, but remained stable in the interferon beta-1a (intramuscular) group [[1158]] Trial name: Koch-Henriksen et al., Neurology, April 2006 trial [[1086]] Phase: Phase IV/Postmarketing trial [[1086]] Study Design: Multicenter, controlled, open-label, randomized, head-to-head trial to compare the effects of interferon beta-1a (22 microg administered subcutaneously once a week) versus interferon beta-1b (250 microg administered subcutaneously every other day) on the annualized relapse rate and the time to first relapse (primary endpoints) and the time to sustained progression (secondary endpoint) [[1131]] [[1138]] Disease Stage: RRMS [[1086]] Enrollment/Number of Patients: 301 [[1086]] Duration: 2 years [[1131]] [[1086]] Status/Outcome: Both drug regimes were associated with virtually equal annual relapse rates (0.70 for interferon beta-1a; 0.71 for interferon beta-1b), times to first relapse, and time to sustained progression [[1086]] Trial name: INdependent COMparison of INterferon (INCOMIN) (publ 2002) [[1138]] Phase: Phase IV/Postmarketing trial [[1138]] Study Design: Prospective, randomized, open-label multicenter study to compare the effects of two different interferon beta preparations and dosing schedules [interferon beta-1a (30 microg administered intramuscularly once a week) versus interferon beta-1b (250 microg administered subcutaneously on alternate days)] on the proportion of patients free from relapses and free from new T2 lesions (primary outcome measures) [[1131]] [[1138]] [[1179]] Disease Stage: RRMS [[1138]] Enrollment/Number of Patients: 188 [[1138]] Duration: 2 years [[1138]] Status/Outcome: The interferon beta-1b regime was more effective than the interferon beta-1a regime; the proportion of patients who remained relapse free over 2 years was 51% for interferon beta-1b versus 36% for interferon beta-1a and the proportion of patients who remained free from new T2 lesions was 55% for interferon beta-1b versus 26% for interferon beta-1a [[1138]]	Trial name: Jokubaitis et al., PLoS One, March 2013 study [[5370]] Phase: Prospective cohort study [[5370]] Study Design: Multicenter Australian cohort study using the MSBase platform to characterize use of disease-modifying therapies (DMTs, which included interferon beta, glatiramer acetate, and natalizumab); specifically, treatment persistence, factors that predict treatment discontinuation, and rates of switching between DMTs were studied [[5370]] Disease Stage: RRMS [[5370]] Enrollment/Number of Patients: 1113 [[5370]] Duration: 4.2 years (median time patients were followed) [[5370]] Status/Outcome: Treatment persistence in this study was short, such that patients remained on their first DMT for 2.5 years (median) and on their next DMT for 2.3 years; annualized switch or cessation rates were 9.5 to 12.5% (interferon beta), 11.6% (glatiramer acetate), and 4.4% (natalizumab); younger age and higher disability scores predicted DMT discontinuation [[5370]] Trial name: Comparison of Patients Treated with Natalizumab and Interferon-Beta/Glatiramer Using Propensity-Matched Multiple Sclerosis Registry Data (press release, 18 March 2013) [[5315]] Phase: Retrospective medical record review [[5315]] Study Design: Data from two MS patient registries [TYSABRI Observational Program (TOP) and MSCOMET] were used in a propensity-matched analysis to compare the effects of natalizumab, interferon beta, and glatiramer acetate on relapses [[5315]] Disease Stage: MS [[5315]] Enrollment/Number of Patients: N/A [[5315]] Duration: N/A [[5315]] Status/Outcome: Natalizumab was associated with a lower rate of first relapse as compared to interferon beta and glatiramer acetate; relapses in patients treated with natalizumab also occurred more slowly than in those treated with the other drugs [[5315]] Trial name: Romeo et al., Eur. J. Neurol., February 2013 study [[5033]] Phase: Observational/open-label study [[5033]] Study Design: Observational study to determine clinical- and MRI-based predictors of response to glatiramer acetate and interferon beta; patients were considered "responders" if clinical and MRI activity were absent during treatment and "non-responders" in the presence of MRI activity or if the reduction in annualized relapse rate (ARR) was <50% of the ARR in the 2 previous years [[5033]] Disease Stage: RRMS [[5033]] Enrollment/Number of Patients: 594 [[5033]] Duration: 2 years [[5033]] Status/Outcome: Later age at disease onset, a lower level of disability, and a lower number of gadolinium-enhancing lesions at baseline were predictors of response, on the basis of a multivariate analysis [[5033]] Trial name: Brandes et al., J. Med. Econ., February 2013 study [[4902]] Phase: Observational study [[4902]] Study Design: Analysis to assess the effect of real-world adherence (estimated from a study of a single claims database of a national pharmacy benefit manager) on the cost-effectiveness (the cost per avoided relapse) of fingolimod, subcutaneous interferon beta-1b (Extavia or Betaseron) and interferon beta-1a, glatiramer acetate, and intramuscular interferon beta-1a [[4902]] Disease Stage: MS [[4902]] Enrollment/Number of Patients: N/A [[4902]] Duration: N/A [[4902]] Status/Outcome: Costs per relapse avoided were estimated at $90,566 (fingolimod), $127,024 (Extavia), $137,492 (Betaseron), $144,016 (subcutaneous inferferon beta-1a), $160,314 (glatiramer acetate), and $312,629 (intramuscular interferon beta-1a) [[4902]] Trial name: Portaccio et al., Eur. J. Neurol., October 2012 study [[3453]] Phase: Pilot study [[3453]] Study Design: Prospective, non-randomized, pilot study to examine the possible benefits of natalizumab versus interferon beta on cognitive changes [[3453]] Disease Stage: RRMS [[3453]] Enrollment/Number of Patients: 26; 12 were treated with natalizumab and 14 with interferon beta [[3453]] Duration: 1.5 years (mean follow-up time) [[3453]] Status/Outcome: Natalizumab treatment was associated with a significantly lower mean number of neuropsychological tests that indicated deteriorating performance, and a significantly lower percentage brain volume change, than was interferon beta treatment, suggesting that natalizumab might help cognitive function by reducing brain atrophy [[3453]] Trial name: Dhib-Jalbut et al., J. Neuroimmunol., September 2012 study [[3247]] Phase: Phase IV study [[3247]] Study Design: Part of a larger, open-label, multicenter, prospective, observational Phase IV clinical study (titled Success of Titration, analgesics, and BETA nurse support on Acceptance Rates to early MS Treatment with Betaseron®, or START); this particular analysis looked for correlations between the response to interferon beta-1b and immune markers [[3247]] Disease Stage: CIS and RRMS [[3247]] Enrollment/Number of Patients: 32 enrolled; 30 were treated [[3247]] Duration: 12 months [[3247]] Status/Outcome: At month 6, interleukin-17 levels were higher in relapsing versus relapse-free patients; at month 3, brain-derived neurotrophic factor levels were higher in relapse-free versus relapsing patients; furthermore, changes in interleukin-4 levels inversely correlated with disability score and changes in the interleukin-10/interferon-gamma ratio inversely correlated with relapse occurrence [[3247]] Trial name: Jacques et al., Mult. Scler. Int., August 2012 study [[3084]] Phase: Phase IIa pilot study [[3084]] Study Design: Randomized, open-label, multicenter, two-arm pilot study to evaluate the safety and tolerability of a combination of the immunosuppressant tacrolimus [orally two times per day at a dose to reach either low (1-5 ng/ml) or high (5-10 ng/ml) blood levels] with interferon beta-1b therapy (250 microg given subcutaneously every other day); the idea is to target more than one autoimmune process by using two drugs [[3084]] Disease Stage: RRMS and SPMS [[3084]] Enrollment/Number of Patients: 25 [[3084]] Duration: 38 weeks [[3084]] Status/Outcome: Combination therapy appeared to be safe and well tolerated [[3084]] Trial name: Lu et al., Neurology, August 2012 study [[2959]] Phase: Retrospective literature review [[2959]] Study Design: Systematic review of the literature for information about the effects of interferon beta, glatiramer acetate, or natalizumab on the offspring of MS patients who used these disease-modifying drugs (DMDs) during pregnancy [[2959]] Disease Stage: MS [[2959]] Enrollment/Number of Patients: 761 interferon beta-exposed pregnancies were identified [[2959]] Duration: N/A [[2959]] Status/Outcome: Interferon beta exposure during pregnancy was associated with preterm birth and lower mean birth weight and length, but not with low birth weight (<2500 g), cesarean delivery, spontaneous abortion, or congenital anomalies; discontinuing DMD use before conception continues to be recommended [[2959]] Trial name: Shirani et al., JAMA, July 2012 study [[2485]] Phase: Retrospective cohort study [[2485]] Study Design: Retrospective cohort study, based on prospectively collected data, to compare the effects of interferon beta (-1a or -1b) versus placebo on the progression to disability, such that the main outcome measure was time from eligibility for treatment with interferon beta to a confirmed sustained score of 6 on the Expanded Disability Status Scale (EDSS) [[2485]] Disease Stage: RRMS [[2485]] Enrollment/Number of Patients: 2656 [868 treated with interferon beta (from 1995 to 2004), 829 untreated (who met criteria to receive interferon beta in that time period), 959 from historical cohorts (who met the same criteria before interferon beta therapies were available)] [[2485]] Duration: N/A [[2485]] Status/Outcome: Interferon beta was not associated with a reduction in the progression of disability, such that 10.8% of patients in the treated group, 5.3% in the contemporary untreated group, and 23.1% in the historical untreated group reached an EDSS score of 6 [[2485]] Trial name: Roskell et al., Curr. Med. Res. Opin., May 2012 study [[3359]] Phase: Retrospective trial review [[3359]] Study Design: Meta-analysis of placebo-controlled and head-to-head trials, which evaluated the effects of one or more drugs (fingolimod, interferon beta-1a, interferon beta-1b, and/or glatiramer acetate), to compare the effects of fingolimod versus the other treatments on the annualized relapse rate (ARR) [[3359]] Disease Stage: RRMS [[3359]] Enrollment/Number of Patients: N/A [[3359]] Duration: N/A [[3359]] Status/Outcome: Meta-analyses indicated that fingolimod significantly reduced the ARR as compared to the other drugs; the relative ARRs for each drug versus fingolimod were 1.43 (glatiramer acetate, 20 mg dose), 1.51 (interferon beta-1b, 250 microg dose), 1.55 (interferon beta-1a, 44 microg dose), 1.67 (interferon beta-1a, 22 microg dose), 1.93 (interferon beta-1a, 30 microg dose), and 2.32 (placebo) [[3359]] Trial name: Del Santo et al., Eur. J. Clin. Pharmacol., April 2012 study [[2482]] Phase: Retrospective trial review [[2482]] Study Design: Review of 10 randomized trials that tested interferon, glatiramer acetate, natalizumab, or fingolimod in RRMS, such that the relapse-free rates at 12 months were compared, either directly or through network meta-analysis [[2482]] Disease Stage: RRMS [[2482]] Enrollment/Number of Patients: N/A [[2482]] Duration: N/A [[2482]] Status/Outcome: Fingolimod was determined to have the most favorable profile with respect to relapse-free rate at the follow-up assessment at 1 year [[2482]] Trial name: Basiri et al., Acta Med. Iran, 2012 study [[1427]] Phase: Open-label study [[1427]] Study Design: Open-label study to evaluate the effectiveness and tolerability of interferon beta in patients younger than 16 years; patients were treated with either interferon beta-1a (30 microg, intramuscularly once a week) or interferon beta-1b (250 microg, subcutaneously every other day) [[1427]] Disease Stage: RRMS [[1427]] Enrollment/Number of Patients: 13 [[1427]] Duration: 9 months [[1427]] Status/Outcome: Use of interferon beta appears safe in pediatric patients over the short term; drugs were also associated with a decrease in the expanded disability status scale score [[1427]] Trial name: Goodin et al., Neurology, April 2012 study [[1389]] Phase: Observational study [[1389]] Study Design: Randomized, long-term cohort study to compare all-cause mortality over 21 years between patients who received either 250 microg interferon beta-1b (administered subcutaneously every other day for up to 5 years) or placebo in a pivotal interferon beta-1b trial published in 1993/1995 [[1136]] [[1389]] Disease Stage: RRMS [[1389]] Enrollment/Number of Patients: 366 (of the 372 who were originally enrolled) [[1389]] Duration: 21 years (time from enrollment in the original trial to present analysis) [[1389]] Status/Outcome: Patients who were originally randomly assigned to 250 microg interferon beta-1b had a significant reduction in all-cause mortality over 21 years as compared with those receiving placebo, such that the hazard rate of death was reduced 46.8% among the treated patients [[1389]]; additional cost-effectiveness analyses indicate that early treatment with interferon beta-1b increases quality-adjusted life-years and is probably a cost-effective therapy for MS [[2860]]; additional analyses showed that the excessive deaths among patients who received placebo during the original randomized controlled trial were primarily related to MS, particularly MS-related pulmonary infections (81 deaths had been recorded among the 366 patients; the cause of death and/or its relationship to MS were determined for 71/81 of the deaths) [[4083]] Trial name: Meca-Lallana et al., J. Neurol. Sci., April 2012 study [[4248]] Phase: Observational study [[4248]] Study Design: Observational, multicenter study to evaluate changes in spasticity after a switch from interferon beta to glatiramer acetate treatment, with the primary endpoint made up of changes in the Penn Spasm Frequency Scale, Modified Ashworth Scale, Adductor Tone Rating Scale, and Global Pain Score at 3 and 6 months after the switch [[4248]] Disease Stage: RMMS, with spasticity [[4248]] Enrollment/Number of Patients: 68 [[4248]] Duration: 6 months [[4248]] Status/Outcome: Switching to glatiramer acetate led to statistically significant improvement in spasm frequence, muscle tone, and pain after 3 and 6 months [[4248]] Trial name: Goodin et al., J. Neurol. Neurosurg. Psychiatry, March 2012 study [[763]] Phase: Observational study [[763]] Study Design: Industry-sponsored, cross-sectional, observational, cohort study to evaluate the long-term benefit of interferon beta-1b therapy in patients who participated in a pivotal interferon beta-1b trial published in 1993/1995 (involving 50 microg or 250 microg interferon beta-1b, administered subcutaneously every other day for up to 5 years), such that treatment and disease status after 16 years was assessed, but interferon beta-1b was not administered as part of this study [[1136]] [[1157]] [[763]] [[1173]] Disease Stage: RRMS [[1173]] Enrollment/Number of Patients: 432 [[1173]] Duration: 16 years [[763]] Status/Outcome: Physical and cognitive outcomes after 16 years correlated with baseline disability; physical outcome but not cognition correlated with disability accrual and annualized relapse rates during the randomised controlled trial, whereas cognitive but not physical outcomes correlated with baseline measures of lesion burden and atrophy as measured by MRI; given that better correlations were seen for several baseline measures, long term outcomes might be determined mostly early during the course of the disease [[763]] Trial name: La Mantia et al., Cochrane Database Syst. Rev., January 2012 study [[2320]]; similar analysis publ April 2013 [[3036]] Phase: Retrospective trial review [[2320]] Study Design: Results from five randomized, placebo-controlled trials (RTCs) were selected for further analysis after assessment of all RTCs that evaluated the efficacy of interferon beta-1a and -1b in SPMS; the goal was to determine whether interferon beta can safely reverse or slow SPMS [[2320]] Disease Stage: SPMS [[2320]] Enrollment/Number of Patients: 3122 patients contributed to the studies involved in the analysis [[2320]] Duration: Analyzed 3 years of treatment [[3036]] Status/Outcome: In SPMS, interferon beta was not observed to stop the development of permanent physical disability, but significantly reduced the risk of relapse and of short-term disability related to relapse [[2320]] Trial name: Khan et al., J. Neurol. Sci., January 2012 study [[3065]] Phase: Retrospective medical record review [[3065]] Study Design: Study to measure the effects of glatiramer acetate (20 mg, injected subcuraneously once a day; 121 patients), interferon beta-1a (30 mcg, injected intramuscularly once a week; 53 patients), and interferon beta-1b (250 mcg, injected subcutaneously every other day; 101 patients), with treatments given for five years, on the loss of brain volume in previously treatment-naïve patients with relatively early RRMS (of less than or equal to five years duration when the study began); patients received brain MRI scans on the same scanner with the same protocol at baseline and year 5 [[3065]] Disease Stage: RRMS [[3065]] Enrollment/Number of Patients: 275 [[3065]] Duration: 5 years [[3065]] Status/Outcome: The disease-modifying therapies were associated with an adjusted (for pseudoatrophy in the first year) percentage change in brain volume (PCBV) over five years of -2.27% (glatiramer acetate), -2.62% (interferon beta-1a), and -3.21% (interferon beta-1b), which were all significantly reduced as compared to the PCBV (-4.75%) for 34 patients who were untreated for 8 to 24 months [[3065]] Trial name: Garcia-Montojo et al., Eur. J. Neurol., Aug 2011 study [[1840]] Phase: Observational study [[1840]] Study Design: Observational, multicentric study to evaluate whether the efficacy of interferon beta-1b in MS might be related to its antiviral properties, as assessed by its effect on human herpes virus 6 (HHV-6) and Epstein-Barr virus (EBV) [[1840]] Disease Stage: MS [[1840]] Enrollment/Number of Patients: 54 [[1840]] Duration: 24 months [[1840]] Status/Outcome: The presence of HHV-6 in serum during treatment with interferon beta-1b was associated with a higher risk of severe relapse; no association was found between EBV and various clinical measures [[1840]] Trial name: Reder et al., Neurology, June 2010 study [[1133]] Phase: Observational study [[1133]] Study Design: Cross-sectional followup study to assess the long-term safety of interferon beta-1b in patients who participated in a pivotal interferon beta-1b trial published in 1993/1995 (involving 50 microg or 250 microg interferon beta-1b, administered subcutaneously every other day for up to 5 years), such that adverse events that occurred in the 16 years since the pivotal trial were recorded, but no particular therapy was stipulated as part of this study [[1133]] [[1136]] [[1157]] Disease Stage: RRMS [[1133]] Enrollment/Number of Patients: 328 [[1133]] Duration: 16 years [[1133]] Status/Outcome: Adverse events related to treatment (such as leukopenia and liver and thyroid dysfunction) were reported and in agreement with previously observed effects; no new interferon beta-1b-related adverse effects were seen; and a higher percentage of patients from the placebo group in the pivotal study had died (18.3%) than from the interferon beta-1b groups (8.3% for the 50 microg group and 5.4% for the 250 microg group), all of which support the long-term safety of this drug [[1133]] Trial name: Kappos et al., Lancet Neurol., November 2009 trial (active treatment extension of the BENEFIT trial) [[1137]] [[1143]] Phase: Phase III trial [[1143]] Study Design: Industry-sponsored, prospectively planned, open-label follow-up study to compare the effects of early versus delayed interferon beta-1b treatment on the time to clinically definite MS and on other measures such as disability progression; patients enrolled in the original trial received either interferon beta-1b (250 microg) or placebo, whereas all patients received interferon beta-1b in the extension (patients and study personnel remained unaware of the initial treatment group) [[1143]] Disease Stage: CIS (at the time the original BENEFIT trial began) [[1137]] [[1143]] Enrollment/Number of Patients: 468 enrolled in the BENEFIT trial; 358 completed the extension [[1143]] Duration: 5 years [[1143]] Status/Outcome: Early treatment with interferon beta-1b reduced the risk of conversion to clinically definite MS by 37% as compared to delayed treatment with interferon beta-1b, but early treatment did not change long-term disability outcomes; early treatment was, however, associated with more improvement in cognition [[1131]] [[1143]] Trial name: OPTimisation of Interferon for MS (OPTIMS) (publ 2008) [[1180]] Phase: Phase II trial [[1180]] Study Design: University-sponsored, prospective, multicenter, randomized trial to test the effects of a high dose of interferon beta-1b (375 microg, given subcutaneously every other day) as compared to the usual dose (250 microg, given subcutaneously every other day) in patients with a suboptimal response to the 250 microg dose; trial had a 6-month run-in phase (to identify suboptimal responders) when all participants received the 250 microg dose and a 6-month open-label clinical and blinded MRI follow-up in which suboptimal responders were randomized to the two doses, with the primary outcome the proportion of patients without MRI activity during months 9 to 12 [[1180]] [[1174]] Disease Stage: RRMS [[1180]] Enrollment/Number of Patients: 216 entered study; 76 suboptimal responders were included in the analysis [[1180]] Duration: 1 year [[1180]] Status/Outcome: 375 microg dose was more frequently associated with no new MRI activity during months 9 to 12 than the 250 microg dose (30/36 versus 16/40) [[1180]]
Laquinimod	Trial name: CONCERTO (press releases, August 2012 and March 2013) [[2768]] [[5223]] Phase: Phase III trial [[2768]] Study Design: Company-sponsored, multinational, randomized, double-blind, placebo-controlled trial to evaluate the effects of laquinimod (either 0.6 mg or 1.2 mg oral dose, once daily) on confirmed disability progression as measured by the Expanded Disability Status Scale (primary outcome measure); the protocol has been granted a Special Protocol Assessment agreement by the US FDA [[2768]] [[5223]] Disease Stage: RRMS [[2768]] Enrollment/Number of Patients: Approximately 1800 [[2768]] Duration: 24 months [[2768]] Status/Outcome: Plans to initiate this trial have been announced (8 August 2012) [[2768]]; first patient enrolled (6 March 2013) [[5223]] Trial name: Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (ALLEGRO) (publ 2012) [[809]] [[883]] [[819]] [[820]] Phase: Phase III trial [[883]] Study Design: Company-sponsored, randomized, double-blind, multicenter, placebo-controlled study to test the effects of laquinimod (0.6 mg oral dose, once daily) on the relapse rate (primary outcome) and other secondary outcomes [[809]] [[883]] Disease Stage: RRMS [[883]] Enrollment/Number of Patients: 1106 [[883]] Duration: 2 years [[883]] Status/Outcome: Drug was associated with a 23% reduction in the annualized relapse rate (0.30 versus 0.39) and a reduction in the risk of confirmed disease progression (11.1% versus 15.7%) [[883]] [[819]] [[820]] Trial name: Comi et al., Lancet, June 2008 trial [[823]] Phase: Phase IIb trial [[823]] Study Design: Company-sponsored, randomized, double-blind, multicenter, placebo-controlled trial to test the effects of laquinimod (0.3 mg or 0.6 mg daily oral dose) on the number of brain lesions in the last four months of the study (primary outcome) [[823]] [[821]] Disease Stage: RRMS [[823]] Enrollment/Number of Patients: 306 [[823]] Duration: 36 weeks [[823]] Status/Outcome: Drug (0.6 mg per day) was associated with a 40.4% reduction in the mean cumulative number of gadolinium enhancing lesions, whereas the 0.3 mg dose was not associated with significant effects [[823]] Trial name: Polman et al., Neurology, March 2005 trial [[564]] Phase: Phase II trial [[564]] Study Design: Company-supported, randomized, double-blind, multicenter placebo-controlled trial to test the effects of laquinimod (0.3 mg or 0.1 mg as three tablets once daily) on the number of active brain lesions (primary outcome) [[564]] Disease Stage: RRMS or SPMS [[564]] Enrollment/Number of Patients: 209 [[564]] Duration: 24 weeks [[564]] Status/Outcome: Drug was associated with a 44% reduction in the mean cumulative number of active lesions (5.24 for the 0.3 mg dose versus 9.44 for placebo); no differences in relapses or disability were found between treatment groups [[564]]	Trial name: Benefit-Risk Assessment of Avonex and Laquinimod (BRAVO) (press release August 2011) [[810]] [[811]] [[817]] Phase: Phase III trial [[810]] Study Design: Company-sponsored, randomized, multicenter, double-blind, parallel-group, placebo-controlled trial designed to compare the effects of a daily oral dose of laquinimod (0.6 mg) versus placebo and compare risk-benefit profiles of laquinimod and interferon beta-1a (Avonex) (30 mcg intramuscular injection once weekly); the number of confirmed relapses is the primary outcome measure and the accumulation of physical disability is a secondary outcome measure [[810]] Disease Stage: RRMS [[810]] Enrollment/Number of Patients: 1331 [[810]] Duration: 2 years [[810]] Status/Outcome: Laquinimod was associated with a significant reduction (21.3%) in the annualized relapse rate (this reduction only became apparent after an imbalance between the placebo and treatment groups in baseline MRI characteristics was corrected) as well as reductions in the risk of disability progression and in loss of brain volume, whereas interferon beta-1a reduced relapse rates but did not appear to reduce the progression of disability or the loss of brain volume; additional analyses are ongoing as of August 2011 [[810]] [[817]]	Trial name: ALLEGRO extension study (conference report, March 2013) [[5362]] Phase: Extension of Phase III trial [[883]] [[5362]] Study Design: Company-sponsored, open-label extension study (in which all patients received laquinimod), which followed the 2-year double-blind ALLEGRO trial, to examine disability progression in patients who received a total of 36 months ("early-start") of laquinimod treatment versus those who only received laquinimod in the open-label phase ("delayed start") [[5362]] Disease Stage: RRMS [[5362]] Enrollment/Number of Patients: 839 (97% of the 864 who participated in the original study) began the extension phase and 735 have completed 1 year of the extension phase [[5362]] Duration: 1 year extension, 3 years total for the ALLEGRO trial [[5362]] Status/Outcome: Early-start patients displayed an 11.8% risk of confirmed disability progression as compared to 16.7% for delayed-start patients [[5362]] Trial name: Comi et al., Mult. Scler., November 2010 trial [[565]] Phase: Extension phase of Comi et al., Lancet, June 2008 trial [[823]] [[565]] Study Design: Company-sponsored, multinational, double-blind extension trial to determine if the findings from a previous Phase II trial, which examined the safety and efficacy of laquinimod, are sustainable; patients who received the 0.3 mg or 0.6 mg daily dose of laquinimod in the original study continued with the same dose and patients who received placebo in the original study were re-randomized to either the 0.3 mg or 0.6 mg dose [[565]] Disease Stage: RRMS [[565]] Enrollment/Number of Patients: 239 (from the previous Phase II trial), with 222 undergoing final scans [[565]] Duration: 36 weeks [[565]] Status/Outcome: Switching from placebo to the 0.3 mg or 0.6 mg dose was associated with a 52% decrease in the number of gadolinium-enhanced lesions; continuation of the 0.6 mg dose maintained the reduction in brain lesions seen in the original study [[565]] Trial name: An Open Label Extension of the LAQ/5062 and LAQ/5063 Studies to Assess the Long Term Safety and Tolerability of Laquinimod 0.6mg in RRMS Patients (ongoing as of February 13, 2012) [[808]] Phase: Extension phase of Comi et al., Lancet, June 2008 trial and Comi et al., Mult. Scler., November 2010 trial [[823]] [[808]] [[565]] Study Design: Company-sponsored, open-label extension trial to continue assessing the long-term safety and tolerability of laquinimod (primary outcome); all patients will receive 0.6 mg of oral laquinimod daily [[808]] Disease Stage: RRMS [[808]] Enrollment/Number of Patients: 211 (from the previous extension study) [[808]] [[565]] Duration: 3 years [[808]] Status/Outcome: Final data collection date for the primary outcome measure is December 2014; estimated study completion date is June 2015 [[808]]
Masitinib	Trial name: Masitinib in Patients with Progressive or Relapse-Free Secondary Multiple Sclerosis [[1382]] Phase: Phase III [[1381]] [[1382]] Study Design: Company-sponsored, prospective, multicenter, randomized, placebo-controlled study examining the safety and efficacy of drug (6 mg/kg/day) judged by changes in multiple sclerosis functional composite score (primary outcome) [[1382]] Disease Stage: PPMS or SPMS [[1381]] [[1382]] Enrollment/Number of Patients: Estimated enrollment 450 patients [[1381]] [[1382]] Duration: 96 weeks [[1381]] [[1382]] Status/Outcome: Recruiting patients; results expected after December, 2014 [[1382]] Trial name: Masitinib in Patients with Primary Progressive Multiple Sclerosis (PPMS) or Relapse-Free Secondary Multiple Sclerosis (SPMS) (Published June 2012) [[1383]] [[2122]] Phase: Phase II [[1383]] [[2122]] Study Design: Company-sponsored, randomized, placebo-controlled trial testing the safety and efficacy of two doses of drug (3 mg/kg/day and 6 mg/kg/day) as measured by changes in multiple sclerosis functional composite (MSFC) score (primary outcome) [[1383]] [[2122]] Disease Stage: PPMS or SPMS [[1383]] [[2122]] Enrollment/Number of Patients: 35 patients [[1383]] [[2122]] Duration: 12 months [[1383]] [[2122]] Status/Outcome: Out of 35 patients, 27 received drug and 8 received placebo. Of those, 7/17 assessable patients – 41% -- reported clinical response to treatment, but the response was not statistically significant: the change in MSFC score was +103% +/- 189 (drug) versus -60% +/- 190 (placebo) at month 12. The drug was also associated with a higher incidence of more severe adverse events [[1383]] [[2122]]
Mitoxantrone	Trial name: Hartung et al., Lancet, Dec 2002 trial [[515]] Phase: Phase III trial [[515]] Study Design: Randomized, double-blind, placebo-controlled, multicenter trial to test the efficacy of mitoxantrone (5mg/m² or 12mg/m² intravenously every 3 months for 24 months), with the primary outcome a multivariate analysis of five clinical measures (change in expanded disability status scale, change in ambulation index, adjusted total number of treated relapses, time to first treated relapse, and change in standardised neurological status), comparing the 12mg/m² and placebo groups [[515]] Disease Stage: Worsening RRMS (also known as progressive relapsing MS) or SPMS [[515]] Enrollment/Number of Patients: 194 enrolled, with 184 in the final analysis [[515]] Duration: 2 years [[515]] Status/Outcome: Drug (12mg/m² dose) was associated with an overall benefit in the multivariate analysis of five clinical measures (0.30 difference overall) [[515]] Trial name: Millefiorini et al., J. Neurol., Mar 1997 trial [[517]] Phase: Phase II trial [[517]] Study Design: Randomized, placebo-controlled, multicenter trial to determine the clinical efficacy of mitoxantrone (intravenous infusion of 8 mg/m² every month for 1 year), with the primary outcome disease progression and the secondary endpoints the growth and appearance of new brain lesions [[517]] Disease Stage: RRMS [[517]] Enrollment/Number of Patients: 51 enrolled, with 42 completing the MRI examinations [[517]] Duration: 2 years [[517]] Status/Outcome: Drug decreased the proportion of patients who showed confirmed disease progression, defined as a one point increase on the Kurtzke expanded disability scale (EDSS), but was not associated with a statistically significant benefit in the mean EDSS progression; drug reduced the mean number of brain lesions [[517]]	Trial name: Edan et al., J. Neurol. Neurosurg. Psychiatry, Dec 2011 trial [[509]] Phase: Phase IV trial [[509]] Study Design: Randomized, two-arm controlled trial to compare the effects of mitoxantrone [12 mg/m² (maximum 20 mg) monthly] combined with methylprednisolone (1 g intravenously each month for 6 months) followed 3 months later by interferon beta-1b (250 ug subcutaneously every other day for 27 months) or methylprednisolone (1 g intravenously each month during the first 6 months) and interferon beta-1b (250 ug every other day for 36 months), with the primary endpoint the time to worsen by one point on the expanded disability status scale (confirmed at 3 months) and the secondary endpoints the relapse rate and accumulation of new lesions [[509]] Disease Stage: Aggressive RRMS [[509]] Enrollment/Number of Patients: 109 [[509]] Duration: 3 years [[509]] Status/Outcome: Mitoxantrone delayed disability by 18 months, as measured by the time to worsen by at least one point on the expanded disability status scale, and reduced the relapse rate, reduced the number of gadolinium-enhancing lesions, and slowed the accumulation of new T2 lesions [[509]] Trial name: Vollmer et al., Mult. Schler., June 2008 trial [[524]] Phase: Phase II trial [[919]][[524]] Study Design: Multicenter, randomized, single-blind trial to compare the effects of glatiramer acetate (daily subcutaneous injections of 20 mg for 15 months) alone or mitoxantrone (monthly 12 mg/m² infusions for 3 months) followed by glatiramer acetate (daily subcutaneous injections of 20 mg for 12 months), with the primary outcome measure the incidence of adverse events and the secondary measures the number of gadolinium-enhancing lesions, the number of confirmed relapses, and changes in the expanded disability status scale [[524]] Disease Stage: RRMS [[524]] Enrollment/Number of Patients: 40 [[524]] Duration: 15 months [[524]] Status/Outcome: Both treatments were well tolerated; combination therapy was associated with an 89% greater reduction in the number of gadolinium-enhancing lesions at 6 and 9 months, a 70% reduction at 12 and 15 months, and a reduction in the mean relapse rate as compared to glatiramer acetate alone [[524]][[525]] 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 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 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: Chanvillard et al., PLoS One, June 2012 study [[2379]] Phase: Open-label study [[2379]] Study Design: Prospective, monocentric, single-arm, open-label study (partly funded by industry) to analyze the effects of mitoxantrone on immunological parameters; the treatment regime was 12 mg per m2 of body surface area given intravenously every three months, up to a cumulative dose of 140 mg per m2, unless reductions were required because of side effects [[2379]] Disease Stage: SPMS [[2379]] Enrollment/Number of Patients: 19 patients were screened, 15 patients enrolled, and 12 patients completed the study [[2379]] Duration: 12 months [[2379]] Status/Outcome: Mitoxantrone persistently suppressed B cells, enriched neutrophils and immunomodulatory CD8(low) T cells, and promoted natural killer (NK) cell enrichment and NK cell maturation; the drug-induced NK cell maturation occurred only in patients who responded to treatment [[2379]]
Mycophenolate Mofetil	Trial name: TIME-MS (Safety Study of Combination Therapy with Intramuscular Avonex and Oral CellCept in Patients with Multiple Sclerosis) (published in 2010) [[425]] [[599]] Phase: Phase II [[425]] [[599]] Study Design: A company-sponsored, randomized, double-blind, placebo-controlled, trial to characterize the adverse events (primary endpoint) of combining CellCept with interferon beta-1a [[425]] [[599]] Disease Stage: RRMS [[425]] [[599]] Enrollment/Number of Patients: 24 treatment-naïve patients [[425]] [[599]] Duration: 1 year [[425]] [[599]] Status/Outcome: No differences between experimental and control groups in terms of patient-reported adverse events, MRI metrics, or laboratory abnormalities, and appeared to be a trend towards therapeutic effect [[425]] [[599]]	Trial name: Frohman et al, Ther Adv Neurol Disord, 2010 [[424]] Phase: Pilot study [[424]] Study Design: Randomized, blinded, parallel-group, multicenter pilot trial comparing the reduction of cumulative mean number of lesions (primary outcome measure) promoted by CellCept versus interferon beta-1a [[424]] Disease Stage: RRMS [[424]] Enrollment/Number of Patients: Enrolled 35 previously untreated patients; 31 completed the trial [[424]] Duration: 6 months [[424]] Status/Outcome: Patients treated with CellCept showed a trend towards a lower accumulation of lesions compared to those treated with interferon beta-1a [[424]]	Trial name: Michel et al., ECTRIMS abstract, 2011 study [[601]] Phase: Retrospective medical record review [[601]] Study Design: Multicenter, retrospective study of all patients treated with the mycophenolate mofetil at three French MS centers, including those who had previously received other immunosuppressive drugs and those who had not, to determine the drug’s efficacy as a monotherapy (judged by annualized relapse rate) [[601]] Disease Stage: Not noted [[601]] Enrollment/Number of Patients: 362 patients included, treatment was stopped in 126 patients [[601]] Duration: 23.7 +/- 20.3 months [[601]] Status/Outcome: Annualized relapse rate fell significantly after treatment, from 0.92 +/- 0.96 to 0.37 +/- 0.72 in previously untreated patients, and similarly with patients previously treated with immunosuppressive drugs; 10.2% of patients experienced adverse events [[601]] Trial name: Vermersch et al., Eur. J Neurol. 2007 trial [[453]] Phase: Pilot study [[453]] Study Design: Company-sponsored, open-label, single-center, non-randomized pilot study examining the effect on disease activity as measured by MRI (primary endpoint) and safety and tolerance of drug combined with interferon beta-1a [[453]] Disease Stage: RRMS [[453]] Enrollment/Number of Patients: 30 enrolled, 28 completed study [[453]] Duration: 6 months [[453]] Status/Outcome: No significant adverse events; drug caused a decrease in Gadolinium-enhanced lesions, annualized relapse rate, and disability score [[453]] Trial name: Frohman et al., Clin Neuropharm, March-April 2004 trial [[457]] Phase: Retrospective medical record review [[457]] Study Design: Retrospective surveillance study [[457]] Disease Stage: 61 patients with SPMS, 14 with RRMS, 4 with PPMS [[457]] Enrollment/Number of Patients: Followed 79 patients (44 already on interferon beta , 20 already on glatiramer acetate, 15 on monotherapy); 22 stopped treatment due to side effects, continued disease progression, or lack of insurance coverage [[457]] Duration: One year [[457]] Status/Outcome: Treatment appeared to be well-tolerated and several patients seemed to stabilize or improve [[457]]
Natalizumab	Trial name: Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) (publ 2006; additional analyses publ 2011, 2013) [[391]] [[4545]] [[4443]] Phase: Phase III trial [[391]] Study Design: Multinational, randomized, placebo-controlled trial to study the efficacy and safety of natalizumab (300 mg, intravenous infusion every 4 weeks), with the primary endpoint at one year being the rate of clinical relapse and the primary endpoint at two years the cumulative probability of sustained progression of disability, measured by the Expanded Disability Status Scale (EDSS) [[391]] Disease Stage: RRMS [[391]] Enrollment/Number of Patients: 942 [[391]] Duration: More than 2 years [[391]] Status/Outcome: Drug reduced the rate of clinical relapse by 68% at one year, the risk of sustained progression of disabilty by 42% over two years, and the accumulation of lesions over two years by 83% [[391]]; post hoc analysis showed that natalizumab increased the cumulative probability of improvement in EDSS scores (which correlated with quality of life measurements) by 69% [[4545]]; additional analysis showed that natalizumab rapidly reduced the annualized relapse rate (within 3 months) overall (0.30 versus 0.71 for placebo), even in patients with highly active disease (0.30 versus 0.94) [[4443]] Trial name: Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) (publ 2006) [[390]] Phase: Phase III trial [[390]] Study Design: Multinational, randomized, double-blind, placebo-controlled, parallel-group trial to determine if natalizumab (300 mg intravenously every 4 weeks) together with interferon beta-1a (30 microg intramuscularly every week) is more effective than interferon beta-1a alone in reducing breakthrough disease activity in patients who had received interferon beta-1a treatment for at least 12 months before randomization in study (with at least one relapse in the 12 months before randomization), with the rate of clinical relapse at 1 year and the cumulative probabilty of disability progression at 2 years the primary end points [[390]] Disease Stage: RRMS [[390]] Enrollment/Number of Patients: 1171, with 1003 completing the study [[390]] Duration: 2 years [[390]] Status/Outcome: Combination therapy was associated with a 23% cumulative probability of sustained disability progression at 2 years versus 29% with interferon beta-1a alone; combination therapy reduced the risk of sustained disability progression by 24% and reduced the annualized rate of relapse by 54% (at 1 year) and 55% (at 2 years) as compared to interferon beta-1a alone; trial was stopped 1 month early because of two cases of progressive multifocal leukoencephalopathy, one of which was fatal [[390]] Trial name: Miller et al., N. Engl. J. Med., Jan 2003 trial [[397]] Phase: Phase II trial [[397]] [[4535]] Study Design: Company-sponsored, multinational, randomized, placebo-controlled trial to test the efficacy of natalizumab (3 mg or 6 mg per kg of body weight every 28 days, by intravenous infusion) in reducing the number of new gadolinium-enhancing brain lesions (primary end point) [[397]] Disease Stage: RRMS or SPMS [[397]] Enrollment/Number of Patients: 213 [[397]] Duration: 6 months [[397]] Status/Outcome: Drug reduced the mean number of new inflammatory brain lesions per patient [such that there were 0.7 (3 mg dose) and 1.1 (6 mg dose) versus 9.6 (placebo)] and reduced the number of relapses [[397]] Trial name: Tubridy et al., Neurology, Aug 1999 trial [[405]] Phase: Phase II trial [[405]] Study Design: Randomized, double-blind, placebo-controlled trial to study the effect of natalizumab (two intravenous infusions 4 weeks apart) on brain lesions (followed up for 24 weeks), as measured by MRI [[405]] Disease Stage: RRMS and SPMS [[405]] Enrollment/Number of Patients: 72 [[405]] Duration: 28 weeks [[405]] Status/Outcome: Drug was associated with fewer new active lesions per patient (mean 1.8 versus 3.6 for placebo) in the first 12 weeks of followup, but no difference was seen in the second 12 weeks [[405]] Trial name: Sheremata et al., Neurology, Mar 1999 trial (publ 1999) [[406]] Phase: Phase I trial [[406]] Study Design: Randomized, placebo-controlled, five-level dose escalation study to examine the safety, tolerability, and pharmacokinetics of a single intravenous dose of natalizumab (0.03 to 3.0 mg per kg) [[406]] Disease Stage: RRMS and SPMS [[406]] Enrollment/Number of Patients: 28 [[406]] Duration: 8 weeks [[406]] Status/Outcome: All doses were found to be safe and serum concentrations of drug (after infusion of 1 to 3 mg per kg) were detectable for 3 to 8 weeks [[406]]	Trial name: Rinaldi et al., Mult. Scler., May 2012 trial [[1697]] Phase: Postmarketing [[1697]] Study Design: Prospective study to determine the efficacy of natalizumab versus interferon beta-1a or glatiramer acetate in reducing the accumulation of new cortical lesions [[1697]] Disease Stage: RRMS [[1697]] Enrollment/Number of Patients: 120 [[1697]] Duration: 2 years [[1697]] Status/Outcome: Natalizumab reduced the accumulation of new cortical lesions and the progression of cortical atrophy as compared to interferon beta-1a, glatiramer acetate, or no treatment [[1697]]	Trial name: Jokubaitis et al., PLoS One, March 2013 study [[5370]] Phase: Prospective cohort study [[5370]] Study Design: Multicenter Australian cohort study using the MSBase platform to characterize use of disease-modifying therapies (DMTs, which included interferon beta, glatiramer acetate, and natalizumab); specifically, treatment persistence, factors that predict treatment discontinuation, and rates of switching between DMTs were studied [[5370]] Disease Stage: RRMS [[5370]] Enrollment/Number of Patients: 1113 [[5370]] Duration: 4.2 years (median time patients were followed) [[5370]] Status/Outcome: Treatment persistence in this study was short, such that patients remained on their first DMT for 2.5 years (median) and on their next DMT for 2.3 years; annualized switch or cessation rates were 9.5 to 12.5% (interferon beta), 11.6% (glatiramer acetate), and 4.4% (natalizumab); younger age and higher disability scores predicted DMT discontinuation [[5370]] Trial name: Comparison of Patients Treated with Natalizumab and Interferon-Beta/Glatiramer Using Propensity-Matched Multiple Sclerosis Registry Data (press release, 18 March 2013) [[5315]] Phase: Retrospective medical record review [[5315]] Study Design: Data from two MS patient registries [TYSABRI Observational Program (TOP) and MSCOMET] were used in a propensity-matched analysis to compare the effects of natalizumab, interferon beta, and glatiramer acetate on relapses [[5315]] Disease Stage: MS [[5315]] Enrollment/Number of Patients: N/A [[5315]] Duration: N/A [[5315]] Status/Outcome: Natalizumab was associated with a lower rate of first relapse as compared to interferon beta and glatiramer acetate; relapses in patients treated with natalizumab also occurred more slowly than in those treated with the other drugs [[5315]] Trial name: Sargento-Freitas et al., J. Clin. Neurosci., February 2013 study [[5251]] Phase: Observational/open-label study [[5251]] Study Design: Study to determine the factors that predict the best clinical response to natalizumab, in patients who had received treatment for at least 12 months; optimal responders were defined as those who exhibited a reduction in the Expanded Disability Status Scale (EDSS) score of ≥1 point or a reduction in the annualized relapse rate (ARR) of >1 [[5251]] Disease Stage: MS [[5251]] Enrollment/Number of Patients: 48 [[5251]] Duration: At least 12 months of treatment [[5251]] Status/Outcome: Factors linked with an optimal response to natalizumab were (i) an ARR ≥2 in the previous year, (ii) age ≤37.5 years at the time of first drug administration, (iii) an EDSS score at baseline of ≤4.5, (iv) disease duration ≤9.5 years, and (v) a progressive phase of ≤4.5 years (in patients with SPMS), whereas initial disease characteristics did not influence responsiveness [[5251]] Trial name: Kornek et al., JAMA Neurol., February 2013 study [[4993]] Phase: Retrospective analysis [[4993]] Study Design: Study to examine the effects of natalizumab (300 mg every 4 weeks) in pediatric patients who began such treatment before 18 years of age, with main outcome measures that included annualized relapse rates (ARRs), Expanded Disability Status Scale (EDSS) scores, and MRI measures [[4993]] Disease Stage: Highly active pediatric MS [[4993]] Enrollment/Number of Patients: 20 [[4993]] Duration: 20 months (mean treatment duration) [[5086]] Status/Outcome: Treatment was linked with decreases in the mean ARR (3.7 without treatment versus 0.4 with treatment), the median EDSS scores (2 without treatment versus 1 with treatment), and the mean number of new lesions detected by MRI (specifically, T2/fluid attenuated inversion recovery lesions) per year (7.8 before treatment versus 0.5 with treatment); thus, natalizumab treatment might be safe and effective in pediatric patients, although some adverse clinical effects were seen [[4993]] Trial name: Ghezzi et al., Mult. Scler., February 2013 study [[4922]] Phase: Observational/open-label study [[4922]] Study Design: Non-sponsored, prospective, cooperative study to examine the long-term effects of natalizumab (300 mg, given intravenously every 4 weeks) in pediatric MS patients (mean age, 14.4 years) [[4922]] Disease Stage: Active MS [[4922]] Enrollment/Number of Patients: 55 [[4922]] Duration: Median, 104 weeks (26 infusions) [[4922]] Status/Outcome: All patients tolerated natalizumab well and the majority experienced strong suppression of disease activity; over the course of treatment, the mean Expanded Disability Status Scale score decreased from 2.7 to 1.9 and most patients were free from MRI activity during the followup [[4922]] Trial name: Sempere et al., Acta Neurol. Scand., January 2013 trial [[4662]] Phase: Observational/open-label study [[4662]] Study Design: Observational study to examine the effects of switching from natalizumab (after treatment of more than 1 year) to fingolimod in JC virus-positive patients; after natalizumab withdrawal, patients received methylprednisolone for 3 months followed by oral fingolimod (0.5 mg) daily [[4662]] Disease Stage: RRMS [[4662]] Enrollment/Number of Patients: 8 JC virus-positive patients who switched drugs and 9 JC virus-negative patients who did not switch [[4662]] Duration: Patients received fingolimod for 4 to 12 months (mean, 9 months); patients who continued receiving natalizumab had a mean followup time of 13 months [[4662]] Status/Outcome: Disease reactivation occurred in patients who switched drugs, with 63% having clinical relapses and 75% showing MRI activity, whereas neither activity was observed in patients who remained on natalizumab [[4662]] Trial name: Cadavid et al., PLoS One, January 2013 study [[4535]] Phase: Retrospective trial review [[4535]] Study Design: Company-sponsored retrospective review of clinical trial results to determine the effects of natalizumab or interferon beta-1a on ambulatory function, as measured by a timed 25-foot walk, in subjects with an Expanded Disability Status Scale score ≥3.5; a response was defined as a faster walking time relative to the predose walking time over different treatment periods (6-9 months or 24-30 months) [[4535]] Disease Stage: RRMS and SPMS [[4535]] Enrollment/Number of Patients: N/A [[4535]] Duration: N/A [[4535]] Status/Outcome: More (2-4 times as many) disabled patients showed a response in the timed 25-foot walk in the natalizumab groups than in the placebo or interferon beta-1a groups; responders were 24%-45% faster than those who did not respond; natalizumab appears to improve walking function in RRMS and potentially in SPMS [[4535]] Trial name: Stephenson et al., Health Qual. Life Outcomes, December 2012 study [[4365]] Phase: Observational study [[4365]] Study Design: Longitudinal study to determine the effect of natalizumab on patient-reported outcomes, including the ability to carry out daily activities, cognitive functioning, fatigue, and disability level, in a real-world setting [[4365]] Disease Stage: RRMS [[4365]] Enrollment/Number of Patients: 333 [[4365]] Duration: 12 months [[4365]] Status/Outcome: Drug was associated with positive patient-reported outcomes (no further decline or an improvement) in all assessed measures in 69% to 88% of patients [[4365]] Trial name: Yousry et al., Ann. Neurol., November 2012 study [[4391]] Phase: Retrospective review [[4391]] Study Design: Review of MRIs from natalizumab-treated patients with progressive multifocal leukoencephalopathy (PML) to define characteristic MRI patterns of PML, to help in the screening for and early diagnosis of PML [[4391]] Disease Stage: MS patients diagnosed with PML in the postmarketing setting [[4391]] Enrollment/Number of Patients: 22 [[4391]] Duration: N/A [[4391]] Status/Outcome: Large, subcortical lesions of several types represented the most frequent lesion pattern in early MRI scans from patients with PML [[4391]] Trial name: Natalizumab Treatment of Progressive Multiple Sclerosis (NAPMS) (meeting presentation, October 2012) [[3772]] [[3773]] Phase: Phase IIa trial [[3772]] [[3773]] Study Design: University hospital-sponsored, open-label, proof-of-concept, single-group assignment trial to study the safety and efficacy of natalizumab in PPMS and SPMS; the trial aims to examine the effect on central nervous system inflammation [by measuring the change in osteopontin levels in cerebrospinal fluid (primary outcome measure)], as well as effects on the expanded disability status scale score, brain volume, and brain lesions (secondary outcome measures) [[3772]] Disease Stage: PPMS and SPMS [[3772]] [[3773]] Enrollment/Number of Patients: 24 [[3772]] Duration: 60 weeks [[3772]] Status/Outcome: Drug reduced inflammation, axonal damage, and demyelination in 17 progressive MS patients (meeting presentation, October 2012) [[3773]] Trial name: Portaccio et al., Eur. J. Neurol., October 2012 study [[3453]] Phase: Pilot study [[3453]] Study Design: Prospective, non-randomized, pilot study to examine the possible benefits of natalizumab versus interferon beta on cognitive changes [[3453]] Disease Stage: RRMS [[3453]] Enrollment/Number of Patients: 26; 12 were treated with natalizumab and 14 with interferon beta [[3453]] Duration: 1.5 years (mean follow-up time) [[3453]] Status/Outcome: Natalizumab treatment was associated with a significantly lower mean number of neuropsychological tests that indicated deteriorating performance, and a significantly lower percentage brain volume change, than was interferon beta treatment, suggesting that natalizumab might help cognitive function by reducing brain atrophy [[3453]] Trial name: TYSABRI Observational Program (TOP) (press release, 11 October 2012; publ of analyses, 2013) [[3589]] [[4443]] Phase: Post-marketing observational study [[3589]] Study Design: Industry-sponsored program to study the long-term safety and efficacy of natalizumab, as well as disease activity and associations between treatment history at baseline and annualized relapse rate (ARR) post baseline in patients treated with natalizumab [[3589]] Disease Stage: RRMS [[3589]] Enrollment/Number of Patients: 4434 (as of 1 June 2012) [[3589]] Duration: 5 years [[3595]] Status/Outcome: Previously treatment-naïve patients (versus previously treated patients), as well as patients with Extended Disability Status Scale scores less than 3.0 at baseline, displayed lower ARRs; serious adverse events were consistent with the known safety profile of this drug [[3589]]; additional analysis showed that natalizumab rapidly reduced the annualized relapse rate (within 3 months) (0.26 for 0-3 months versus 1.99 at baseline) [[4443]] Trial name: TYNERGY trial (press release, 11 October 2012; publ 21 March 2013) [[3589]] [[5491]] Phase: Observational study [[3589]] [[5491]] Study Design: Industry-sponsored, multicenter, single-arm, non-randomized, open-label, prospective, observational study to evaluate changes in MS-related fatigue during natalizumab treatment in patients who were natalizumab treatment-naïve at baseline [[3589]] [[3596]]; the Fatigue Scale for Motor and Cognitive functions questionnaire was used to evaluate fatigue at baseline and after 12 months of treatment [[5491]] Disease Stage: RRMS [[3589]] Enrollment/Number of Patients: 195 [[5491]] Duration: 12 months [[3589]] [[5491]] Status/Outcome: Drug may ameliorate fatigue related to MS; the measured variables (fatigue score, quality of life, sleepiness, depression, cognition, disability progression, and walking speed) all improved after 1 year of natalizumab treatment [[3589]] [[5491]] Trial name: Mellergård et al., PLoS One, September 2012 study [[3310]] Phase: Observational study [[3310]] Study Design: Study that aimed (i) to examine changes in metabolites in normal appearing white matter (NAWM) during natalizumab treatment (300 mg given intravenously once per month), as determined by using quantitative proton magnetic resonance spectroscopy (1H-MRS) to detect such metabolites, and (ii) to examine associations between changes in these 1H-MRS-detected metabolites and markers of ongoing inflammation in the cerebrospinal fluid (CSF) [[3310]] Disease Stage: Relapsing MS [[3310]] Enrollment/Number of Patients: 27 MS patients enrolled (with 25 providing CSF samples); 20 healthy controls [[3310]] Duration: 1 year [[3310]] Status/Outcome: Group levels of 1H-MRS-detected metabolite concentrations did not change between pre- and posttreatment periods, but there were correlations between changes in the concentrations of individual 1H-MRS-detected metabolites (total creatine and total choline) and levels of the pro-inflammatory markers interleukin-1 beta and CXCL8 in CSF, such that high levels of those markers were associated with an increase in the metabolites, indicating the ongoing development of gliosis and membrane turnover in NAWM [[3310]] Trial name: Arnal-Garcia et al., Eur. J. Paediatr. Neurol., September 2012 study [[3295]] Phase: Retrospective medical record review [[3295]] Study Design: Study to analyze the safety and effficacy of natalizumab (300 mg given as a monthly infusion, except in one patient who received 150 mg per month) in pediatric patients (mean age, 15 years) [[3295]] Disease Stage: RRMS [[3295]] Enrollment/Number of Patients: 9 [[3295]] Duration: Varied, with patients receiving a median of 17 natalizumab infusions [[3295]] Status/Outcome: Three patients experienced at least one adverse drug reaction; for patients receiving at least 12 infusions, the median annualized relapse rate decreased from 3.0 to 0 and the Expanded Disability Status Scale score decreased from 3.0 to 1.0; as such, the safety and efficacy of natalizumab in the pediatric patients was similar to that in adult patients [[3295]] Trial name: Wickström et al., Mult. Scler., September 2012 study [[3263]] Phase: Observational study [[3263]] Study Design: Study to examine the effects of natalizumab on the ability to work [[3263]] Disease Stage: MS [[3263]] Enrollment/Number of Patients: All MS patients in Sweden who began natalizumab treatment between June 2007 and May 2008 [[3263]] Duration: 1 year [[3263]] Status/Outcome: In relation to patients' total employment rate, natalizumab approximately doubled their working ability; a positive effect was more likely in those with short disease duration, younger age, and a lower Expanded Disability Status Scale score when treatment began [[3263]] Trial name: Prosperini et al., J. Neurol. Sci., September 2012 study [[3260]] Phase: Observational study [[3260]] Study Design: Study that aimed to identify baseline predictors of natalizumab response; clinical and MRI data were prospectively collected from patients treated with natalizumab who were then followed and ranked according to their responses to the drug [[3260]] Disease Stage: RRMS [[3260]] Enrollment/Number of Patients: 210 [[3260]] Duration: 24 months [[3260]] Status/Outcome: After 24 months, 57.1% of patients were full responders to natalizumab [no relapses, no worsening of disability on the Expanded Disability Status Scale (EDSS), no MRI activity], 17.1% were partial responders (MRI activity, but no relapses and/or worsening of EDSS score), and 25.8% were poor responders (relapses and/or worsening of EDSS score); a full response was more likely in patients with ≤2 relapses in the year before treatment started and in those with an EDSS score ≤2.5 at baseline [[3260]] Trial name: Lu et al., Neurology, Aug 2012 study [[2959]] Phase: Retrospective literature review [[2959]] Study Design: Systematic review of the literature for information about the effects of interferon beta, glatiramer acetate, or natalizumab on the offspring of MS patients who used these disease-modifying drugs (DMDs) during pregnancy [[2959]] Disease Stage: MS [[2959]] Enrollment/Number of Patients: 35 natalizumab-exposed pregnancies were identified [[2959]] Duration: N/A [[2959]] Status/Outcome: Natalizumab exposure during pregnancy was not associated with reduced mean birth length or weight or lower mean gestational age, but discontinuing DMD use before conception continues to be recommended [[2959]] Trial name: Bloomgren et al., N. Engl. J. Med., May 2012 study [[1821]] Phase: Retrospective medical record review [[1821]] Study Design: Company-funded, retrospective review to quantify risk factors for progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment; factors considered were (i) the presence of anti JC-virus antibodies (JC, or John Cunningham, virus is present in many people; it causes diseases such as PML only with immunodeficiency or immunosuppression), (ii) previous use of immunosuppressants, and (iii) duration of natalizumab treatment [[1821]] Disease Stage: MS patients treated with natalizumab [[1821]] Enrollment/Number of Patients: 99,571 patients treated with natalizumab; blood samples were available from 5896 MS patients and from 54 MS patients treated with natalizumab who developed PML later [[1821]] Duration: Duration of treatment was classified as either 1 to 24 months or 25 to 48 months [[1821]] Status/Outcome: 212 confirmed cases of PML had occurred in 99,571 patients treated with natalizumab as of 29 Feb 2012 (2.1 cases per 1000 patients), and the 54 PML patients for whom blood samples were available all were positive for anti-JC antibodies; overall, the presence of anti-JC antibodies, use of immunosuppressants before natalizumab treatment, and 25 to 48 months of natalizumab treatment were associated with the greatest estimated risk of PML (11.1 cases per 1000 patients) [[1821]] Trial name: Trampe et al., Neurology, May 2012 study [[1815]] Phase: Retrospective medical record review [[1815]] Study Design: Blinded, retrospective cross-sectional and longitudinal analysis to assess anti-JC virus antibody status before diagnosis of progressive multifocal leukoencephalopathy (PML) (JC, or John Cunningham, virus is present in many people; it causes diseases such as PML only with immunodeficiency or immunosuppression) [[1815]] Disease Stage: MS patients treated with natalizumab [[1815]] Enrollment/Number of Patients: 2253 patients [[1815]] Duration: N/A [[1815]] Status/Outcome: 58.8% of patients treated with natalizumab tested positive for anti-JC virus antibodies; 9.8% of patients converted from negative to positive over 7.7 months and 4.7% converted from positive to negative over 7.9 months; in general, antibody levels were low; and all samples from the 10 patients who developed PML were positive and antibody levels in these samples were higher than in antibody-positive samples from patients who did not develop PML [[1815]] Trial name: Del Santo et al., Eur. J. Clin. Pharmacol., April 2012 study [[2482]] Phase: Retrospective trial review [[2482]] Study Design: Review of 10 randomized trials that tested interferon, glatiramer acetate, natalizumab, or fingolimod in RRMS, such that the relapse-free rates at 12 months were compared, either directly or through network meta-analysis [[2482]] Disease Stage: RRMS [[2482]] Enrollment/Number of Patients: N/A [[2482]] Duration: N/A [[2482]] Status/Outcome: Fingolimod was determined to have the most favorable profile with respect to relapse-free rate at the follow-up assessment at 1 year [[2482]] Trial name: Ghezzi et al., Neurology, Sept 2010 trial [[349]] Phase: Observational/open-label study [[349]] Study Design: Study to examine the effects of natalizumab (300 mg every 28 days, with a mean treatment period of 15.2 months) in children (younger than 18 years) with active MS [[349]] Disease Stage: Active MS [[349]] Enrollment/Number of Patients: 19 [[349]] Duration: Mean treatment period, 15.2 months [[349]] Status/Outcome: Drug suppressed disease activity, such that the median Expanded Disability Status Scale decreased from 2.5 to 2.0 [[349]]
Ocrelizumab	Trial name: A Study of Ocrelizumab in Patients with Primary Progressive Multiple Sclerosis (ORATORIO) [[655]] [[879]] Phase: Phase III trial [[655]] Study Design: Company-funded, randomized, parallel-group, multi-center, multi-national placebo-controlled study evaluating efficacy of ocrelizumab on delaying progression of disability (primary endpoint) [[655]] Disease Stage: PPMS [[655]] Enrollment/Number of Patients: Estimated enrollment 630 patients [[655]] Duration: 120 weeks to 5.5 years[[655]] Status/Outcome: Recruitment began September 2011 [[655]]	Trial name: A Study of Ocrelizumab in Comparison with Interferon Beta 1a (Rebif) in Patients with Relapsing Multiple Sclerosis (OPERA I) [[875]] [[879]] Phase: Phase III trial [[875]] Study Design: Company-funded, randomized, double-blind, double-dummy parallel-group, multicenter, multinational study comparing the effect of ocrelizumab (600 mg) to interferon beta-1a on annualized relapse rate (primary endpoint) [[875]] Disease Stage: RRMS [[875]] Enrollment/Number of Patients: Estimated enrollment 800 patients [[875]] Duration: 96 weeks [[875]] Status/Outcome: Recruitment began in September 2011; results are expected in February 2015 [[875]] Trial name: A Study of Ocrelizumab in Comparison with Interferon Beta 1a (Rebif) in Patients with Relapsing Multiple Sclerosis (OPERA II) [[876]] [[879]] Phase: Phase III trial [[876]] Study Design: Company-funded, randomized, double-blind, double-dummy parallel-group, multicenter, multinational study comparing the effect of ocrelizumab (600 mg) to interferon beta-1a on annualized relapse rate (primary endpoint) [[876]] Disease Stage: RRMS [[876]] Enrollment/Number of Patients: Estimated enrollment 800 patients [[876]] Duration: 96 weeks [[876]] Status/Outcome: Recruitment began in August 2011; results are expected in February 2015 [[876]] Trial name: Kappos et al., Lancet, November 2011 trial [[878]] [[5528]] Phase: Phase II trial [[878]] [[879]] [[5528]] Study Design: Company-funded, multicenter, randomized, parallel, double-blind, placebo-controlled trial to test the efficacy and safety of low-dose (600 mg) or high-dose (2000 mg) ocrelizumab, given in two doses on day 1 and day 15, versus interferon beta-1a (30 microg one time per week, intramuscularly); the primary outcome measure was the total number of gadolinium-enhancing T1 lesions at weeks 12, 16, 20, and 24 [[878]] [[879]] [[5528]] Disease Stage: RRMS [[878]] [[879]] [[5528]] Enrollment/Number of Patients: 220 patients [[879]] [[5528]] Duration: Initial phase, 24 weeks [[5528]] Status/Outcome: At 24 weeks, the 600 mg dose of ocrelizumab was associated with an 89% reduction in the number of gadolinium-enhancing lesions as compared to placebo, and the 2000 mg dose a 96% reduction; both doses reduced the number of lesions better than interferon beta-1a [[5528]]	Trial name: Extension of Kappos et al., Lancet, November 2011 trial; meeting report, March 2013 [[5528]] [[5513]] Phase: Extension of Phase II trial [[5513]] Study Design: Patients originally received placebo, low-dose (600 mg), or high-dose (2000 mg) ocrelizumab, given in two doses on day 1 and day 15, or interferon beta-1a (30 microg one time per week, intramuscularly); from week 24 through 72, patients who had received placebo, interferon beta-1a, or 600 mg ocrelizumab were given 600 mg ocrelizumab every 24 weeks, whereas those who had received 2000 mg ocrelizumab were given 1000 mg every 24 weeks; from week 73 to 96, all patients were given the 600 mg per 24 weeks dose; for the final 48 weeks, no drug was given [[5528]] [[5513]] Disease Stage: RRMS [[5513]] Enrollment/Number of Patients: Of the original 218 patients, 168 remained in the study for the full 144 weeks [[5513]] Duration: 144 weeks [[5513]] Status/Outcome: Gadolinium-enhancing lesion numbers were reduced to zero by week 48, and stayed at zero through week 120, in the patients receiving either dose of ocrelizumab (from mean levels of 1.5 to 4 in the four original groups of patients); lesion number rose to a mean of 0.3 in the final scan; adjusted annualized relapse rates, weeks 96 to 144, were as follows: 0.116 (original placebo group); 0.082 (original low-dose ocrelizumab group); 0.352 (original high-dose ocrelizumab group); 0.076 (original interferon beta-1a group) [[5513]]
Ofatumumab	Trial name: Ofatumumab Dose-finding in RRMS Patients, part A (interim data reported September 2010) [[648]] [[649]] [[650]] Phase: Phase I/ II [[648]] Study Design: Company-funded, randomized, parallel-group, multi-center, multi-national placebo-controlled study evaluating effect of three doses (100mg, 300mg, and 700mg) of ofatumumab on lesion number (primary endpoint) [[648]] [[649]] [[650]] Disease Stage: RRMS [[648]] [[649]] [[650]] Enrollment/Number of Patients: 38 patients in part A; 288 patients expected in part B [[648]] [[649]] [[650]] Duration: 24 weeks part A; 48 weeks part B [[648]] [[649]] [[650]] Status/Outcome: The drug was associated with reduction in gadolinium-enhancing lesions and raised no dose-related or other safety concerns in patients followed for 48 weeks (Part A) [[649]]; part B data expected in September, 2012 [[648]] Trial name: Ofatumumab Subcutaneous Administration in Subjects With Relapsiing-Remitting Multiple Sclerosis (MIRROR) [[651]] Phase: Phase II [[651]] Study Design: Company-funded, randomized, double-blind, parallel-group, placebo-controlled multi-center, multi-national study evaluating efficacy of ofatumumab as measured by cumulative number of Gadolinium-enhancing lesions (primary endpoint) [[651]] Disease Stage: RRMS [[651]] Enrollment/Number of Patients: Estimated enrollment 196 patients [[651]] Duration: 24 weeks [[651]] Status/Outcome: Estimated study completion date October 2014 [[651]]
ONO-4641	Trial name: DreaMS (Drug Research Evaluation for Multiple Sclerosis) (reported April 2012) [[626]][[627]] Phase: Phase II [[627]][[2754]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multicenter, multinational study examining the effect of three doses of ONO-4641 on total number of gadolinium-enhanced lesions measured every 4 weeks (primary endpoint) [[627]] Disease Stage: RRMS [[627]][[2754]] Enrollment/Number of Patients: 407 patients [[2754]] Duration: 26 weeks [[627]][[2754]] Status/Outcome: Patients given taking 0.05, 0.10, or 0.15 mg of drug had 82 percent, 92 percent and 77 percent fewer Gd-enhancing brain lesions, respectively, compared to placebo; adverse events appeared to be dose related [[2754]] Trial name: A Safety and Efficacy Extension Study of ONO-4641 in Patients With Relapsing-Remitting Multiple Sclerosis (DreaMS) [[628]] Phase: Phase II [[628]] Study Design: Extension study examining long-term safety and tolerability of ONO-4641(primary endpoint) [[628]] Disease Stage: RRMS [[628]] Enrollment/Number of Patients: Estimated enrollment 376 patients [[628]] Duration: 122 weeks [[628]] Status/Outcome: Results expected June 2014 [[628]]
Rituximab	Trial name: Naismith et al., Neurology, Jun 2010 trial [[352]] Phase: Phase II trial [[352]] Study Design: MRI-blinded, single-center study to evaluate the effects of rituximab (375 mg/m2 weekly for four weeks) on gadolinium-enhancing lesions (primary objective) in patients who had been treated with a standard injectable disease-modifying agent in the past 18 months but had shown an inadequate response and were then given rituximab as add-on therapy [[352]] Disease Stage: RRMS [[352]] Enrollment/Number of Patients: 30 [[352]] Duration: 52 weeks, such that the drug was given for the first four weeks and MRI scans were performed monthly beginning 12 weeks after the first drug treatment [[352]] Status/Outcome: Drug caused a reduction in the number of gadolinium-enhancing lesions, such that 74% of posttreatment MRI scans were free of gadolinium-enhancing activity versus 26% of baseline MRI scans [[352]] Trial name: Hawker et al., Ann. Neurol., Oct 2009 trial [[359]] Phase: Phase II/III trial [[359]] Study Design: Randomized, double-blind, placebo-controlled, multicenter trial to evaluate the effects of rituximab (two 1000 mg infusions or placebo every 24 weeks) on time to confirmed disease progression (primary endpoint) and T2 lesion volume and total brain volume (secondary endpoints) [[359]] Disease Stage: PPMS [[359]] Enrollment/Number of Patients: 439 [[359]] Duration: 96 weeks [[359]] Status/Outcome: Drug was not associated with a decrease in time to confirmed disease progression (but there was a suggestion of a potential decrease in younger patients, especially those with inflammatory lesions) [[359]] [[484]] Trial name: Hauser et al., N. Engl. Med., Feb 2008 trial [[376]] Phase: Phase II trial [[376]] Study Design: Double-blind, placebo-controlled trial to evaluate the effects of intravenous rituximab (1000 mg or placebo on weeks 1 and 15) on the total count of gadolinium-enhancing lesions (primary endpoint) and on the proportion of patients with relapses [[376]] Disease Stage: RRMS [[376]] Enrollment/Number of Patients: 104 [[376]] Duration: 48 weeks [[376]] Status/Outcome: Drug was associated with a reduced number of inflammatory brain lesions and a reduced number of relapses (14.5% vs 34.3% at week 24 and 20.3% vs 40% at week 48) [[376]]		Trial name: Bar-Or et al., Ann. Neurol., Mar 2008 trial [[375]] Phase: Phase I trial [[375]] Study Design: Open-label trial to evaluate the safety, tolerability, pharmacodynamics, and activity of two courses of rituximab (total dose, 4000 mg), six months apart, in MS [[375]] Disease Stage: RRMS [[375]] Enrollment/Number of Patients: 26, with 22 completing the trial [[375]] Duration: 72 weeks [[375]] Status/Outcome: The drug was not associated with any serious adverse effects, although mild and moderate infusion-associated events were seen; furthermore, the drug was associated with fewer new gadolinium-enhancing or T2 lesions [[375]]
RPC1063	Trial name: Efficacy and Safety Study of RPC1063 in Relapsing Multiple Sclerosis Patients; also referred to as RPC01-201 (press release, 22 October 2012) [[3775]] [[3776]] Phase: Phase II portion of a Phase II/III trial [[3775]] [[3776]] Study Design: Industry-sponsored, randomized, parallel assignment, double-blind, placebo-controlled trial to study whether an oral, daily dose (low or high) of RPC1063 can effectively reduce the cumulative number of total gadolinium enhancing lesions in relapsing MS (primary outcome measure) from week 12 to week 24 [[3775]] [[3776]] Disease Stage: Relapsing MS [[3775]] [[3776]] Enrollment/Number of Patients: 210 (estimated) [[3776]] Duration: 24 weeks [[3775]] [[3776]] Status/Outcome: Administered to first patient (22 October 2012) [[3775]]	Trial name: RPC01-201 (press release, 22 October 2012) [[3775]] Phase: Phase III portion of a Phase II/III trial [[3775]] Study Design: Industry-sponsored, randomized, double-blind, double-dummy comparison of RPC1063 (low or high dose) to the active control, interferon beta-1a (weekly 30 microg intramuscular injection), to assess whether RPC1063 can more effectively reduce the rate of relapse at 24 months [[3775]] Disease Stage: Relapsing MS [[3775]] Enrollment/Number of Patients: More than 1100 (expected) [[3775]] Duration: At least 2 years [[3775]] Status/Outcome: Planned, 22 October 2012 [[3775]]	Trial name: Safety and Tolerability of Orally Administered RPC1063, a Novel S1P1 Receptor Agonist, in Healthy Adult Volunteers (press releases, 27 January 2011 and 9 October 2012) [[3777]] [[3778]] Phase: Phase I trial [[3777]] Study Design: Industry-sponsored, single-site, single ascending and multiple ascending daily dose trial to determine whether RPC1063 meets pre-specified pharmacokinetic, pharmacodynamic, and safety criteria, such as half-life determination for once-a-day dosing and the extent and speed of lymphopenia reversibility [[3777]] Disease Stage: Healthy volunteers [[3777]] Enrollment/Number of Patients: Not reported in press release [[3777]] Duration: Not reported in press release [[3777]] Status/Outcome: Administered to first volunteer (27 January 2011) [[3777]]
RTL1000	Trial name: Phase 1 Safety Study of RTL1000-(Recombinant T Cell Receptor Ligand) in Subjects With Multiple Sclerosis (published February, 2011) [[427]][[624]] Phase: Phase I [[427]] Study Design: Company-sponsored, randomized, placebo-controlled, escalating dose study to examine safety, laboratory, and disease parameters (primary outcome measures) at 6 dosage levels (20-200 mg) [[427]][[624]] Disease Stage: RRMS and SPMS patients with the HLA-DR2 gene [[427]][[624]] Enrollment/Number of Patients: 34 enrolled, 34 completed the study [[427]][[624]] Duration: 3 months [[427]] Status/Outcome: All subjects tolerated 2-60mg dose [[427]] ; Doses of 100mg and above caused hypotension and diarrhea [[427]] ; Percentage of subjects with gadolinium-positive lesions did not increase [[427]] ; Data suggested decrease in disease activity with increasing dose [[427]]
Teriflunomide	Trial name: Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC) (press release, 25 April 2013) [[5801]] [[5802]] Phase: Phase III trial [[5801]] Study Design: Company-sponsored, international, multicenter, randomized, double-blind, placebo-controlled, parallel group trial to study the safety and efficacy of teriflunomide (7 mg or 14 mg once a day) in preventing or delaying the conversion of CIS to clinically definite MS (primary endpoint) [[5801]] [[5802]] Disease Stage: CIS [[5801]] [[5802]] Enrollment/Number of Patients: 618 [[5801]] [[5802]] Duration: Up to 108 weeks (placebo-controlled period) [[5801]] Status/Outcome: 14 mg dose was associated with a 43% reduction in risk of conversion to clinically definite MS over 2 years, and the 7 mg dose with a 37% reduction in the risk, relative to placebo [[5802]] Trial name: Teriflunomide Oral in people With relapsing remitting multiplE scleRosis (TOWER) trial (press releases, June 2012 and October 2012) [[2006]] [[3593]] Phase: Phase III trial [[2006]] Study Design: Company-sponsored, double-blind, placebo-controlled, multicenter trial to test the efficacy and safety of oral teriflunomide (7 mg or 14 mg once daily), with the primary endpoint the reduction in the annualized relapse rate (ARR) and the main secondary endpoint the reduction in the risk of 12-week sustained accumulation of disability [[2006]] Disease Stage: RRMS [[2006]] Enrollment/Number of Patients: 1169 [[2006]] Duration: Average duration of drug exposure was 18 months; patients were followed from 48 to 173 weeks [[2006]] Status/Outcome: 14 mg dose (as compared with placebo) was associated with a 36.3% reduction in the ARR and a 31.5% reduction in the risk of 12-week sustained accumulation of disability (as measured by the expanded disability status scale); 7 mg dose was associated with a 22.3% reduction in the ARR and no difference in the risk of 12-week sustained accumulation of disability [[2006]]; 14 mg dose was associated with a 36.3% reduction in ARR (0.319 versus 0.501 for placebo) and a 31.5% reduction in the risk of 12-week sustained accumulation of disability, whereas the 7 mg dose was associated with a 22.3% reduction in ARR (0.389) but did not affect the risk of 12-week sustained accumulation of disability [[3593]] Trial name: Freedman et al., Neurology, May 2012 trial [[1880]] Phase: Phase II trial [[1880]] Study Design: Randomized, placebo-controlled trial to test the safety of oral teriflunomide (7 or 14 mg, once daily) as an add-on therapy to interferon-beta (primary objective); the effects on disease activity were also tested (secondary objectives) [[1880]] Disease Stage: RRMS [[1880]] Enrollment/Number of Patients: 118, with 86 entering the 24-week extension [[1880]] Duration: 24 weeks, with a 24-week extension [[1880]] Status/Outcome: Teriflunomide was generally well tolerated and safe when added to ongoing interferon-beta treatment, such that 4.9%, 8.1%, and 7.9% of patients in the placebo, 7 mg, and 14 mg groups discontinued treatment because of treatment-emergent adverse events; the addition of teriflunomide was also associated with a reduction in the number of gadolinium-enhancing T1 lesions as compared to treatment with interferon-beta alone [[1880]] Trial name: Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO) (publ 2011, 2013) [[341]] [[339]] [[5095]] Phase: Phase III trial [[341]] [[339]] Study Design: Randomized, double-blind, placebo-controlled trial to test the effects of teriflunomide (7 mg or 14 mg once per day) on the annualized relapse rate (primary endpoint) and the confirmed progression of disability for at least 12 weeks (key secondary endpoint) [[339]]; change in total lesion volume was the principal MRI outcome [[5095]] Disease Stage: RRMS [[339]] Enrollment/Number of Patients: 1088 [[339]] Duration: 108 weeks [[339]] Status/Outcome: Drug reduced annualized relapse rate by 31% (at either dose), disability progression (at 14 mg dose), and lesion load (assayed by MRI) relative to placebo [[341]] [[339]]; additional analysis showed that the positive effects of the drug were consistent across a variety of patient subgroups [[2194]]; 14 mg and 7 mg doses were associated with 67.4% and 39.4% lower increases in total lesion volume as compared to placebo [[5095]]; patients who completed this study were given the option to participate in an extension study with a total duration about about 6 years (from the time the first patient enrolled), to continue receiving 7 mg or 14 mg drug or, if received placebo, to be randomized to receive 7 mg or 14 mg [[581]] Trial name: O'Connor et al., Neurology, Mar 2006 trial [[389]] Phase: Phase II trial [[389]] Study Design: Randomized, double-blind, placebo-controlled trial to study the safety and effects of teriflunomide (7 mg or 14 mg per day) on the number of unique and active lesions per MRI scan (primary endpoint) [[389]] Disease Stage: RRMS and SPMS [[389]] Enrollment/Number of Patients: 179 (157 with RRMS and 22 with SPMS) [[389]] Duration: 36 weeks [[389]]

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