Fingolimod

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

MS Trust, 12 Jun 2014

Accessed on 12 Jun 2014 from http://www.mstrust.org.uk/news/article.jsp?id=6381.

Administration:

First oral treatment for RRMS available in US

(1)

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

0.5 mg orally once daily (information provided by the manufacturer)

(18)

Gilenya prescribing information

Novartis

Accessed on 4 Jan 2012 from http://www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf.

Decreased dosage (such that fingolimod was given every other day or every third day) did not result in clinical relapses, but did improve laboratory abnormalities (involving increased liver function tests and reduced lymphocyte counts), in a study of seven individuals

(226)

Efficacy of lower fingolimod doses in the treatment of MS.

Yamout B, Zeineddine MM, Khoury SJ

Mult Scler Relat Disord. 2014 Nov; 3(6):758. Epub 2014 Nov 21. PMID: 25891604. Abstract

Decreased dosage (such that fingolimod was given every other day or every third day) reversed laboratory abnormalities (involving increased liver function tests and reduced lymphocyte counts) in a study of eight individuals; although no relapses occurred, five individuals exhibited new brain lesions and one converted to SPMS

(263)

Safety and efficacy of reduced fingolimod dosage treatment.

Yamout BI, Zeineddine MM, Sawaya RA, Khoury SJ

J Neuroimmunol. 2015 Aug 15; 285:13-5. Epub 2015 May 15. PMID: 26198913. Abstract

Label has been updated to say that all patients should have an electrocardiogram before the first dose, according to information from the manufacturer (April, 2012)

(26)

Novartis updates US label on Gilenya® following discussions with the FDA

Novartis, 20 Apr 2012

Accessed on 16 May 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1604414.shtml.

Contraindicated in the presence of specific cardiac conditions, according to information from the manufacturer

(26)

Novartis updates US label on Gilenya® following discussions with the FDA

Novartis, 20 Apr 2012

Accessed on 16 May 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1604414.shtml.

Contraindicated in the presence of certain cardiac conditions, which were found to be present in 9.2% of individuals with MS in a retrospective cohort study involving 136,542 hospital discharges

(163)

Frequency and economic impact of comorbid cardiac conditions with multiple sclerosis.

Franklin MA, Happe LE, Dillman R, Marshall LZ

J Manag Care Pharm. 2014 Aug; 20(8):795-9. PMID: 25062072. Abstract

As a result of a drug safety communication from the US Food and Drug Administration, the label has been adjusted to indicate that one definite case, and an additional probable case, of progressive multifocal leukoencephalopathy have been reported in individuals taking fingolimod, who had not previously been exposed to immunosuppressant drugs (4 August 2015)

(266)

FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs

US Food and Drug Administration, 4 Aug 2015

Accessed on 11 Aug 2015 from http://www.fda.gov/Drugs/DrugSafety/ucm456919.htm.

To minimize fingolimod-associated risks, the European Medicines Agency has issued new recommendations for screening for progressive multifocal leukoencephalopathy and basal cell carcinoma before and during treatment (December 2015)

(309)

New EMA Advice for PML Prevention With Fingolimod in MS

Anderson P, Medscape, 18 Dec 2015

Accessed on 22 Dec 2015 from http://www.medscape.com/viewarticle/856208.

Used in one individual with highly active multiple sclerosis, severe idiopathic pulmonary arterial hypertension, and coronary artery disease; treatment did not change the cardiopulmonary conditions over 9 months

(151)

Fingolimod in a patient with heart failure on the background of pulmonary arterial hypertension and coronary artery disease.

Thomas K, Schrötter H, Halank M, Ziemssen T

BMC Neurol. 2014; 14(1):126. Epub 2014 Jun 07. PMID: 24906818. Abstract

Drug-drug interactions are not observed with a combined oral contraceptive (ethinylestradiol/levonorgestrel)

(29)

Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results.

David OJ, Ocwieja M, Meiser K, Emotte C, Jakab A, Wemer J, den Daas I, Schmouder R

Int J Clin Pharmacol Ther. 2012 Jun 26. PMID: 22735460. Abstract

Commercial:

Clinical trials have been sponsored by Novartis Pharma

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Marketed by Novartis

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

Licensed from Mitsubishi Tanabe Pharma Corporation

(16)

Novartis receives European Commission approval for Gilenya®, the first oral multiple sclerosis treatment for use in the EU

Novartis

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2011/1498377.shtml.

US patent covering the process of fingolimod preparation has been granted to Mapi Pharma Ltd. of Israel, which plans to develop a generic version in anticipation of the loss of market exclusivity by Novartis (an event that will occur in 2017 in some markets) (18 February 2014)

(120)

Mapi Pharma granted United States patent covering the process for the preparation of fingolimod for multiple sclerosis

Market Watch, The Wall Street Journal, 18 Feb 2014

Accessed on 20 Feb 2014 from http://www.marketwatch.com/story/mapi-pharma-granted-united-states-patent-covering-the-process-for-the-preparation-of-fingolimod-for-multiple-sclerosis-2014-02-18?reflink=MW_news_stmp.

Positive opinion for expansion of EU label to include adult individuals with RRMS who have not responded to at least one other disease-modifying therapy has been issued by the Committee for Medicinal Products for Human Use (29 April 2014)

(141)

Novartis: CHMP Issues Positive Opinion To Expand EU Label For Gilenya In RRMS

RTT News, 29 Apr 2014

Accessed on 19 May 2014 from http://www.rttnews.com/2309584/novartis-chmp-issues-positive-opinion-to-expand-eu-label-for-gilenya-in-rrms.aspx?type=qf&utm_source=google&utm_campaign=sitemap.

; extended license has been approved by the European Commission (June, 2014)

(148)

Fingolimod (Gilenya) eligibility extended by NHS England

MS Trust, 12 Jun 2014

Accessed on 12 Jun 2014 from http://www.mstrust.org.uk/news/article.jsp?id=6381.

Under a new policy from the National Health Service in England, can now be prescribed to individuals who have not responded to beta interferons or glatiramer acetate or who are at risk for side effects of natalizumab, rather than just those who have not responded to interferon (2 July 2014)

(154)

MS Trust, 2 July 2014

Accessed on 3 July 2014 from http://www.mstrust.org.uk/news/article.jsp?id=6400.

Endorsed by the Scottish Medicines Consortium for treating rapidly evolving, severe RRMS (October, 2014)

(184)

Novartis MS pill heads stream of SMC approvals

McKee S, PharmaTimes, 13 Oct 2014

Accessed on 21 Oct 2014 from http://www.pharmatimes.com/Article/14-10-13/Novartis_MS_pill_heads_stream_of_SMC_approvals.aspx.

Generic version Neskler has been approved by the Russian Ministry of Health (November 2014)

(318)

Biointegrator announced that it has successfully launched Neskler® - a first generic of Gilenya® in Russia and EuroAsian Economic Union

ChemRar, 11 Jan 2016

Accessed on 19 Jan 2016 from http://www.chemrar.ru/eng/press/press.php?ELEMENT_ID=20580.

Generic version Neskler has been launched in Russia and other countries in the EuroAsian Economic Union by Biointegrator after Novartis claims against Biointegrator were rejected in a series of court hearings (11 January 2016)

(318)

Biointegrator announced that it has successfully launched Neskler® - a first generic of Gilenya® in Russia and EuroAsian Economic Union

ChemRar, 11 Jan 2016

Accessed on 19 Jan 2016 from http://www.chemrar.ru/eng/press/press.php?ELEMENT_ID=20580.

Names

Name:

Fingolimod

Trade name:

Gilenya

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

Neskler (generic version marketed in Russia)

(318)

Biointegrator announced that it has successfully launched Neskler® - a first generic of Gilenya® in Russia and EuroAsian Economic Union

ChemRar, 11 Jan 2016

Accessed on 19 Jan 2016 from http://www.chemrar.ru/eng/press/press.php?ELEMENT_ID=20580.

Synonyms:

2-Amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol

(5)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

FTY-720

(5)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

FTY720

(5)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Fingolimod

(5)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Gilenia

(5)

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Gilenya

(5)

Biointegrator announced that it has successfully launched Neskler® - a first generic of Gilenya® in Russia and EuroAsian Economic Union

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Neskler

(318)

ChemRar, 11 Jan 2016

Accessed on 19 Jan 2016 from http://www.chemrar.ru/eng/press/press.php?ELEMENT_ID=20580.

TDI-132

(55)

FDA approves clinical trial of TDI-132 (Gilenya) in ALS patients

ALS Therapy Development Institute, 11 Feb 2013

Accessed on 18 Feb 2013 from http://www.als.net/TDI-132/?f=hr.

UNII-3QN8BYN5QF

(5)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

United States National Library of Medicine

Accessed on 29 Jul 2013 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

Systematic name:

1,3-Propanediol, 2-amino-2-(2-(4-octylphenyl)ethyl)-

(6)

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

Physiology

Class:

Immunomodulator

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Neuroprotector (?)

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Target:

Sphingosine 1-phosphate receptors

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Immune cell migration

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Histone deacetylases

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Oligodendrocyte progenitors?

(210)

Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis.

Zhang J, Zhang Z G, Li Y, Ding X, Shang X, Lu M, Elias SB, Chopp M

Neurobiol Dis. 2015 Feb 11; 76:57-66. PMID: 25680941. Abstract

Properties:

Structural sphingosine analog

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

(2)

Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation.

Hla T, Brinkmann V

Neurology. 2011 Feb 22; 76(8 Suppl 3):S3-8. PMID: 21339489. Abstract

Phosphorylated to fingolimod phosphate by sphingosine kinase-2

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

; phosphorylated form binds to 4/5 of sphingosine 1-phosphate (S1P) receptor subtypes (S1P1, S1P3, S1P4, S1P5)

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

(21)

The immune modulator FTY720 targets sphingosine 1-phosphate receptors.

Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, et al.

J Biol Chem. 2002 Jun 14; 277(24):21453-7. Epub 2002 Apr 19. PMID: 11967257. Abstract

Crosses blood-brain barrier

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Lipophilic

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Derived from myriocin, a metabolite from the fungus Isaria sinclairii (used in traditional Chinese medicine)

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Can be measured in human plasma and mouse subcellular compartments by an analytical method involving liquid chromatography-tandem mass spectrometry

(24)

LC-MS/MS determination of FTY720 and FTY720-phosphate in murine intracellular compartments and human plasma.

Ferreirós N, Labocha S, Schröder M, Radeke HH, Geisslinger G

J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Mar 1; 887-888:122-7. Epub 2012 Jan 30. PMID: 22341683. Abstract

Unphosphorylated and phosphorylated forms accumulate in immune cells at micromolar concentrations, based on experiments using spleen cells from mice

(213)

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells - another aspect of Fingolimod action relevant for therapeutic application.

Schröder M, Arlt O, Schmidt H, Huwiler A, Angioni C, Pfeilschifter JM, Schwiebs A, Radeke HH

Biol Chem. 2015 Jan 14. PMID: 25720062. Abstract

Pharmacokinetics are not altered by a combined oral contraceptive (ethinylestradiol/levonorgestrel)

(29)

Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results.

David OJ, Ocwieja M, Meiser K, Emotte C, Jakab A, Wemer J, den Daas I, Schmouder R

Int J Clin Pharmacol Ther. 2012 Jun 26. PMID: 22735460. Abstract

Does not affect the pharmacokinetics of a combined oral contraceptive (ethinylestradiol/levonorgestrel)

(29)

Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results.

David OJ, Ocwieja M, Meiser K, Emotte C, Jakab A, Wemer J, den Daas I, Schmouder R

Int J Clin Pharmacol Ther. 2012 Jun 26. PMID: 22735460. Abstract

Potency against the sphingosine-1-phosphate (S1P) receptor subtype S1P1, selectivity against other S1P receptors, and species cross-reactivity have been compared for multiple S1P1 receptor agonists (including fingolimod, siponimod, and CS-0777)

(92)

No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation.

Lukas S, Patnaude L, Haxhinasto S, Slavin A, Hill-Drzewi M, Horan J, Modis L K

J Biomol Screen. 2013 Sep 3. PMID: 24003058. Abstract

Multiple sphingosine-1-phosphate (S1P) receptor subtype S1P1 agonists (including fingolimod, siponimod, and CS-0777) all signal identically through the S1P1 receptor, causing receptor degradation

(92)

No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation.

Lukas S, Patnaude L, Haxhinasto S, Slavin A, Hill-Drzewi M, Horan J, Modis L K

J Biomol Screen. 2013 Sep 3. PMID: 24003058. Abstract

Nonproprietary fingolimod varients display different properties (such as particle size and the presence of impurities) than does proprietary fingolimod, according to a company-sponsored study

(160)

Assessing the potential impact of non-proprietary drug copies on quality of medicine and treatment in patients with relapsing multiple sclerosis: the experience with fingolimod.

Correale J, Chiquete E, Milojevic S, Frider N, Bajusz I

Drug Des Devel Ther. 2014; 8:859-67. Epub 2014 Jun 25. PMID: 25028537. Abstract

Single-crystal structures have been determined

(216)

Insight into the conformational polymorph transformation of a block-buster multiple sclerosis drug fingolimod hydrochloride (FTY 720).

Wang J-R, Li S, Zhu B, Mei X

J Pharm Biomed Anal. 2015 Feb 19; 109C:45-51. PMID: 25746505. Abstract

Three different crystalline forms have been identified and characterized

(216)

Insight into the conformational polymorph transformation of a block-buster multiple sclerosis drug fingolimod hydrochloride (FTY 720).

Wang J-R, Li S, Zhu B, Mei X

J Pharm Biomed Anal. 2015 Feb 19; 109C:45-51. PMID: 25746505. Abstract

Mechanisms/Effects

Human:

Exact mechanism unknown

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

Phosphorylated version is a strong agonist of four sphingosine 1-phosphate (S1P) receptor subtypes, as shown in experiments using recombinant human receptors

(21)

The immune modulator FTY720 targets sphingosine 1-phosphate receptors.

Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, et al.

J Biol Chem. 2002 Jun 14; 277(24):21453-7. Epub 2002 Apr 19. PMID: 11967257. Abstract

, but unlike the natural ligand S1P, ultimately induces degradation of the S1P1 receptor in cell culture, showing that the drug is a functional antagonist of this receptor

(22)

Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor.

Oo M L, Thangada S, Wu M-T, Liu CH, Macdonald TL, Lynch KR, Lin C-Y, Hla T

J Biol Chem. 2007 Mar 23; 282(12):9082-9. Epub 2007 Jan 21. PMID: 17237497. Abstract

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

(23)

FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system.

Brinkmann V

Br J Pharmacol. 2009 Nov; 158(5):1173-82. Epub 2009 Oct 08. PMID: 19814729. Abstract

Depletes T cells with a lymph node-homing phenotype (naïve and central memory cells) from the peripheral blood of MS patients with varying kinetics, such that naïve CD4+ T cell counts decrease 2 hours after the first dose, naïve CD8+ T cell counts after 3 hours, and central memory CD4+ T cell counts after 5 hours, whereas CD8+ central memory cell counts do not decrease significantly after the first dose

(80)

Homing frequency of human T cells inferred from peripheral blood depletion kinetics after sphingosine-1-phosphate receptor blockade.

Mehling M, Brinkmann V, Burgener A-V, Gubser P, Luster AD, Kappos L, Hess C

J Allergy Clin Immunol. 2013 May; 131(5):1440-3.e7. Epub 2013 Feb 21. PMID: 23434284. Abstract

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

(14)

Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis.

Mehling M, Lindberg R, Raulf F, Kuhle J, Hess C, Kappos L, Brinkmann V

Neurology. 2010 Aug 3; 75(5):403-10. Epub 2010 Jun 30. PMID: 20592255. Abstract

Decreases the proportion of central memory T cells and naïve T cells in the peripheral blood, but increases the proportion of effectory memory T cells and suppressor precursor T cells, and an increased percentage of CD4+ central memory T cells is associated with an increased risk of relapse, as shown in a study of 23 individuals with RRMS

(236)

Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod.

Song Z-Y, Yamasaki R, Kawano Y, Sato S, Masaki K, Yoshimura S, Matsuse D, Murai H, Matsushita T, Kira J-I

PLoS One. 2014; 10(4):e0124923. Epub 2015 Apr 28. PMID: 25919001. Abstract

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)

(33)

Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes.

van Doorn R, Nijland PG, Dekker N, Witte ME, Lopes-Pinheiro MA, van Het Hof B, Kooij G, Reijerkerk A, Dijkstra C, van van der Valk P, et al.

Acta Neuropathol. 2012 Jul 19. Epub 2012 Jul 19. PMID: 22810490. Abstract

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

(33)

Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes.

van Doorn R, Nijland PG, Dekker N, Witte ME, Lopes-Pinheiro MA, van Het Hof B, Kooij G, Reijerkerk A, Dijkstra C, van van der Valk P, et al.

Acta Neuropathol. 2012 Jul 19. Epub 2012 Jul 19. PMID: 22810490. Abstract

May help prevent disruption of the blood-brain barrier, based on experiments with immortalized human brain microvascular endothelial cells

(217)

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T

PLoS One. 2015; 10(3):e0121488. Epub 2015 Mar 16. PMID: 25774903. Abstract

Phosphorylated form increases the level of the tight junction protein claudin-5 in immortalized human brain microvascular endothelial cells

(217)

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T

PLoS One. 2015; 10(3):e0121488. Epub 2015 Mar 16. PMID: 25774903. Abstract

Does not affect levels of occludin (a tight junction protein), intercellular adhesion molecule-1, or melanoma cell-adhesion molecule in immortalized human brain microvascular endothelial cells

(217)

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T

PLoS One. 2015; 10(3):e0121488. Epub 2015 Mar 16. PMID: 25774903. Abstract

Phosphorylated form increases transendothelial electrical resistance in immortalized human brain microvascular endothelial cells

(217)

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T

PLoS One. 2015; 10(3):e0121488. Epub 2015 Mar 16. PMID: 25774903. Abstract

Pretreatment with the phosphorylated form reverses the decrease in levels of the tight junction protein claudin-5 in immortalized human brain microvascular endothelial cells caused by exposure to sera from individuals with RRMS or SPMS

(217)

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T

PLoS One. 2015; 10(3):e0121488. Epub 2015 Mar 16. PMID: 25774903. Abstract

Pretreatment with the phosphorylated form reverses the decrease in transendothelial electrical resistance in immortalized human brain microvascular endothelial cells caused by exposure to sera from individuals with RRMS or SPMS

(217)

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T

PLoS One. 2015; 10(3):e0121488. Epub 2015 Mar 16. PMID: 25774903. Abstract

Pretreatment with the phosphorylated form reverses the increase in levels of vascular cell adhesion molecule 1 in immortalized human brain microvascular endothelial cells caused by exposure to sera from individuals with RRMS or SPMS

(217)

Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T

PLoS One. 2015; 10(3):e0121488. Epub 2015 Mar 16. PMID: 25774903. Abstract

Decreases inflammatory cytokine-induced death of cultured human brain microvascular endothelial cells, an effect that is mediated by the sphingosine-1 phosphate receptor 1

(264)

Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?

Spampinato SF, Obermeier B, Cotleur A, Love A, Takeshita Y, Sano Y, Kanda T, Ransohoff RM

PLoS One. 2015; 10(7):e0133392. Epub 2015 Jul 21. PMID: 26197437. Abstract

Induces the release of granulocyte macrophage colony-stimulating factor from human astrocytes, which in turn decreases inflammatory cytokine-induced death of human brain microvascular endothelial cells in vitro

(264)

Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?

Spampinato SF, Obermeier B, Cotleur A, Love A, Takeshita Y, Sano Y, Kanda T, Ransohoff RM

PLoS One. 2015; 10(7):e0133392. Epub 2015 Jul 21. PMID: 26197437. Abstract

Reduces transmigration of human peripheral blood mononuclear cells in an in vitro co-culture model of the blood-brain barrier involving cytokine-activated human brain microvascular endothelial cells and human astrocytes under conditions of shear stress

(264)

Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?

Spampinato SF, Obermeier B, Cotleur A, Love A, Takeshita Y, Sano Y, Kanda T, Ransohoff RM

PLoS One. 2015; 10(7):e0133392. Epub 2015 Jul 21. PMID: 26197437. Abstract

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

(58)

The role of natural killer cells in multiple sclerosis and their therapeutic implications.

Chanvillard C, Jacolik RF, Infante-Duarte C, Nayak RC

Front Immunol. 2013; 4:63. Epub 2013 Mar 13. PMID: 23493880. Abstract

One month of treatment does not change the frequency of CCR6+ and CD161+ T cells (CCR6 and CD161 are indicative of Th17 cells) in the pool of circulating CD4+ and CD8+ cells in MS patients

(67)

Fingolimod Modulates Peripheral Effector and Regulatory T Cells in MS Patients.

Serpero LD, Filaci G, Parodi A, Battaglia F, Kalli F, Brogi D, Mancardi G L, Uccelli A, Fenoglio D

J Neuroimmune Pharmacol. 2013 May 7. Epub 2013 May 07. PMID: 23649711. Abstract

One month of treatment reduces the frequencies of CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ cells that express pro-inflammatory cytokines (interferon gamma with or without interleukin-17)

(67)

Fingolimod Modulates Peripheral Effector and Regulatory T Cells in MS Patients.

Serpero LD, Filaci G, Parodi A, Battaglia F, Kalli F, Brogi D, Mancardi G L, Uccelli A, Fenoglio D

J Neuroimmune Pharmacol. 2013 May 7. Epub 2013 May 07. PMID: 23649711. Abstract

One month of treatment increases the frequency of CD4+ CD24(high)CD127(low) regulatory T cells, which is reduced in MS patients versus healthy controls

(67)

Fingolimod Modulates Peripheral Effector and Regulatory T Cells in MS Patients.

Serpero LD, Filaci G, Parodi A, Battaglia F, Kalli F, Brogi D, Mancardi G L, Uccelli A, Fenoglio D

J Neuroimmune Pharmacol. 2013 May 7. Epub 2013 May 07. PMID: 23649711. Abstract

Treatment is associated with different amounts of fluctuation in total lymphocyte counts in different individuals, such that higher counts in "fluctuating" individuals reflect higher levels of CCR7-CD8+ effector cells, which are controlled less by fingolimod than other subsets

(99)

Basis for fluctuations in lymphocyte counts in fingolimod-treated patients with multiple sclerosis.

Henault D, Galleguillos L, Moore C, Johnson T, Bar-Or A, Antel J

Neurology. 2013 Oct 16. PMID: 24132373. Abstract

Two weeks of treatment reduces the frequency of activated memory B cells [CD38(int-high)], especially those that express a marker of cell proliferation, Ki-67, in individuals with MS

(116)

Differential effects of fingolimod on B-cell populations in multiple sclerosis.

Nakamura M, Matsuoka T, Chihara N, Miyake S, Sato W, Araki M, Okamoto T, Lin Y, Ogawa M, Murata M, et al.

Mult Scler. 2014 Feb 18. Epub 2014 Feb 13. PMID: 24526661. Abstract

Two weeks of treatment increases the frequency of activated plasmablasts (CD138+) within the plasmablast population in individuals with MS, indicating that these activated plasmablasts are relatively resistant to the drug

(116)

Differential effects of fingolimod on B-cell populations in multiple sclerosis.

Nakamura M, Matsuoka T, Chihara N, Miyake S, Sato W, Araki M, Okamoto T, Lin Y, Ogawa M, Murata M, et al.

Mult Scler. 2014 Feb 18. Epub 2014 Feb 13. PMID: 24526661. Abstract

Affects T cell activation, such that the resulting phenotype is less inflammatory (with diminished expression of interferon gamma and granzyme B, two pathogenic cytokines), and this effect requires T cell factor 1 upregulation, as shown in in vitro studies of T cells from individuals with MS and healthy controls

(314)

Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation.

Mazzola M A, Raheja R, Murugaiyan G, Rajabi H, Kumar D, Pertel T, Regev K, Griffin R, Aly L, Kivisakk P, et al.

J Neuroinflammation. 2015; 12(1):245. Epub 2015 Dec 30. PMID: 26714756. Abstract

Upregulates T cell factor 1 (which downregulates interferon gamma and granzyme B, two pathogenic cytokines), as shown in in vitro studies of T cells from individuals with MS and healthy controls

(314)

Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation.

Mazzola M A, Raheja R, Murugaiyan G, Rajabi H, Kumar D, Pertel T, Regev K, Griffin R, Aly L, Kivisakk P, et al.

J Neuroinflammation. 2015; 12(1):245. Epub 2015 Dec 30. PMID: 26714756. Abstract

Upregulates expression of T cell factor 1 (which is expressed at lower levels by T cells from individuals with MS versus healthy controls) in individuals with MS

(314)

Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation.

Mazzola M A, Raheja R, Murugaiyan G, Rajabi H, Kumar D, Pertel T, Regev K, Griffin R, Aly L, Kivisakk P, et al.

J Neuroinflammation. 2015; 12(1):245. Epub 2015 Dec 30. PMID: 26714756. Abstract

Decreases expression of the proinflammatory micro-RNA miR-155, as shown by studies of monocytes isolated from treated versus untreated individuals with MS

(320)

Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis.

Michell-Robinson MA, Moore CS, Healy LM, Osso LA, Zorko N, Grouza V, Touil H, Poliquin-Lasnier L, Trudelle A-M, Giacomini PS, et al.

Ann Clin Transl Neurol. 2016 Jan; 3(1):27-41. Epub 2015 Dec 02. PMID: 26783548. Abstract

Decreases expression of the antioxidant genes HMOX1 and OSGIN1, as shown by studies of monocytes isolated from treated versus untreated individuals with MS

(320)

Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis.

Michell-Robinson MA, Moore CS, Healy LM, Osso LA, Zorko N, Grouza V, Touil H, Poliquin-Lasnier L, Trudelle A-M, Giacomini PS, et al.

Ann Clin Transl Neurol. 2016 Jan; 3(1):27-41. Epub 2015 Dec 02. PMID: 26783548. Abstract

Reduces the number of B cells in circulation in individuals with MS

(124)

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

Miyazaki Y, Niino M, Fukazawa T, Takahashi E, Nonaka T, Amino I, Tashiro J, Minami N, Fujiki N, Doi S, et al.

Clin Immunol. 2014 Feb 14; 151(2):127-135. PMID: 24607506. Abstract

Reduces the proportion of memory B cells, and increases the proportion of naïve B cells (and transitional B cells in the naïve B cell population), in circulation in individuals with MS

(124)

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

Miyazaki Y, Niino M, Fukazawa T, Takahashi E, Nonaka T, Amino I, Tashiro J, Minami N, Fujiki N, Doi S, et al.

Clin Immunol. 2014 Feb 14; 151(2):127-135. PMID: 24607506. Abstract

Reduces levels of the costimulatory molecule CD80 on B cells from individuals with MS to levels seen in healthy individuals

(124)

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

Miyazaki Y, Niino M, Fukazawa T, Takahashi E, Nonaka T, Amino I, Tashiro J, Minami N, Fujiki N, Doi S, et al.

Clin Immunol. 2014 Feb 14; 151(2):127-135. PMID: 24607506. Abstract

Reduces the production of the pro-inflammatory cytokine tumor necrosis factor alpha, and increases the production of the anti-inflammatory cytokine interleukin-10, by B cells from individuals with MS, findings that may be related to the fingolimod-related decrease in circulating memory B cells and increase in circulating transitional B cells

(124)

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

Miyazaki Y, Niino M, Fukazawa T, Takahashi E, Nonaka T, Amino I, Tashiro J, Minami N, Fujiki N, Doi S, et al.

Clin Immunol. 2014 Feb 14; 151(2):127-135. PMID: 24607506. Abstract

Reduces the proportion of non class-switched and class-switched memory B cells (both of which are linked with MS pathogenesis), but increases the proportion of naïve B cells, in peripheral blood of individuals with MS, as shown in a 12 month followup study

(188)

Compositional Changes of B and T Cell Subtypes during Fingolimod Treatment in Multiple Sclerosis Patients: A 12-Month Follow-Up Study.

Claes N, Dhaeze T, Fraussen J, Broux B, Van Wijmeersch B, Stinissen P, Hupperts R, Hellings N, Somers V

PLoS One. 2014; 9(10):e111115. Epub 2014 Oct 31. PMID: 25360562. Abstract

Increases the proportion of memory conventional and regulatory T cells, and decreases the proportion of naïve conventional and regulatory T cells (which drive MS pathogenesis) in peripheral blood of individuals with MS, as shown in a 12 month followup study

(188)

Compositional Changes of B and T Cell Subtypes during Fingolimod Treatment in Multiple Sclerosis Patients: A 12-Month Follow-Up Study.

Claes N, Dhaeze T, Fraussen J, Broux B, Van Wijmeersch B, Stinissen P, Hupperts R, Hellings N, Somers V

PLoS One. 2014; 9(10):e111115. Epub 2014 Oct 31. PMID: 25360562. Abstract

Associated with increased expression of CD80 and CD86 on B cells and of programmed death-1 on circulating follicular helper T cells in individuals with MS, as shown in a 12 month followup study

(188)

Compositional Changes of B and T Cell Subtypes during Fingolimod Treatment in Multiple Sclerosis Patients: A 12-Month Follow-Up Study.

Claes N, Dhaeze T, Fraussen J, Broux B, Van Wijmeersch B, Stinissen P, Hupperts R, Hellings N, Somers V

PLoS One. 2014; 9(10):e111115. Epub 2014 Oct 31. PMID: 25360562. Abstract

Increases mRNA levels of CD39 (an ectoenzyme expressed by T regulatory cells that decreases extracellular concentrations of ATP, a molecule with proinflammatory effects), aryl hydrocarbon receptor (AHR, a transcription factor that can regulate CD39 expression), and CYP1B1 (the expression of which is induced by AHR), as shown by an analysis of peripheral blood mononuclear cells from individuals with RRMS

(195)

Fingolimod Increases CD39-Expressing Regulatory T Cells in Multiple Sclerosis Patients.

Muls N, Dang H A, Sindic CJM, van Pesch V

PLoS One. 2014; 9(11):e113025. Epub 2014 Nov 20. PMID: 25411844. Abstract

Decreases mRNA levels of interleukin-17 (IL-17), IL-22, and FOXP3 (expressed by T regulatory cells and recently activated T cells), as shown by an analysis of peripheral blood mononuclear cells from individuals with RRMS

(195)

Fingolimod Increases CD39-Expressing Regulatory T Cells in Multiple Sclerosis Patients.

Muls N, Dang H A, Sindic CJM, van Pesch V

PLoS One. 2014; 9(11):e113025. Epub 2014 Nov 20. PMID: 25411844. Abstract

Reduces circulating CD4+ T cells, CD19+ B cells, and T regulatory cells (Tregs); cells in the remaining CD4+ T cell population were enriched for FOXP3+ cells and Tregs expressing CD39, as shown by an analysis of peripheral blood mononuclear cells from individuals with RRMS

(195)

Fingolimod Increases CD39-Expressing Regulatory T Cells in Multiple Sclerosis Patients.

Muls N, Dang H A, Sindic CJM, van Pesch V

PLoS One. 2014; 9(11):e113025. Epub 2014 Nov 20. PMID: 25411844. Abstract

Decreases the level of newly-produced T and B lymphocytes in the peripheral blood of individuals with MS, based on studies of blood samples taken before treatment began and after 6 and 12 months

(190)

Newly produced T and B lymphocytes and T-cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients.

Chiarini M, Sottini A, Bertoli D, Serana F, Caimi L, Rasia S, Capra R, Imberti L

Mult Scler. 2014 Nov 12. PMID: 25392322. Abstract

Reduces T cell receptor repertoire diversity in the peripheral blood of individuals with MS, based on studies of blood samples taken before treatment began and after 6 and 12 months

(190)

Newly produced T and B lymphocytes and T-cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients.

Chiarini M, Sottini A, Bertoli D, Serana F, Caimi L, Rasia S, Capra R, Imberti L

Mult Scler. 2014 Nov 12. PMID: 25392322. Abstract

Does not interfere with T cell release from the thymus, as shown in a study of individuals with MS treated with fingolimod and healthy controls

(202)

Fingolimod does not impair T-cell release from the thymus and beneficially affects Treg function in patients with multiple sclerosis.

Haas J, Schwarz A, Korporal-Kunke M, Jarius S, Wiendl H, Kieseier BC, Wildemann B

Mult Scler. 2015 Jan 12. PMID: 25583847. Abstract

Reduces the number of conventional CD4+ T cells that express CCR7, and thereby increases the relative proportion of regulatory T cells, as shown in a study of individuals with MS treated with fingolimod and healthy controls

(202)

Fingolimod does not impair T-cell release from the thymus and beneficially affects Treg function in patients with multiple sclerosis.

Haas J, Schwarz A, Korporal-Kunke M, Jarius S, Wiendl H, Kieseier BC, Wildemann B

Mult Scler. 2015 Jan 12. PMID: 25583847. Abstract

Does not have a negative effect on the phenotypes of naïve T cells or on surrogate markers of thymic T cell development (which include T cell receptor diversity in regulatory T cells, as well as the frequency of cells that express T cell receptors with dual specificity), as shown in a study of individuals with MS treated with fingolimod and healthy controls

(202)

Fingolimod does not impair T-cell release from the thymus and beneficially affects Treg function in patients with multiple sclerosis.

Haas J, Schwarz A, Korporal-Kunke M, Jarius S, Wiendl H, Kieseier BC, Wildemann B

Mult Scler. 2015 Jan 12. PMID: 25583847. Abstract

Decreases leukocyte counts in the cerebrospinal fluid (CSF), but does not affect oligoclonal bands in the CSF or intrathecal IgG synthesis

(209)

Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.

Kowarik MC, Pellkofer HL, Cepok S, Korn T, Kümpfel T, Buck D, Hohlfeld R, Berthele A, Hemmer B

Neurology. 2011 Apr 5; 76(14):1214-21. PMID: 21464424. Abstract

Has little effect on B cells in the cerebrospinal fluid, but strongly reduces B cells in the peripheral blood

(209)

Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.

Kowarik MC, Pellkofer HL, Cepok S, Korn T, Kümpfel T, Buck D, Hohlfeld R, Berthele A, Hemmer B

Neurology. 2011 Apr 5; 76(14):1214-21. PMID: 21464424. Abstract

Decreases the proportion of CS4+ T cells in the cerebrospinal fluid, but this effect is less extreme than that in peripheral blood

(209)

Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.

Kowarik MC, Pellkofer HL, Cepok S, Korn T, Kümpfel T, Buck D, Hohlfeld R, Berthele A, Hemmer B

Neurology. 2011 Apr 5; 76(14):1214-21. PMID: 21464424. Abstract

Reduces levels of neurofilament light chain subunit (a marker of axonal injury) in the cerebrospinal fluid, as shown by an analysis of a subset of participants in the FREEDOMS trial

(218)

Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis.

Kuhle J, Disanto G, Lorscheider J, Stites T, Chen Y, Dahlke F, Francis G, Shrinivasan A, Radue E-W, Giovannoni G, et al.

Neurology. 2015 Mar 25. PMID: 25809304. Abstract

Increases the proportion of regulatory B cells (CD38+ CD27- CD24+ CD5+) relative to all B cells in the peripheral blood as compared with that in treatment-naïve individuals with MS and healthy controls

(215)

Fingolimod treatment promotes regulatory phenotype and function of B cells.

Grützke B, Hucke S, Gross CC, Herold MVB, Posevitz-Fejfar A, Wildemann BT, Kieseier BC, Dehmel T, Wiendl H, Klotz L

Ann Clin Transl Neurol. 2015 Feb; 2(2):119-30. Epub 2015 Jan 16. PMID: 25750917. Abstract

Increases the production of interleukin-10 by regulatory B cells

(215)

Fingolimod treatment promotes regulatory phenotype and function of B cells.

Grützke B, Hucke S, Gross CC, Herold MVB, Posevitz-Fejfar A, Wildemann BT, Kieseier BC, Dehmel T, Wiendl H, Klotz L

Ann Clin Transl Neurol. 2015 Feb; 2(2):119-30. Epub 2015 Jan 16. PMID: 25750917. Abstract

Increases the movement of regulatory B cells across a monolayer of primary human brain microvascular endothelial cells

(215)

Fingolimod treatment promotes regulatory phenotype and function of B cells.

Grützke B, Hucke S, Gross CC, Herold MVB, Posevitz-Fejfar A, Wildemann BT, Kieseier BC, Dehmel T, Wiendl H, Klotz L

Ann Clin Transl Neurol. 2015 Feb; 2(2):119-30. Epub 2015 Jan 16. PMID: 25750917. Abstract

Increases the frequency of regulatory B cells in the cerebrospinal fluid

(215)

Fingolimod treatment promotes regulatory phenotype and function of B cells.

Grützke B, Hucke S, Gross CC, Herold MVB, Posevitz-Fejfar A, Wildemann BT, Kieseier BC, Dehmel T, Wiendl H, Klotz L

Ann Clin Transl Neurol. 2015 Feb; 2(2):119-30. Epub 2015 Jan 16. PMID: 25750917. Abstract

Increases the ratio of B cells (and naïve B cell, memory B cell, and regulatory B cell subsets) in the cerebrospinal fluid versus the blood, in agreement with the observation that fingolimod increases transendothelial migration of B cells in vitro

(215)

Fingolimod treatment promotes regulatory phenotype and function of B cells.

Grützke B, Hucke S, Gross CC, Herold MVB, Posevitz-Fejfar A, Wildemann BT, Kieseier BC, Dehmel T, Wiendl H, Klotz L

Ann Clin Transl Neurol. 2015 Feb; 2(2):119-30. Epub 2015 Jan 16. PMID: 25750917. Abstract

Increases the proportion of regulatory B cells relative to all B cells in the peripheral blood, and individuals who exhibit higher fractions of such cells in the blood tend to display stable clinical and radiological measures of disease, whereas those with lower fractions tend to exhibit active disease

(215)

Fingolimod treatment promotes regulatory phenotype and function of B cells.

Grützke B, Hucke S, Gross CC, Herold MVB, Posevitz-Fejfar A, Wildemann BT, Kieseier BC, Dehmel T, Wiendl H, Klotz L

Ann Clin Transl Neurol. 2015 Feb; 2(2):119-30. Epub 2015 Jan 16. PMID: 25750917. Abstract

Reduces levels of markers of inflammatory activity (CXCL13, CHI3L1, and CHIT1) and axonal damage (neurofilament light protein) in cerebrospinal fluid when administered to individuals switching from first-line disease-modifying therapies, but does not affect levels of these markers in individuals switching from natalizumab, as shown in a study of 43 individuals with RRMS

(335)

Cerebrospinal fluid biomarkers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosis.

Novakova L, Axelsson M, Khademi M, Zetterberg H, Blennow K, Malmeström C, Piehl F, Olsson T, Lycke J

Mult Scler. 2016 Mar 21. PMID: 27003946. Abstract

Changes the distribution of lymphocyte subsets in peripheral blood, such that the mean percentage of natural killer cells increased from 11.2 to 53.9, the mean percentage of CD4+ cells decreased from 58.7 to 8.3, and the CD4+:CD8+ ratio decreased from 3.6 to 0.35 in a 6-month study involving 25 previously untreated individuals with MS

(301)

Influence of fingolimod on basic lymphocyte subsets frequencies in the peripheral blood of multiple sclerosis patients - preliminary study.

Rudnicka J, Czerwiec M, Grywalska E, Siwicka-Gieroba D, Walankiewicz M, Grafka A, Zgurski M, Surdacka A, Bartosik-Psujek H, Roliński J

Cent Eur J Immunol. 2015; 40(3):354-9. Epub 2015 Oct 15. PMID: 26648781. Abstract

Reduces plasma levels of endothelial cell-derived microparticles to levels similar to those in healthy individuals, as shown by studies of treated and untreated individuals with MS and healthy individuals

(331)

Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients.

Zinger A, Latham SL, Combes V, Byrne S, Barnett MH, Hawke S, Grau GE

Mult Scler. 2016 Mar 1. PMID: 26931477. Abstract

Increases plasma levels of B cell-derived microparticles to levels similar to those in healthy individuals, as shown by studies of treated and untreated individuals with MS and healthy individuals

(331)

Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients.

Zinger A, Latham SL, Combes V, Byrne S, Barnett MH, Hawke S, Grau GE

Mult Scler. 2016 Mar 1. PMID: 26931477. Abstract

Elevates the ratio of naïve to memory B cells in the blood of individuals with MS

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Increases the percentage of plasma cells in the blood of individuals with MS

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Increases the proportion of transitional B cells in the blood of individuals with MS

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Increases the proportion of regulatory B cell subsets (interleukin 10+, CD25+, and CD5+ B cells) in the blood of individuals with MS

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Increases the percentage of activated CD69+ B cells among circulating B cells that remain in the blood of individuals with MS

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Decreases ICAM-1+ cells in the blood of individuals with MS, which might imply reduced capacity for antigen presentation

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Elevates the ratio of transforming growth factor beta to pro-inflammatory cytokines in the blood of individuals with MS

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Phosphorylated form activates Bcl2 (an anti-apoptotic protein) in transformed B cells from individuals with MS

(343)

Fingolimod therapy modulates circulating B cell composition, increases B regulatory subsets and production of IL-10 and TGFβ in patients with Multiple Sclerosis.

Blumenfeld S, Staun-Ram E, Miller A

J Autoimmun. 2016 Apr 4. PMID: 27055778. Abstract

Slightly reduces the T-cell response to varicella-zoster virus and Epstein-Barr virus

(71)

T-cell response against varicella-zoster virus in fingolimod-treated MS patients.

Ricklin ME, Lorscheider J, Waschbisch A, Paroz C, Mehta SK, Pierson DL, Kuhle J, Fischer-Barnicol B, Sprenger T, Lindberg RLP, et al.

Neurology. 2013 May 22. PMID: 23700335. Abstract

Reduces vaccination-induced immune responses against influenza antigens and tetanus toxoid antigens in some individuals with MS, as shown by a randomized, placebo-controlled trial

(205)

Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.

Kappos L, Mehling M, Arroyo R, Izquierdo G, Selmaj K, Curovic-Perisic V, Keil A, Bijarnia M, Singh A, von Rosenstiel P

Neurology. 2015 Jan 30. PMID: 25636714. Abstract

Associated with an increased T-cell response specific for varicella-zoster virus and varicella zoster virion component IE63 (relative to the number of CD3+ T cells) that peaks after 6 months of treatment and then reverts to baseline after 12 and 24 months, as shown in a study of 31 fingolimod-treated individuals; two individuals who lacked such a response developed herpes zoster

(329)

The VZV/IE63-specific T cell response prevents herpes zoster in fingolimod-treated patients.

Mathias A, Perriard G, Canales M, Vuilleumier F, Perrotta G, Schluep M, Du Pasquier R

Neurol Neuroimmunol Neuroinflamm. 2016 Apr; 3(2):e209. Epub 2016 Feb 10. PMID: 26913291. Abstract

Enhances the ability of human natural killer cells (activated by interleukin 2) to lyse several cell types (cells from tumor cell lines and immature and mature dendritic cells)

(152)

Effects of vitamin d3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells.

Al-Jaderi Z, Maghazachi AA

Toxins (Basel). 2013; 5(11):1932-47. PMID: 24169587. Abstract

Enhances the ability of human NK17/NK1 cells (which express CD56 and CCR4) to lyse cells from a tumor cell line

(152)

Effects of vitamin d3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells.

Al-Jaderi Z, Maghazachi AA

Toxins (Basel). 2013; 5(11):1932-47. PMID: 24169587. Abstract

Increases the expression of NKp30 and NKp44 (natural killer cytotoxicity receptors) and NKG2D on the surface of human natural killer cells

(152)

Effects of vitamin d3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells.

Al-Jaderi Z, Maghazachi AA

Toxins (Basel). 2013; 5(11):1932-47. PMID: 24169587. Abstract

Decreases the expression of CD158 (a killer inhibitory receptor) on the surface of human natural killer cells

(152)

Effects of vitamin d3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells.

Al-Jaderi Z, Maghazachi AA

Toxins (Basel). 2013; 5(11):1932-47. PMID: 24169587. Abstract

Decreases the expression of CCR6 on the surface of immature human dendritic cells

(152)

Effects of vitamin d3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells.

Al-Jaderi Z, Maghazachi AA

Toxins (Basel). 2013; 5(11):1932-47. PMID: 24169587. Abstract

Does not reduce the number of CD1c+ dendritic cells or monocytes in peripheral blood in individuals with MS

(212)

FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis.

Luessi F, Kraus S, Trinschek B, Lerch S, Ploen R, Paterka M, Roberg T, Poisa-Beiro L, Klotz L, Wiendl H, et al.

Mult Scler. 2015 Mar 2. PMID: 25732840. Abstract

Does not impair activation of CD1c+ dendritic cells (based on upregulation of CD86 on these cells)

(212)

FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis.

Luessi F, Kraus S, Trinschek B, Lerch S, Ploen R, Paterka M, Roberg T, Poisa-Beiro L, Klotz L, Wiendl H, et al.

Mult Scler. 2015 Mar 2. PMID: 25732840. Abstract

Reduces lipopolysaccharide-induced secretion of tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-6 by ex vivo CD1c+ dendritic cells and monocytes, based on experiments using cells from fingolimod-treated and untreated individuals with MS and healthy individuals

(212)

FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis.

Luessi F, Kraus S, Trinschek B, Lerch S, Ploen R, Paterka M, Roberg T, Poisa-Beiro L, Klotz L, Wiendl H, et al.

Mult Scler. 2015 Mar 2. PMID: 25732840. Abstract

Reduces platelet counts, as shown in a study of 80 individuals with MS, with samples taken one month before and one month after fingolimod treatment began

(327)

Effect of Fingolimod on Platelet Count Among Multiple Sclerosis Patients.

Farrokhi M, Beni A A, Etemadifar M, Rezaei A, Rivard L, Zadeh A R, Sedaghat N, Ghadimi M

Int J Prev Med. 2015; 6:125. Epub 2015 Dec 23. PMID: 26900439. Abstract

Inhibits myeloid cell activation

(298)

Myeloid cells as target of fingolimod action in multiple sclerosis.

Di Dario M, Colombo E, Govi C, De Feo D, Messina M J, Romeo M, Sangalli F, Moiola L, Rodegher M, Martino G, et al.

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e157. Epub 2015 Nov 04. PMID: 26587553. Abstract

In vitro exposure inhibits lipopolysaccharide-induced expression of the activation markers CD25 and CD150 and secretion of tumor necrosis factor alpha in human monocytes, but does not affect their survival

(298)

Myeloid cells as target of fingolimod action in multiple sclerosis.

Di Dario M, Colombo E, Govi C, De Feo D, Messina M J, Romeo M, Sangalli F, Moiola L, Rodegher M, Martino G, et al.

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e157. Epub 2015 Nov 04. PMID: 26587553. Abstract

Impairs the ability of monocytes to be activated by low or intermediate concentrations of lipopolysaccharide, but not by saturating concentrations, thus raising the activation threshold of the monocytes, as shown in experiments with cells from healthy individuals, individuals with untreated MS, and individuals with MS treated with fingolimod

(298)

Myeloid cells as target of fingolimod action in multiple sclerosis.

Di Dario M, Colombo E, Govi C, De Feo D, Messina M J, Romeo M, Sangalli F, Moiola L, Rodegher M, Martino G, et al.

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e157. Epub 2015 Nov 04. PMID: 26587553. Abstract

Inhibits subsequent sphingosine 1-phosphate-induced signaling of extracellular-signal-regulated kinase (pERK1/2) in cultured human fetal astrocytes

(60)

Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation.

Wu C, Leong SY, Moore CS, Cui Q L, Gris P, Bernier L-P, Johnson TA, Séguéla P, Kennedy TE, Bar-Or A, et al.

J Neuroinflammation. 2013 Mar 19; 10(1):41. Epub 2013 Mar 19. PMID: 23509960. Abstract

Does not inhibit serum- or interleukin-1beta-induced signaling of extracellular-signal-regulated kinase (pERK1/2) in cultured human fetal astrocytes

(60)

Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation.

Wu C, Leong SY, Moore CS, Cui Q L, Gris P, Bernier L-P, Johnson TA, Séguéla P, Kennedy TE, Bar-Or A, et al.

J Neuroinflammation. 2013 Mar 19; 10(1):41. Epub 2013 Mar 19. PMID: 23509960. Abstract

Might desensitize astrocytes to sphingosine 1-phosphate receptor stimulation, but sustain reactions that are independent of such stimulation, thus modulating specific neuroinflammatory responses

(60)

Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation.

Wu C, Leong SY, Moore CS, Cui Q L, Gris P, Bernier L-P, Johnson TA, Séguéla P, Kennedy TE, Bar-Or A, et al.

J Neuroinflammation. 2013 Mar 19; 10(1):41. Epub 2013 Mar 19. PMID: 23509960. Abstract

Phosphorylated form increases levels of mRNAs encoding the neurotrophic mediators leukemia inhibitory factor, interleukin 11, and heparin-binding EGF-like growth factor in human astrocytes, an effect mediated by sphingosine-1-phosphate receptors 1 and 3

(284)

Fingolimod induces neuroprotective factors in human astrocytes.

Hoffmann FS, Hofereiter J, Rübsamen H, Melms J, Schwarz S, Faber H, Weber P, Pütz B, Loleit V, Weber F, et al.

J Neuroinflammation. 2015; 12(1):184. Epub 2015 Sep 30. PMID: 26419927. Abstract

Phosphorylated form increases secretion of the neurotrophic mediators leukemia inhibitory factor and interleukin 11 from human astrocytes

(284)

Fingolimod induces neuroprotective factors in human astrocytes.

Hoffmann FS, Hofereiter J, Rübsamen H, Melms J, Schwarz S, Faber H, Weber P, Pütz B, Loleit V, Weber F, et al.

J Neuroinflammation. 2015; 12(1):184. Epub 2015 Sep 30. PMID: 26419927. Abstract

Phosphorylated form blocks the tumor necrosis factor-induced expression of inflammatory mediators (CXCL10, BAFF, MX1, and OAS2) by human astrocytes

(284)

Fingolimod induces neuroprotective factors in human astrocytes.

Hoffmann FS, Hofereiter J, Rübsamen H, Melms J, Schwarz S, Faber H, Weber P, Pütz B, Loleit V, Weber F, et al.

J Neuroinflammation. 2015; 12(1):184. Epub 2015 Sep 30. PMID: 26419927. Abstract

Phosphorylated version promotes differentiation of fetal oligodendrocyte progenitor cells in culture

(137)

Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors.

Cui Q L, Fang J, Kennedy TE, Almazan G, Antel JP

Glia. 2014 May 9. PMID: 24810969. Abstract

Reduces relapses and decreases brain volume loss in RRMS, and these two effects independently predict the effect of therapy on disability, as shown by analysis of data from the FREEDOMS clinical trial

(208)

Fingolimod effect on brain volume loss independently contributes to its effect on disability.

Sormani M, De Stefano N, Francis G, Sprenger T, Chin P, Radue E, Kappos L

Mult Scler. 2015 Feb 6. PMID: 25662353. Abstract

Associated with a consistent reduction in the annualized rate of brain atrophy, as shown by analysis of data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials and their extensions; furthermore, participants who switched to fingolimod from the comparator were found to then display atrophy rates similar to those who were randomized to fingolimod initially

(224)

Consistent reduction in the annualized rate of brain volume loss across phase 3 core and extension trials of fingolimod in relapsing multiple sclerosis.

Radue E, Sprenger T, Chin P, Meier DP, Sfikas N, Barkhof F

Mult Scler Relat Disord. 2014 Nov; 3(6):750-1. Epub 2014 Nov 21. PMID: 25891586. Abstract

Associated with a trend toward reduction of the conversion of acute gadolinium-enhancing lesions to chronic T1 hypointensities (or "chronic black holes"), as shown in a retrospective, nonrandomized comparison of 26 individuals with MS treated with fingolimod with 30 individuals with MS on no therapy

(291)

The Effect of Fingolimod on Conversion of Acute Gadolinium-Enhancing Lesions to Chronic T1 Hypointensities in Multiple Sclerosis.

Oommen VV, Tauhid S, Healy BC, Chua AS, Malik MT, Diaz-Cruz C, Dupuy SL, Weiner HL, Chitnis T, Bakshi R

J Neuroimaging. 2015 Oct 8. PMID: 26445919. Abstract

Suppressed paroxysmal dysarthria–ataxia syndrome (which involves transient alterations in speech and limb or gait ataxia) in an individual with RRMS

(211)

Paroxysmal dysarthria-ataxia syndrome resolving after fingolimod treatment.

Rossi S, Studer V, Motta C, Centonze D

J Neurol Sci. 2015 Jan 28. PMID: 25676590. Abstract

Comparison of a Markov transition model approach and survival analysis methods for quantifying the effects of fingolimod on disability progression has been published

(56)

Estimating Time to Disease Progression Comparing Transition Models and Survival Methods-An Analysis of Multiple Sclerosis Data.

Mandel M, Mercier F, Eckert B, Chin P, Betensky RA

Biometrics. 2013 Feb 14. PMID: 23410536. Abstract

Associated with an increase in macular volume within 5 months in a longitudinal observational study

(47)

Fingolimod treatment in multiple sclerosis leads to increased macular volume.

Nolan R, Gelfand JM, Green AJ

Neurology. 2012 Dec 5. PMID: 23223539. Abstract

Fingolimod directly inhibits the human ether-a-go-go-related gene (hERG) current, whereas siponimod does not, in a model in which hERG channels are expressed in human embryonic kidney 293 cells

(176)

Analysis of Onset Mechanisms of a Sphingosine 1-Phosphate Receptor Modulator Fingolomod-Induced Atrioventricular Conduction Block and QT-Interval Prolongation.

Yagi Y, Nakamura Y, Kitahara K, Harada T, Kato K, Ninomiya T, Cao X, Ohara H, Izumi-Nakaseko H, Suzuki K, et al.

Toxicol Appl Pharmacol. 2014 Sep 16. PMID: 25223691. Abstract

Stimulates protein phosphatase 2A (PP2A) or PP2A-like activity in the Jurkat human T cell line; PP2A is a tumor suppressor that is inactive in some cancers

(84)

A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells.

Matsuoka Y, Nagahara Y, Ikekita M, Shinomiya T

Br J Pharmacol. 2003 Apr; 138(7):1303-12. PMID: 12711631. Abstract

(85)

Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies.

Oaks JJ, Santhanam R, Walker CJ, Roof S, Harb JG, Ferenchak G, Eisfeld A K, Van Brocklyn JR, Briesewitz R, Saddoughi SA, et al.

Blood. 2013 Aug 7. PMID: 23926298. Abstract

Decreases the viability of human tumor cells (melanoma, cervix carcinoma, and breast carcinoma) in vitro

(133)

FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system.

Pereira FV, Arruda DC, Figueiredo CR, Massaoka MH, Matsuo AL, Bueno V, Rodrigues EG

Clinics (Sao Paulo). 2013 Jul; 68(7):1018-27. PMID: 23917669. Abstract

Induces apoptosis in acute myeloid leukemia cells, M2 subtype, by rapidly increasing levels of pro-apoptotic ceramide

(165)

FTY720 induces apoptosis of m2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels.

Chen L, Luo L-F, Lu J, Li L, Liu Y-F, Wang J, Liu H, Song H, Jiang H, Chen S-J, et al.

PLoS One. 2014; 9(7):e103033. Epub 2014 Jul 22. PMID: 25050888. Abstract

In combination with monomethyl fumarate (MMF, the active metabolite of dimethyl fumarate), reduces the viability of primary human glioblastoma cells and activated microglia more than MMF alone

(198)

Regulation of dimethyl-fumarate toxicity by proteasome inhibitors.

Booth L, Cruickshanks N, Tavallai S, Roberts JL, Peery M, Poklepovic A, Dent P

Cancer Biol Ther. 2014 Sep 24. PMID: 25482938. Abstract

Sensitizes human hepatocellular carcinoma cells to the cytotoxic effects of the kinase inhibitor drug sorafenib

(294)

FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib-mediated cytotoxicity.

Ahmed D, de Verdier PJ, Ryk C, Lunqe O, Stål P, Flygare J

Pharmacol Res Perspect. 2015 Oct; 3(5):e00171. Epub 2015 Aug 19. PMID: 26516583. Abstract

Potently inhibits transient receptor potential melastatin 7 (TRPM7), a channel kinase, based on studies involving stable expression of TRPM7 in human embryonic kidney 293 cells

(89)

Sphingosine and FTY720 are potent inhibitors of the transient receptor potential melastatin 7 (TRPM7) channels.

Qin X, Yue Z, Sun B, Yang W, Xie J, Ni E, Feng Y, Mahmood R, Zhang Y, Yue L

Br J Pharmacol. 2013 Mar; 168(6):1294-312. Epub 1969 Dec 31. PMID: 23145923. Abstract

Has been used to treat two individuals with natalizumab-associated progressive multifocal leukoencephalopathy (PML) who displayed severe MS relapses after natalizumab discontinuation; the MS symptoms improved and the PML did not worsen

(110)

Fingolimod to treat severe multiple sclerosis after natalizumab-associated progressive multifocal leukoencephalopathy: a valid option?

Maillart E, Louapre C, Lubetzki C, Papeix C

Mult Scler. 2013 Dec 23. PMID: 24367037. Abstract

May not confer benefit in individuals who are positive for aquaporin-4 antibodies, based on results from 4 individuals; 3 of these individuals exhibited disease exacerbations soon after beginning treatment

(114)

Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension.

Kira J-I, Itoyama Y, Kikuchi S, Hao Q, Kurosawa T, Nagato K, Tsumiyama I, von Rosenstiel P, Zhang-Auberson L, Saida T

BMC Neurol. 2014; 14(1):21. Epub 2014 Jan 29. PMID: 24475777. Abstract

Ability to affect sphingosine 1-phosphate receptor 1 (S1P1R) appears to be affected by genetic variations in S1P1R identified by exon sequencing of >12,000 individuals

(183)

Individual variation of human sphingosine 1-phosphate receptor 1 coding sequence leads to heterogeneity in receptor function and drug interactions.

Obinata H, Gutkind S, Stitham J, Okuno T, Yokomizo T, Hwa J, Hla T

J Lipid Res. 2014 Oct 7. PMID: 25293589. Abstract

Phosphorylated form induces endocytosis and degradation of wild-type sphingosine 1-phosphate receptor 1 (S1P1R), but only weakly affects the endocytosis and degradation of two mutant forms of S1P1R (I45T and G305C), which are encoded by natural variants of the S1P1R gene, as shown by experiments involving expression of these proteins in cultured cells

(183)

Individual variation of human sphingosine 1-phosphate receptor 1 coding sequence leads to heterogeneity in receptor function and drug interactions.

Obinata H, Gutkind S, Stitham J, Okuno T, Yokomizo T, Hwa J, Hla T

J Lipid Res. 2014 Oct 7. PMID: 25293589. Abstract

Phosphorylated form accumulates in the nucleus of human neuroblastoma cells

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Increases acetylation of specific lysine residues in histone H3 (Lys9), histone H4 (Lys5), and histone H2B (Lys12) in human neuroblastoma cells

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Phosphorylated form (but not the unphosphorylated form) strongly inhibits the activity of recombinant human class I histone deacetylases (HDAC1, HDAC2, HDAC3, and HDAC8)

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Binds to histone deacetylase I, as shown by experiments with recombinant enzyme and immunoprecipitation from HeLa cells

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Phosphorylated form protects neuronal cells from damage caused by synthetic human prion protein peptide

(147)

FTY720 protects neuronal cells from damage induced by human prion protein by inactivating the JNK pathway.

Moon M-H, Jeong J-K, Lee Y-J, Park S-Y

Int J Mol Med. 2013 Dec; 32(6):1387-93. Epub 2013 Oct 16. PMID: 24142108. Abstract

May shield neurons from degenerating in the presence of human immunodeficiency virus (HIV), as shown in experiments monitoring gene expression in differentiated human neuronal progenitor cells exposed to HIV (meeting report)

(286)

Fingolimod May Protect Neurons from Degeneration

Blum K, MedPage Today, 5 Oct 2015

Accessed on 13 Oct 2015 from http://www.medpagetoday.com/MeetingCoverage/ANA/53913.

Reduces intracortical excitability, which is primarily mediated by glutamate, in individuals with RRMS

(161)

Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis.

Landi D, Vollaro S, Pellegrino G, Mulas D, Ghazaryan A, Falato E, Pasqualetti P, Rossini P, Filippi M

Clin Neurophysiol. 2014 Jun 19. PMID: 25022794. Abstract

Dramatically reduced gadolinium-enhancing lesions in an individual with highly active RRMS, who had previously discontinued natalizumab because of side effects

(168)

Fingolimod in active multiple sclerosis: an impressive decrease in Gd-enhancing lesions.

Muris A-H, Rolf L, Damoiseaux J, Koeman E, Hupperts R

BMC Neurol. 2014 Aug 20; 14(1):164. Epub 2014 Aug 20. PMID: 25138918. Abstract

May increase the probability of conception in woman with RRMS linked with secondary infertility

(231)

Fingolimod (Gilenya) may improve the chances of conception in women with multiple sclerosis (MS) associated with secondary infertlity.

Inshasi J, Almadani A, Alrukn S, Alboudi A

Mult Scler Relat Disord. 2014 Nov; 3(6):749-50. Epub 2014 Nov 21. PMID: 25891583. Abstract

Associated with a reduction in heart rate as compared with baseline when therapy is initiated; the lowest heart rate occurs 5 hours after the first dose, as shown in a prospective study of 27 individuals with RRMS

(250)

Effects of Three Months Fingolimod Therapy on Heart Rate.

Simula S, Laitinen T, Laitinen TM, Tarkiainen T, Hartikainen JEK, Hartikainen P

J Neuroimmune Pharmacol. 2015 Jun 20. Epub 2015 Jun 20. PMID: 26092537. Abstract

Associated with a reduced nighttime heart rate as compared with baseline, but a normal daytime heart rate, after three months of therapy, as shown in a prospective study of 24 individuals with RRMS

(250)

Effects of Three Months Fingolimod Therapy on Heart Rate.

Simula S, Laitinen T, Laitinen TM, Tarkiainen T, Hartikainen JEK, Hartikainen P

J Neuroimmune Pharmacol. 2015 Jun 20. Epub 2015 Jun 20. PMID: 26092537. Abstract

Did not cause significant changes in the cerebral blood flow, platelet function, or macular thickness in a double-blind, placebo-controlled study of healthy volunteers

(155)

Effect of fingolimod (FTY720) on cerebral blood flow, platelet function, and macular thickness in healthy volunteers.

Ocwieja M, Meiser K, David OJ, Valencia J, Wagner F, Schreiber SJ, Pleyer U, Ziemer S, Schmouder R

Br J Clin Pharmacol. 2014 Jun 29. PMID: 24976291. Abstract

Animal:

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

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

May have beneficial effects in the central nervous system beyond effects on immune cell trafficking

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

; role in neuroprotection might result from interactions with neuron and glia sphingosine 1-phosphate receptors

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

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

(9)

Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice.

Webb M, Tham C-S, Lin F-F, Lariosa-Willingham K, Yu N, Hale J, Mandala S, Chun J, Rao TS

J Neuroimmunol. 2004 Aug; 153(1-2):108-21. PMID: 15265669. Abstract

Active phosphorylated form reduces Schwann cell-mediated myelination in cultured rat cells

(31)

Fingolimod Impedes Schwann Cell-Mediated Myelination: Implications for the Treatment of Immune Neuropathies?Effect of Fingolimod on Schwann Cells.

Köhne A, Stettner M, Jangouk P, Dehmel T, Hartung H-P, Lehmann HC, Kieseier BC

Arch Neurol. 2012 Jul 2:1-10. PMID: 22751954. Abstract

Reduces breakdown of the blood-brain barrier during delayed-type hypersensitivity lesion formation in a Lewis rat model of MS

(112)

Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.

Anthony DC, Sibson NR, Losey P, Meier D P, Leppert D

Neuropharmacology. 2014 Jan 9. PMID: 24412675. Abstract

Reduces recruitment of lymphocytes and macrophages/activated microglia to delayed-type hypersensitivity lesions during lesion formation in a Lewis rat model of MS

(112)

Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.

Anthony DC, Sibson NR, Losey P, Meier D P, Leppert D

Neuropharmacology. 2014 Jan 9. PMID: 24412675. Abstract

Reduces the area of demyelination, but does not affect recruitment of lymphocytes within lesions, during the chronic disease phase (when the blood-brain barrier has resealed) in a focal delayed-type hypersensitivity model of MS in Lewis rats

(112)

Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.

Anthony DC, Sibson NR, Losey P, Meier D P, Leppert D

Neuropharmacology. 2014 Jan 9. PMID: 24412675. Abstract

Reduces levels of circulating γδ T cells, as well as levels of conventional αβ T cells, in mice

(258)

IL-17-Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions.

Maeda Y, Seki N, Kataoka H, Takemoto K, Utsumi H, Fukunari A, Sugahara K, Chiba K

J Immunol. 2015 Jul 13. PMID: 26170380. Abstract

Results in the accumulation of interleukin-17 (IL-17)+Vγ4+, IL-17+Vγ4-, and IL-17-Vγ4- T cells in the lymph nodes in mice

(258)

IL-17-Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions.

Maeda Y, Seki N, Kataoka H, Takemoto K, Utsumi H, Fukunari A, Sugahara K, Chiba K

J Immunol. 2015 Jul 13. PMID: 26170380. Abstract

Results in the sequestration of interleukin-17-producing Vγ4+ γδ T cells in the draining lymph nodes under inflammatory conditions at the skin; these cells would normally infiltrate the inflammed skin

(258)

IL-17-Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions.

Maeda Y, Seki N, Kataoka H, Takemoto K, Utsumi H, Fukunari A, Sugahara K, Chiba K

J Immunol. 2015 Jul 13. PMID: 26170380. Abstract

Results in the sequestration of interleukin-17-producing Vγ4+ γδ T cells in the draining lymph nodes in experimental autoimmune encephalomyelitis, inhibiting the infiltration of these cells into the central nervous system

(258)

IL-17-Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions.

Maeda Y, Seki N, Kataoka H, Takemoto K, Utsumi H, Fukunari A, Sugahara K, Chiba K

J Immunol. 2015 Jul 13. PMID: 26170380. Abstract

Downregulates sphingosine 1-phosphate receptor 1 expression, and the ability to respond to sphingosine 1-phosphate, in Vγ4+ γδ T cells in mice

(258)

IL-17-Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions.

Maeda Y, Seki N, Kataoka H, Takemoto K, Utsumi H, Fukunari A, Sugahara K, Chiba K

J Immunol. 2015 Jul 13. PMID: 26170380. Abstract

Phosphorylated form reduces levels of the tight junction protein occludin in rat brain microvascular endothelial cell culture under inflammatory conditions

(312)

Fingolimod (FTY720-P) Does Not Stabilize the Blood-Brain Barrier under Inflammatory Conditions in an in Vitro Model.

Schuhmann MK, Bittner S, Meuth SG, Kleinschnitz C, Fluri F

Int J Mol Sci. 2015; 16(12):29454-66. PMID: 26690412. Abstract

Phosphorylated form does not reduce endothelial barrier permeability in rat brain microvascular endothelial cell culture under inflammatory conditions

(312)

Fingolimod (FTY720-P) Does Not Stabilize the Blood-Brain Barrier under Inflammatory Conditions in an in Vitro Model.

Schuhmann MK, Bittner S, Meuth SG, Kleinschnitz C, Fluri F

Int J Mol Sci. 2015; 16(12):29454-66. PMID: 26690412. Abstract

Phosphorylated form does not affect levels of endothelial matrix metalloproteinases MMP-9 and MMP-2 in rat brain microvascular endothelial cell culture under inflammatory conditions

(312)

Fingolimod (FTY720-P) Does Not Stabilize the Blood-Brain Barrier under Inflammatory Conditions in an in Vitro Model.

Schuhmann MK, Bittner S, Meuth SG, Kleinschnitz C, Fluri F

Int J Mol Sci. 2015; 16(12):29454-66. PMID: 26690412. Abstract

Systemic treatment causes dendritic cells to accumulate in the central nervous system in normal mice

(121)

Immune cell trafficking from the brain maintains CNS immune tolerance.

Mohammad MG, Tsai VWW, Ruitenberg MJ, Hassanpour M, Li H, Hart PH, Breit SN, Sawchenko PE, Brown DA

J Clin Invest. 2014 Mar 3; 124(3):1228-41. Epub 2014 Feb 24. PMID: 24569378. Abstract

Reduces the egress of dendritic cells (DCs) from the central nervous system to the cervical lymph nodes (a site where CNS-specific T cells are activated) as the DCs travel via the rostral migratory stream

(121)

Immune cell trafficking from the brain maintains CNS immune tolerance.

Mohammad MG, Tsai VWW, Ruitenberg MJ, Hassanpour M, Li H, Hart PH, Breit SN, Sawchenko PE, Brown DA

J Clin Invest. 2014 Mar 3; 124(3):1228-41. Epub 2014 Feb 24. PMID: 24569378. Abstract

Although systemic delivery inhibits experimental autoimmune encephalomyelitis (EAE), delivery to the rostral migratory stream, through which dendritic cells normally migrate to the cervical lymph nodes and modulate regulatory T cell function, increases the severity of EAE

(121)

Immune cell trafficking from the brain maintains CNS immune tolerance.

Mohammad MG, Tsai VWW, Ruitenberg MJ, Hassanpour M, Li H, Hart PH, Breit SN, Sawchenko PE, Brown DA

J Clin Invest. 2014 Mar 3; 124(3):1228-41. Epub 2014 Feb 24. PMID: 24569378. Abstract

Delivery to the rostral migratory stream induces experimental autoimmune encephalomyelitis in a disease-resistant mouse strain by reducing dendritic cell (DC) egress from the central nervous system (CNS) to the cervical lymph nodes, where DCs normally enhance regulatory T cell function and downregulate CNS autoimmunity

(121)

Immune cell trafficking from the brain maintains CNS immune tolerance.

Mohammad MG, Tsai VWW, Ruitenberg MJ, Hassanpour M, Li H, Hart PH, Breit SN, Sawchenko PE, Brown DA

J Clin Invest. 2014 Mar 3; 124(3):1228-41. Epub 2014 Feb 24. PMID: 24569378. Abstract

Does not change the inflammatory activity of dendritic cells from the central nervous system

(121)

Immune cell trafficking from the brain maintains CNS immune tolerance.

Mohammad MG, Tsai VWW, Ruitenberg MJ, Hassanpour M, Li H, Hart PH, Breit SN, Sawchenko PE, Brown DA

J Clin Invest. 2014 Mar 3; 124(3):1228-41. Epub 2014 Feb 24. PMID: 24569378. Abstract

Inhibits experimental autoimmune encephalomyelitis in Cbl-b-deficient mice, indicating that fingolimod may still be useful in individuals with MS with Cbl-b abnormalities

(255)

Cbl-b-deficient mice express alterations in trafficking-related molecules but retain sensitivity to the multiple sclerosis therapeutic agent, FTY720.

Fujiwara M, Anstadt EJ, Khanna KM, Clark RB

Clin Immunol. 2015 Mar 28; 158(1):103-113. PMID: 25829233. Abstract

(CBLB polymorphisms in humans have been linked to MS risk; one has been shown to affect T cell response to type I interferons

(256)

A Multiple Sclerosis-Associated Variant of CBLB Links Genetic Risk with Type I IFN Function.

Stürner K H, Borgmeyer U, Schulze C, Pless O, Martin R

J Immunol. 2014 Sep 26. PMID: 25261476. Abstract

)

Ameliorates experimental autoimmune encephalomyelitis (EAE), even when administered after pathology onset, in EAE mice

(304)

Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice.

Hou H, Cao R, Miao J, Sun Y, Liu X, Song X, Guo L

Int Immunopharmacol. 2015 Nov 26. PMID: 26632437. Abstract

Inhibits the Akt-mTOR signaling pathway, which is activated in experimental autoimmune encephalomyelitis (EAE), in EAE mice

(304)

Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice.

Hou H, Cao R, Miao J, Sun Y, Liu X, Song X, Guo L

Int Immunopharmacol. 2015 Nov 26. PMID: 26632437. Abstract

Increases the frequency of Treg cells [which is reduced in experimental autoimmune encephalomyelitis (EAE)] and reduces the frequency of Th1 cells (which is increased in EAE) in the spleen in EAE mice

(304)

Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice.

Hou H, Cao R, Miao J, Sun Y, Liu X, Song X, Guo L

Int Immunopharmacol. 2015 Nov 26. PMID: 26632437. Abstract

Late-therapeutic treatment improves sociability deficits and prophylactic treatment improves gait in one experimental autoimmune encephalomyelitis mouse model, but neither form of treatment reduces clinical scores in this model

(311)

Multiple rodent models and behavioral measures reveal unexpected responses to FTY720 and DMF in experimental autoimmune encephalomyelitis.

de Bruin NMWJ, Schmitz K, Schiffmann S, Tafferner N, Schmidt M, Jordan H, Häußler A, Tegeder I, Geisslinger G, Parnham MJ

Behav Brain Res. 2015 Dec 12. PMID: 26692368. Abstract

Causes subtle changes in behavior (longer ultrasonic vocalizations and more motor activity as compared with vehicle treatment) in experimental autoimmune encephalomyelitis mice in the period before clinical symptoms (weight loss and limb paralysis) become apparent

(143)

Targeting S1P receptors in experimental autoimmune encephalomyelitis in mice improves early deficits in locomotor activity and increases ultrasonic vocalisations.

Sheridan GK, Dev KK

Sci Rep. 2014; 4:5051. PMID: 24851861. Abstract

Active phosphorylated form induces apoptosis in cultured rat Schwann cells

(31)

Fingolimod Impedes Schwann Cell-Mediated Myelination: Implications for the Treatment of Immune Neuropathies?Effect of Fingolimod on Schwann Cells.

Köhne A, Stettner M, Jangouk P, Dehmel T, Hartung H-P, Lehmann HC, Kieseier BC

Arch Neurol. 2012 Jul 2:1-10. PMID: 22751954. Abstract

Inhibits demyelination induced by lysolecithin in rat cerebellar slice cultures

(102)

S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures.

Sheridan GK, Dev KK

Glia. 2012 Mar; 60(3):382-92. Epub 2011 Nov 22. PMID: 22108845. Abstract

With the sphingosine-1-phosphate receptor 1 (S1P1R) agonist SEW2871, increases S1P1R expression in astrocytes in rat cerebellar slice cultures

(102)

S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures.

Sheridan GK, Dev KK

Glia. 2012 Mar; 60(3):382-92. Epub 2011 Nov 22. PMID: 22108845. Abstract

Inhibits the release of chemokines LIX, MIP-1alpha, and MIP-3alpha in rat cerebellar slice cultures in which demyelination was induced by lysolecithin

(102)

S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures.

Sheridan GK, Dev KK

Glia. 2012 Mar; 60(3):382-92. Epub 2011 Nov 22. PMID: 22108845. Abstract

May inhibit demyelination, in part, by reducing chemokine-mediated communication between immune and central nervous system cells

(102)

S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures.

Sheridan GK, Dev KK

Glia. 2012 Mar; 60(3):382-92. Epub 2011 Nov 22. PMID: 22108845. Abstract

Inhibits events mediated by sphingosine-1-phosphate (S1P) and inflammatory cytokines (translocation of NFkappaB and nitric oxide production) in astrocytes, and thus astrocyte-mediated neurodegeneration, as shown by experiments with an in vitro model; S1P and cytokines are upregulated in astrocytes in MS and experimental autoimmune encephalomyelitis lesions

(166)

Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide.

Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, Farina C

Ann Neurol. 2014 Jul 4. PMID: 25043204. Abstract

Inhibits activation of astrocytes and production of nitric oxide in experimental autoimmune encephalomyelitis mice

(166)

Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide.

Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, Farina C

Ann Neurol. 2014 Jul 4. PMID: 25043204. Abstract

When used In vitro to treat myelin oligodendrocyte glycoprotein-reactive splenocytes from mice, reduces demyelination caused by these cells in mouse cerebellar slices

(149)

Fingolimod attenuates splenocyte-induced demyelination in cerebellar slice cultures.

Pritchard AJ, Mir AK, Dev KK

PLoS One. 2014; 9(6):e99444. Epub 2014 Jun 09. PMID: 24911000. Abstract

When used In vitro to treat mouse splenocytes that have been engineered to be stimulated by myelin oligodendrocyte glycoprotein (MOG), reduces the release of pro-inflammatory cytokines (interferon gamma and interleukin-6) by these cells during MOG stimulation

(149)

Fingolimod attenuates splenocyte-induced demyelination in cerebellar slice cultures.

Pritchard AJ, Mir AK, Dev KK

PLoS One. 2014; 9(6):e99444. Epub 2014 Jun 09. PMID: 24911000. Abstract

Phosphorylated form, but not nonphosphorylated form, inhibits interleukin-2 (IL-2) production stimulated by IL-33 in a mouse lymphoma cell line overexpressing the IL-33 receptor

(313)

Fingolimod targeting protein phosphatase 2A differently affects IL-33 induced IL-2 and IFN-γ production in CD8(+) lymphocytes.

Ottenlinger F, Schwiebs A, Pfarr K, Wagner A, Grüner S, Mayer C, Pfeilschifter JM, Radeke HH

Eur J Immunol. 2015 Dec 18. PMID: 26683421. Abstract

Increases oligodendrocyte progenitor cell number and proliferation in the brain and spinal cord white matter, concurrent with its associated reduction in disease score, in mice with experimental autoimmune encephalomyelitis

(210)

Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis.

Zhang J, Zhang Z G, Li Y, Ding X, Shang X, Lu M, Elias SB, Chopp M

Neurobiol Dis. 2015 Feb 11; 76:57-66. PMID: 25680941. Abstract

Increases oligodendrocytes, myelination, and oligodendrocyte progenitor cell differentiation in mice with experimental autoimmune encephalomyelitis

(210)

Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis.

Zhang J, Zhang Z G, Li Y, Ding X, Shang X, Lu M, Elias SB, Chopp M

Neurobiol Dis. 2015 Feb 11; 76:57-66. PMID: 25680941. Abstract

Increases levels of Sonic hedgehog (Shh), as well as levels of the Shh receptor Smoothened and effector Gli1, in the central nervous system white matter of mice with experimental autoimmune encephalomyelitis

(210)

Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis.

Zhang J, Zhang Z G, Li Y, Ding X, Shang X, Lu M, Elias SB, Chopp M

Neurobiol Dis. 2015 Feb 11; 76:57-66. PMID: 25680941. Abstract

Improves symptoms and increases oligodendrocyte progenitor proliferation and differentiation, but this effect is abolished by the Sonic hedgehog pathway inhibitor cyclopamine, in mice with experimental autoimmune encephalomyelitis

(210)

Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis.

Zhang J, Zhang Z G, Li Y, Ding X, Shang X, Lu M, Elias SB, Chopp M

Neurobiol Dis. 2015 Feb 11; 76:57-66. PMID: 25680941. Abstract

Modestly accelerates remyelination in the central nervous system after acute but not chronic exposure to the toxin cuprizone, which induces demyelination

(177)

FTY720 is neuroprotective after cuprizone-induced central nervous system demyelination.

Slowik A, Schmidt T, Beyer C, Amor S, Clarner T, Kipp M

Br J Pharmacol. 2014 Sep 14. PMID: 25220526. Abstract

Appears to reduce ongoing axonal damage (assessed by the axonal buildup of amyloid precursor protein-positive spheroids) after cuprizone-induced central nervous system demyelination

(177)

FTY720 is neuroprotective after cuprizone-induced central nervous system demyelination.

Slowik A, Schmidt T, Beyer C, Amor S, Clarner T, Kipp M

Br J Pharmacol. 2014 Sep 14. PMID: 25220526. Abstract

Enhances remyelination in a mouse model of local demyelination

(293)

Enhanced remyelination following lysolecithin-induced demyelination in mice under treatment with fingolimod (FTY720).

Yazdi A, Baharvand H, Javan M

Neuroscience. 2015 Dec 17; 311:34-44. Epub 2015 Oct 17. PMID: 26475743. Abstract

Does not increase remyelination in the mouse cerebellum when given after demyelination is induced by cuprizone

(262)

Fingolimod does not enhance cerebellar remyelination in the cuprizone model.

Alme M N, Nystad AE, Bø L, Myhr K-M, Vedeler CA, Wergeland S, Torkildsen Ø

J Neuroimmunol. 2015 Aug 15; 285:180-6. Epub 2015 Jun 19. PMID: 26198937. Abstract

Does not change the number of microglia, astrocytes, or mature oligodendrocytes in the mouse cerebellum when given after demyelination is induced by cuprizone

(262)

Fingolimod does not enhance cerebellar remyelination in the cuprizone model.

Alme M N, Nystad AE, Bø L, Myhr K-M, Vedeler CA, Wergeland S, Torkildsen Ø

J Neuroimmunol. 2015 Aug 15; 285:180-6. Epub 2015 Jun 19. PMID: 26198937. Abstract

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

(10)

Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment.

Fujino M, Funeshima N, Kitazawa Y, Kimura H, Amemiya H, Suzuki S, Li X-K

J Pharmacol Exp Ther. 2003 Apr; 305(1):70-7. PMID: 12649354. Abstract

Reduces microglial activation in chronic delayed type hypersensitivity-like lesions in experimental autoimmune encephalitis, an effect that can be monitored in vivo by positron emission tomography and a radioligand

(203)

In vivo Positron Emission Tomography Imaging Demonstrates Diminished Microglial Activation after Fingolimod Treatment in an Animal Model of Multiple Sclerosis.

Airas L, Dickens A, Elo P, Marjamäki P M, Johansson J, Eskola O, Jones P, Trigg W, Solin O, Haaparanta-Solin M, et al.

J Nucl Med. 2015 Jan 8. PMID: 25572093. Abstract

Inhibits intracellular vesicle mobility and secretion, thereby affecting regulated exocytosis, in cultured rat astrocytes

(27)

Fingolimod-A sphingosine-like molecule inhibits vesicle mobility and secretion in astrocytes.

Trkov S, Stenovec M, Kreft M, Potokar M, Parpura V, Davletov B, Zorec R

Glia. 2012 May 25. PMID: 22639011. Abstract

Does not affect T and B cell memory activation or expansion upon viral infection in animal models

(12)

FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory.

Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, Zinkernagel RM

J Immunol. 2000 Jun 1; 164(11):5761-70. PMID: 10820254. Abstract

Reduces anti-viral immune responses (by reducing the accumulation of virus-specific T cells in the central nervous system) in mice infected with a neurotropic strain of mouse hepatitis virus, increasing disease severity and mortality

(169)

FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.

Blanc CA, Rosen H, Lane TE

J Neuroinflammation. 2014 Aug 20; 11(1):138. Epub 2014 Aug 20. PMID: 25138356. Abstract

Reduces neuroinflammation and demyelination in mice infected with a neurotropic strain of mouse hepatitis virus

(169)

FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.

Blanc CA, Rosen H, Lane TE

J Neuroinflammation. 2014 Aug 20; 11(1):138. Epub 2014 Aug 20. PMID: 25138356. Abstract

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

(35)

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome.

Deogracias R, Yazdani M, Dekkers MPJ, Guy J, Ionescu M CS, Vogt KE, Barde Y-A

Proc Natl Acad Sci U S A. 2012 Aug 28; 109(35):14230-5. Epub 2012 Aug 13. PMID: 22891354. Abstract

Increases brain-derived neurotrophic factor levels in the cortex, hippocampus, and striatum of mice

(35)

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome.

Deogracias R, Yazdani M, Dekkers MPJ, Guy J, Ionescu M CS, Vogt KE, Barde Y-A

Proc Natl Acad Sci U S A. 2012 Aug 28; 109(35):14230-5. Epub 2012 Aug 13. PMID: 22891354. Abstract

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

(35)

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome.

Deogracias R, Yazdani M, Dekkers MPJ, Guy J, Ionescu M CS, Vogt KE, Barde Y-A

Proc Natl Acad Sci U S A. 2012 Aug 28; 109(35):14230-5. Epub 2012 Aug 13. PMID: 22891354. Abstract

Increases the frequency and amplitude of excitatory postsynaptic currents, but reduces the amplitude and frequency of inhibitory postsynaptic currents, in cultured mouse neurons

(35)

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome.

Deogracias R, Yazdani M, Dekkers MPJ, Guy J, Ionescu M CS, Vogt KE, Barde Y-A

Proc Natl Acad Sci U S A. 2012 Aug 28; 109(35):14230-5. Epub 2012 Aug 13. PMID: 22891354. Abstract

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

(45)

Fingolimod protects cultured cortical neurons against excitotoxic death.

Di Menna L, Molinaro G, Di Nuzzo L, Riozzi B, Zappulla C, Pozzilli C, Turrini R, Caraci F, Copani A, Battaglia G, et al.

Pharmacol Res. 2012 Oct 13. PMID: 23073075. Abstract

Reduces excitotoxic cell death (induced by N-methyl-D-aspartic acid) of primary rat neuronal cells and in cerebrocortical cultures from rat pups

(240)

FTY720 attenuates excitotoxicity and neuroinflammation.

Cipriani R, Chara J C, Rodríguez-Antigüedad A, Matute C

J Neuroinflammation. 2015; 12(1):86. Epub 2015 May 08. PMID: 25953296. Abstract

Chronic treatment reduces hippocampal neurodegeneration and microglial activation induced by intracerebroventricular administration of kainic acid in rats

(240)

FTY720 attenuates excitotoxicity and neuroinflammation.

Cipriani R, Chara J C, Rodríguez-Antigüedad A, Matute C

J Neuroinflammation. 2015; 12(1):86. Epub 2015 May 08. PMID: 25953296. Abstract

Reduces lipopolysaccharide (LPS)-induced phosphorylation of the mitogen-activated protein kinase (MAPK) p38, but not JNK, in primary rat microglial cells; MAPK signaling is involved in inflammatory responses to brain injury that are mediated by microglia

(240)

FTY720 attenuates excitotoxicity and neuroinflammation.

Cipriani R, Chara J C, Rodríguez-Antigüedad A, Matute C

J Neuroinflammation. 2015; 12(1):86. Epub 2015 May 08. PMID: 25953296. Abstract

Direct administration to the central nervous system reduces, but does not eliminate, the upregulation in neuronal Ca2+ signaling and the excitotoxic morphological alterations caused by later direct administration of 100 mM glutamate, as shown by experiments in transgenic Ca2+ reporter mice

(306)

In vivo and in vitro effects of multiple sclerosis immunomodulatory therapeutics on glutamatergic excitotoxicity.

Luchtman D, Gollan R, Ellwardt E, Birkenstock J, Robohm K, Siffrin V, Zipp F

J Neurochem. 2015 Dec 10. PMID: 26662167. Abstract

Prevents destabliization of dendrites and dendrite loss induced by denervation in enterohino-hippocampal slice cultures from mice

(339)

Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy.

Willems LM, Zahn N, Ferreirós N, Scholich K, Maggio N, Deller T, Vlachos A

Acta Neuropathol Commun. 2016; 4(1):28. Epub 2016 Mar 31. PMID: 27036416. Abstract

Inhibits myeloid cell activation

(298)

Myeloid cells as target of fingolimod action in multiple sclerosis.

Di Dario M, Colombo E, Govi C, De Feo D, Messina M J, Romeo M, Sangalli F, Moiola L, Rodegher M, Martino G, et al.

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e157. Epub 2015 Nov 04. PMID: 26587553. Abstract

Reduces production of tumor necrosis factor alpha by myeloid cells in the central nervous system and spleen in an experimental autoimmune encephalomyelitis mouse model

(298)

Myeloid cells as target of fingolimod action in multiple sclerosis.

Di Dario M, Colombo E, Govi C, De Feo D, Messina M J, Romeo M, Sangalli F, Moiola L, Rodegher M, Martino G, et al.

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e157. Epub 2015 Nov 04. PMID: 26587553. Abstract

Protects against damage (white matter abnormalities and long-term cognitive defects) in a neonatal model of oxygen toxicity

(290)

Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia.

Serdar M, Herz J, Kempe K, Lumpe K, Reinboth BS, Sizonenko SV, Hou X, Herrmann R, Hadamitzky M, Heumann R, et al.

Brain Behav Immun. 2015 Oct 12. PMID: 26456693. Abstract

Reduces oxidative stress, activation of microglia, and expression of proinflammatory cytokines in a neonatal model of oxygen toxicity

(290)

Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia.

Serdar M, Herz J, Kempe K, Lumpe K, Reinboth BS, Sizonenko SV, Hou X, Herrmann R, Hadamitzky M, Heumann R, et al.

Brain Behav Immun. 2015 Oct 12. PMID: 26456693. Abstract

Reduces hypomyelination and oligodendrocyge degeneration and increases oligodendrocyte maturation in a neonatal model of oxygen toxicity

(290)

Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia.

Serdar M, Herz J, Kempe K, Lumpe K, Reinboth BS, Sizonenko SV, Hou X, Herrmann R, Hadamitzky M, Heumann R, et al.

Brain Behav Immun. 2015 Oct 12. PMID: 26456693. Abstract

Rapidly reduces the activity of P-glycoprotein, a drug efflux pump, in rat brain capillaries and in in vivo experiments in rat brains

(36)

Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.

Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS

Proc Natl Acad Sci U S A. 2012 Sep 4. PMID: 22949658. Abstract

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

(36)

Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.

Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS

Proc Natl Acad Sci U S A. 2012 Sep 4. PMID: 22949658. Abstract

Induces cell cycle arrest in G(0)/G(1) phase in mouse lymphocytes

(37)

FTY720 mediates activation suppression and G(0)/G (1) cell cycle arrest in a concanavalin A-induced mouse lymphocyte pan-activation model.

Zeng X, Wang T, Zhu C, Ye Y, Song B, Lai X, Zeng Y

Inflamm Res. 2012 Jun; 61(6):623-34. Epub 2012 Mar 10. PMID: 22407397. Abstract

Blocks concanavalin A-induced mitogenesis in mouse lymphocytes

(37)

FTY720 mediates activation suppression and G(0)/G (1) cell cycle arrest in a concanavalin A-induced mouse lymphocyte pan-activation model.

Zeng X, Wang T, Zhu C, Ye Y, Song B, Lai X, Zeng Y

Inflamm Res. 2012 Jun; 61(6):623-34. Epub 2012 Mar 10. PMID: 22407397. Abstract

Inhibits production of proinflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta, and interleukin-6) by activated microglia from mice via interactions with S1P1 receptors

(54)

Fingolimod phosphate promotes the neuroprotective effects of microglia.

Noda H, Takeuchi H, Mizuno T, Suzumura A

J Neuroimmunol. 2013 Jan 3. PMID: 23290828. Abstract

Enhances production of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor by activated microglia from mice

(54)

Fingolimod phosphate promotes the neuroprotective effects of microglia.

Noda H, Takeuchi H, Mizuno T, Suzumura A

J Neuroimmunol. 2013 Jan 3. PMID: 23290828. Abstract

Reduces interferon gamma and Granzyme B production (a measure of effector function) by splenic CD8+ T cells from experimental autoimmune encephalomyelitis mice; the unphosphorylated form (and not the phosphorylated form) has this effect in vitro, indicating that it is independent of the effect on sphingosine-1-phosphate receptors

(130)

FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway.

Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, Klein SL, Calabresi PA, Gocke AR

J Neuroimmunol. 2014 Mar 11. Epub 1969 Dec 31. PMID: 24680062. Abstract

Reduces the cytotoxic function of murine CD8+ T cells in vitro; the unphosphorylated form (and not the phosphorylated form) has this effect, indicating that it is independent of the effect on sphingosine-1-phosphate receptors

(130)

FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway.

Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, Klein SL, Calabresi PA, Gocke AR

J Neuroimmunol. 2014 Mar 11. Epub 1969 Dec 31. PMID: 24680062. Abstract

Ability to suppress murine CD8+ T cell function is reversed by arachidonic acid (AA), suggesting that the effect is due to inhibition of cytosolic phospholipase A2 (which functions in AA production)

(130)

FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway.

Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, Klein SL, Calabresi PA, Gocke AR

J Neuroimmunol. 2014 Mar 11. Epub 1969 Dec 31. PMID: 24680062. Abstract

Nearly doubles the mortality rate during murine influenza virus infection

(130)

FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway.

Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, Klein SL, Calabresi PA, Gocke AR

J Neuroimmunol. 2014 Mar 11. Epub 1969 Dec 31. PMID: 24680062. Abstract

Decreases the infiltration of both CD4+ and CD8+ T cells into the lungs during murine influenza virus infection

(130)

FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway.

Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, Klein SL, Calabresi PA, Gocke AR

J Neuroimmunol. 2014 Mar 11. Epub 1969 Dec 31. PMID: 24680062. Abstract

Reduces production of Granzyme B (a protease that mediates apoptosis in target cells) by CD8+ T cells during murine influenza virus infection

(130)

FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway.

Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, Klein SL, Calabresi PA, Gocke AR

J Neuroimmunol. 2014 Mar 11. Epub 1969 Dec 31. PMID: 24680062. Abstract

Both fingolimod and siponimod induce atrioventricular conduction block at high dose, whereas fingolimod but not siponimod prolongs the QT interval at high dose and siponimod but not fingolimod prolongs the PR interval at low dose, in a guinea-pig model

(176)

Analysis of Onset Mechanisms of a Sphingosine 1-Phosphate Receptor Modulator Fingolomod-Induced Atrioventricular Conduction Block and QT-Interval Prolongation.

Yagi Y, Nakamura Y, Kitahara K, Harada T, Kato K, Ninomiya T, Cao X, Ohara H, Izumi-Nakaseko H, Suzuki K, et al.

Toxicol Appl Pharmacol. 2014 Sep 16. PMID: 25223691. Abstract

Prolongs the cycle length when applied directly to rat atrioventricular nodal tissue in vitro, as measured using extracellular potentials recordings

(222)

The effect of the sphingosine-1-phosphate analogue FTY720 on atrioventricular nodal tissue.

Egom EE, Kruzliak P, Rotrekl V, Lei M

J Cell Mol Med. 2015 Apr 13. PMID: 25864579. Abstract

Reduces disturbances in atrioventricular nodal pacemaker activity induced by both ischaemia and reperfusion when applied directly to rat atrioventricular nodal tissue in vitro

(222)

The effect of the sphingosine-1-phosphate analogue FTY720 on atrioventricular nodal tissue.

Egom EE, Kruzliak P, Rotrekl V, Lei M

J Cell Mol Med. 2015 Apr 13. PMID: 25864579. Abstract

Phosphorylated version activates ERK1/2, CREB, and p38MAPK in cultured rat neurons and astrocytes

(137)

Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors.

Cui Q L, Fang J, Kennedy TE, Almazan G, Antel JP

Glia. 2014 May 9. PMID: 24810969. Abstract

When administered in eye drop form, reduces symptoms of dry eye disease (specifically, reduces signs of inflammation, restores goblet cells, and reduces ocular surface lesions), as shown in experiments in non-obese diabetic mice

(308)

FTY720 ameliorates Dry Eye Disease in NOD mice: Involvement of leukocytes inhibition and goblet cells regeneration in ocular surface tissue.

Xiao W, Xu G-T, Zhang J, Zhang J, Zhang Y, Ye W

Exp Eye Res. 2015 Sep; 138:145-52. Epub 2015 Jul 14. PMID: 26187517. Abstract

Attenuates learning and memory impairment induced by intrahippocampus injection of beta-amyloid peptide in rats

(57)

FTY720 (Fingolimod) Attenuates Beta-amyloid Peptide (Aβ(42))-Induced Impairment of Spatial Learning and Memory in Rats.

Asle-Rousta M, Kolahdooz Z, Oryan S, Ahmadiani A, Dargahi L

J Mol Neurosci. 2013 Feb 26. Epub 2013 Feb 26. PMID: 23435938. Abstract

Reduces production of amyloid-beta in cultured mouse neurons

(69)

FTY720/Fingolimod, a Sphingosine Analogue, Reduces Amyloid-β Production in Neurons.

Takasugi N, Sasaki T, Ebinuma I, Osawa S, Isshiki H, Takeo K, Tomita T, Iwatsubo T

PLoS One. 2013; 8(5):e64050. Epub 2013 May 07. PMID: 23667698. Abstract

Decreases brain levels of amyloid-beta 40, but increases levels of amyloid-beta 42, in APP transgenic mice, a model of Alzheimer's disease

(69)

FTY720/Fingolimod, a Sphingosine Analogue, Reduces Amyloid-β Production in Neurons.

Takasugi N, Sasaki T, Ebinuma I, Osawa S, Isshiki H, Takeo K, Tomita T, Iwatsubo T

PLoS One. 2013; 8(5):e64050. Epub 2013 May 07. PMID: 23667698. Abstract

Restores memory, and concurrently alters the expression of certain genes, in a rat model of Alzheimer's disease

(75)

Neurorestorative effect of FTY720 in a rat model of Alzheimer's disease: Comparison with Memantine.

Hemmati F, Dargahi L, Nasoohi S, Omidbakhsh R, Mohamed Z, Chik Z, Naidu M, Ahmadiani A

Behav Brain Res. 2013 Jun 15. PMID: 23777795. Abstract

Enhances motor function, increases survival, strengthens neuronal activity, and decreases brain atrophy in a mouse model of Huntington's disease

(107)

FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease.

Di Pardo A, Amico E, Favellato M, Castrataro R, Fucile S, Squitieri F, Maglione V

Hum Mol Genet. 2013 Dec 18. Epub 2013 Dec 02. PMID: 24301680. Abstract

Reduces long-term memory problems and loss of dendritic spines in CA1 hippocampal neurons in a mouse model of Huntington's disease

(260)

Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation.

Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J

Hum Mol Genet. 2015 Jun 10. Epub 2015 Jun 10. PMID: 26063761. Abstract

Inhibits astrogliosis in the hippocampus in a mouse model of Huntington's disease

(260)

Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation.

Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J

Hum Mol Genet. 2015 Jun 10. Epub 2015 Jun 10. PMID: 26063761. Abstract

Reduces levels of tumor necrosis factor alpha and induced nitric oxide synthase, and normalizes levels of p75NTR, in the hippocampus in a mouse model of Huntington's disease

(260)

Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation.

Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J

Hum Mol Genet. 2015 Jun 10. Epub 2015 Jun 10. PMID: 26063761. Abstract

Treatment either before or after intracerebral lipopolysaccharide (LPS) injection (which causes neuroinflammation) in rats reduces memory impairment induced by LPS

(167)

Fingolimod affects gene expression profile associated with LPS-induced memory impairment.

Omidbakhsh R, Rajabli B, Nasoohi S, Khallaghi B, Mohamed Z, Naidu M, Ahmadiani A, Dargahi L

Exp Brain Res. 2014 Aug 7. Epub 2014 Aug 07. PMID: 25098558. Abstract

Alters a gene expression profile (involving mitogen-activated protein kinase and inflammatory genes) that is associated with memory impairment induced by intracerebral lipopolysaccharide injection in rats

(167)

Fingolimod affects gene expression profile associated with LPS-induced memory impairment.

Omidbakhsh R, Rajabli B, Nasoohi S, Khallaghi B, Mohamed Z, Naidu M, Ahmadiani A, Dargahi L

Exp Brain Res. 2014 Aug 7. Epub 2014 Aug 07. PMID: 25098558. Abstract

Improves memory and learning in mice injected with the neurotoxic protein amyloid beta, an effect that is linked with the re-establishment of normal levels of brain-derived neurotrophic factor in the hippocampus and cerebral cortices

(132)

Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment.

Fukumoto K, Mizoguchi H, Takeuchi H, Horiuchi H, Kawanokuchi J, Jin S, Mizuno T, Suzumura A

Behav Brain Res. 2014 Jul 15; 268:88-93. Epub 2014 Apr 05. PMID: 24713151. Abstract

Inhibits apoptosis of islet beta-cells and prevents the development of diabetes in db/db mice, a model of diabetes

(76)

FTY720 preserved islet β-cell mass by inhibiting apoptosis and increasing survival of β-cells in db/db mice.

Moon H, Chon J, Joo J, Kim D, In J, Lee H, Park J, Choi J

Diabetes Metab Res Rev. 2013 Jan; 29(1):19-24. PMID: 22936676. Abstract

Reduces the growth of metastatic melanoma in mice

(133)

FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system.

Pereira FV, Arruda DC, Figueiredo CR, Massaoka MH, Matsuo AL, Bueno V, Rodrigues EG

Clinics (Sao Paulo). 2013 Jul; 68(7):1018-27. PMID: 23917669. Abstract

Modulates the immune system in mice with metastatic melanoma, decreasing the frequency of Foxp3+ cells (T regulatory cells) but not affecting CD8+ T cells or the production of interferon gamma by lymphocytes

(133)

FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system.

Pereira FV, Arruda DC, Figueiredo CR, Massaoka MH, Matsuo AL, Bueno V, Rodrigues EG

Clinics (Sao Paulo). 2013 Jul; 68(7):1018-27. PMID: 23917669. Abstract

In vitro, decreases the viability of murine melamona cells by inducing apoptosis

(133)

FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system.

Pereira FV, Arruda DC, Figueiredo CR, Massaoka MH, Matsuo AL, Bueno V, Rodrigues EG

Clinics (Sao Paulo). 2013 Jul; 68(7):1018-27. PMID: 23917669. Abstract

Systemic administration reduces chemotherapy-induced neuropathic pain, and associated activation of neuroinflammatory processes (dependent on sphingosine 1-phosphate receptor subtype 1), in a rat model

(162)

The Development and Maintenance of Paclitaxel-Induced Neuropathic Pain Requires Activation of the Sphingosine 1-Phosphate Receptor Subtype 1.

Janes K, Little JW, Li C, Bryant L, Chen C, Chen Z, Kamocki K, Doyle T, Snider A, Esposito E, et al.

J Biol Chem. 2014 May 29. PMID: 24876379. Abstract

Reduces inflammation in obstructed kidneys in mice

(131)

Treatment with the Immunomodulator FTY720 (Fingolimod) Significantly Reduces Renal Inflammation in Murine Unilateral Ureteral Obstruction.

Thangada S, Shapiro LH, Silva C, Yamase H, Hla T, Ferrer FA

J Urol. 2014 Mar 25. PMID: 24679864. Abstract

Reduces urinary protein, inflammatory cell infiltration into the tubulointerstitial tissue of the kidney, and tubulointerstitial injury in a rat model of nephropathy

(275)

FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway.

Xu M, Liu D, Ding L-hong, Ma K-ling, Wu M, Lv L-li, Wen Y, Liu H, Tang R-ning, Liu B-cheng

Acta Pharmacol Sin. 2014 Dec; 35(12):1537-45. Epub 2014 Nov 17. PMID: 25399649. Abstract

Reduces the expression of inflammatory cytokines monocyte chemoattractant protein-1, tumor necrosis factor-alpha, interleukin-6 (IL-6), and IL-10, as well as arginase-1, in the kidney cortex in a rat model of nephropathy

(275)

FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway.

Xu M, Liu D, Ding L-hong, Ma K-ling, Wu M, Lv L-li, Wen Y, Liu H, Tang R-ning, Liu B-cheng

Acta Pharmacol Sin. 2014 Dec; 35(12):1537-45. Epub 2014 Nov 17. PMID: 25399649. Abstract

Reduces levels of Sphk1 [an enzyme that synthesizes sphingosine 1-phosphate (S1P)], S1P receptors 1 and 3, and S1P in the kidney in a rat model of nephropathy (in which levels of these proteins, and that of S1P, are increased)

(275)

FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway.

Xu M, Liu D, Ding L-hong, Ma K-ling, Wu M, Lv L-li, Wen Y, Liu H, Tang R-ning, Liu B-cheng

Acta Pharmacol Sin. 2014 Dec; 35(12):1537-45. Epub 2014 Nov 17. PMID: 25399649. Abstract

Stimulates purified bovine protein phosphatase 2A

(84)

A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells.

Matsuoka Y, Nagahara Y, Ikekita M, Shinomiya T

Br J Pharmacol. 2003 Apr; 138(7):1303-12. PMID: 12711631. Abstract

Stimulates Ca2+ influx and calcineurin activity in fission yeast

(106)

Fingolimod (FTY720) stimulates ca(2+)/calcineurin signaling in fission yeast.

Hagihara K, Kita A, Mizukura A, Yao M, Kitai Y, Kunoh T, Masuko T, Matzno S, Chiba K, Sugiura R

PLoS One. 2013; 8(12):e81907. Epub 2013 Dec 03. PMID: 24312601. Abstract

Phosphorylated form accumulates in the nucleus of primary hippocampal neurons from mice

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Increases acetylation of a lysine 9 in histone H3 in primary hippocampal neurons from mice

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Phosphorylated form accumulates in mouse brain

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Inhibits histone deacetylase activity, and increases acetylation of lysine 9 in histone 3, in the hippocampus in mice

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Enhances fear extinction, but does not alter the acquisition of fear memories, as shown by experiments in severe combined immune deficient mice, which lack functional B and T cells (thus, these effects appear to be independent of fingolimod's effects on lymphocyte trafficking)

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Exhibits an antidepressant-like activity in mice under chronic unpredictable stress or chronically treated with corticosterone

(257)

Di Nuzzo L, Orlando R, Tognoli C, Di Pietro P, Bertini G, Miele J, Bucci D, Motolese M, Scaccianoce S, Caruso A, et al.

Pharmacol Res Perspect. 2015 Jun; 3(3):e00135. Epub 2015 May 24. PMID: 26171219. Abstract

Chronic treatment reverses the stress-induced decrease in brain-derived neurotrophic factor and increase in histone deacetylase 2 levels in the hippocampus in "responder" mice (those who exhibit less immobility in a forced swim test in response to fingolimod)

(257)

Di Nuzzo L, Orlando R, Tognoli C, Di Pietro P, Bertini G, Miele J, Bucci D, Motolese M, Scaccianoce S, Caruso A, et al.

Pharmacol Res Perspect. 2015 Jun; 3(3):e00135. Epub 2015 May 24. PMID: 26171219. Abstract

Does not affect the abundance of brain-derived neurotrophic factor or histone deacetylase 2 at the protein level in the hippocampus of unstressed mice

(257)

Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory.

Di Nuzzo L, Orlando R, Tognoli C, Di Pietro P, Bertini G, Miele J, Bucci D, Motolese M, Scaccianoce S, Caruso A, et al.

Pharmacol Res Perspect. 2015 Jun; 3(3):e00135. Epub 2015 May 24. PMID: 26171219. Abstract

Increases neural progenitor proliferation and survival in the dentate gyrus of the hippocampus in adult mice

(321)

Efstathopoulos P, Kourgiantaki A, Karali K, Sidiropoulou K, Margioris AN, Gravanis A, Charalampopoulos I

Transl Psychiatry. 2015; 5:e685. PMID: 26795749. Abstract

Increases proliferation and survival of cultured mouse hippocampal neural stem and precursor cells that express the sphingosine-1 phosphate receptor type 1

(321)

Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory.

Efstathopoulos P, Kourgiantaki A, Karali K, Sidiropoulou K, Margioris AN, Gravanis A, Charalampopoulos I

Transl Psychiatry. 2015; 5:e685. PMID: 26795749. Abstract

Improves the ability of mice to discriminate between a hostile and a similar non-hostile environment after fear conditioning

(321)

Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory.

Efstathopoulos P, Kourgiantaki A, Karali K, Sidiropoulou K, Margioris AN, Gravanis A, Charalampopoulos I

Transl Psychiatry. 2015; 5:e685. PMID: 26795749. Abstract

Does not affect survival of mice infected with the neuroinvasive parasite Toxoplasma gondii, but does affect leukocyte numbers and parasite load in the brain

(174)

Testing effects of glatiramer acetate and fingolimod in an infectious model of CNS immune surveillance.

Castro-Rojas C, Deason K, Hussain RZ, Hayardeny L, Cravens PC, Yarovinsky F, Eagar TN, Arellano B, Stüve O

J Neuroimmunol. 2014 Sep 2. PMID: 25227585. Abstract

Decreases histone deacetylase activity and reverses the loss of estrogen and progesterone receptor expression induced by a high-fat diet in breast carcinomas in a line of transgenic mice that spontaneously develop such tumors

(247)

The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.

Hait NC, Avni D, Yamada A, Nagahashi M, Aoyagi T, Aoki H, Dumur CI, Zelenko Z, Gallagher EJ, Leroith D, et al.

Oncogenesis. 2015; 4:e156. PMID: 26053034. Abstract

Suppresses breast tumors in a line of transgenic mice that spontaneously develop such tumors, an effect that is more dramatic in mice fed a high-fat diet, which promotes such cancer

(247)

The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.

Hait NC, Avni D, Yamada A, Nagahashi M, Aoyagi T, Aoki H, Dumur CI, Zelenko Z, Gallagher EJ, Leroith D, et al.

Oncogenesis. 2015; 4:e156. PMID: 26053034. Abstract

Regulatory and Commercial Status

Status for MS:

Approved in US, EU, and other countries for RRMS

(7)

FDA approves first oral drug to reduce MS relapses

FDA

Accessed on 4 Jan 2012 from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226755.htm.

(15)

Novartis announces Russian regulatory approval for Gilenya®, a once-daily oral multiple sclerosis therapy and first in a new class

Novartis

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1443688.shtml.

(16)

Novartis receives European Commission approval for Gilenya®, the first oral multiple sclerosis treatment for use in the EU

Novartis

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2011/1498377.shtml.

(17)

Novartis gains approval for Gilenya® as a first-line disease modifying oral therapy for multiple sclerosis in Switzerland and Australia

Novartis

Accessed on 4 Jan 2012 from http://www.novartis.is/newsroom/media-releases/en/2011/1481634.shtml.

License in the EU was for adult individuals with RRMS who have not responded to interferon treatment or whose MS is severe and rapidly evolving (29 April 2014)

(141)

Novartis: CHMP Issues Positive Opinion To Expand EU Label For Gilenya In RRMS

RTT News, 29 Apr 2014

Accessed on 19 May 2014 from http://www.rttnews.com/2309584/novartis-chmp-issues-positive-opinion-to-expand-eu-label-for-gilenya-in-rrms.aspx?type=qf&utm_source=google&utm_campaign=sitemap.

License in the EU has been expanded to include individuals with RRMS who have not responded to any other disease-modifying therapy (June, 2014)

(148)

FDA approves first oral drug to reduce MS relapses

MS Trust, 12 Jun 2014

Accessed on 12 Jun 2014 from http://www.mstrust.org.uk/news/article.jsp?id=6381.

Highest status achieved (for any condition):

Approved

(7)

FDA

Accessed on 4 Jan 2012 from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226755.htm.

Other uses:

Initially tested in preclinical trials for ability to prevent rejection of allografts

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Prolongs survival of allografts

(3)

Fingolimod is a potential novel therapy for multiple sclerosis.

Aktas O, Küry P, Kieseier B, Hartung H-P

Nat Rev Neurol. 2010 Jul; 6(7):373-82. Epub 2010 Jun 15. PMID: 20551946. Abstract

Caused remission of a case of demyelinating polyneuropathy

(150)

Remission with fingolimod in a case of demyelinating polyneuropathy.

Erdener SE, Nurlu G, Göçmen R, Erdem-Özdamar S, Tuncer Kurne A

Muscle Nerve. 2014 Jun 7. PMID: 24909140. Abstract

Effectively used to treat a case of Balò's concentric sclerosis, which is considered a variant of MS

(251)

Balò's concentric sclerosis: still to be considered as a variant of multiple sclerosis?

Pietroboni AM, Arighi A, De Riz MA, Ghezzi L, Calvi A, Avignone S, Scola E, Galimberti D, Triulzi F, Scarpini E

Neurol Sci. 2015 Jun 25. Epub 2015 Jun 25. PMID: 26109007. Abstract

Showed efficacy in treating MS associated with Sjögren syndrome in one case

(204)

Fingolimod efficacy in multiple sclerosis associated with Sjogren syndrome.

Signoriello E, Sagliocchi A, Fratta M, Lus G

Acta Neurol Scand. 2015 Feb; 131(2):140-3. PMID: 25622658. Abstract

Approval has been granted by the US Food and Drug Administration for a Phase IIA clinical trial in amyotrophic lateral sclerosis (11 February 2013)

(55)

FDA approves clinical trial of TDI-132 (Gilenya) in ALS patients

ALS Therapy Development Institute, 11 Feb 2013

Accessed on 18 Feb 2013 from http://www.als.net/TDI-132/?f=hr.

Reduced secondary brain injury after intracerebral hemorrhage in a proof-of-concept study in humans

(157)

Fingolimod for the Treatment of Intracerebral Hemorrhage: A 2-Arm Proof-of-Concept Study.

Fu Y, Hao J, Zhang N, Ren L, Sun N, Li Y-J, Yan Y, Huang D, Yu C, Shi F-D

JAMA Neurol. 2014 Jul 7. PMID: 25003359. Abstract

Suppressed paroxysmal dysarthria–ataxia syndrome (which involves transient alterations in speech and limb or gait ataxia) in an individual with RRMS

(211)

Paroxysmal dysarthria-ataxia syndrome resolving after fingolimod treatment.

Rossi S, Studer V, Motta C, Centonze D

J Neurol Sci. 2015 Jan 28. PMID: 25676590. Abstract

Might be useful for treating Alzheimer's disease, on the basis of experiments in primary cortical neurons from mice showing that fingolimod phosphate upregulates neuronal expression of brain-derived neurotrophic factor and thereby protects against neurotoxicity induced by amyloid beta oligomers

(62)

Fingolimod Phosphate Attenuates Oligomeric Amyloid β-Induced Neurotoxicity via Increased Brain-Derived Neurotrophic Factor Expression in Neurons.

Doi Y, Takeuchi H, Horiuchi H, Hanyu T, Kawanokuchi J, Jin S, Parajuli B, Sonobe Y, Mizuno T, Suzumura A

PLoS One. 2013; 8(4):e61988. Epub 2013 Apr 12. PMID: 23593505. Abstract

Might be useful for treating Alzheimer's disease, on the basis of fingolimod's ability to improve learning and memory, and restore brain-derived neurotrophic factor levels, in mice injected with amyloid beta

(132)

Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment.

Fukumoto K, Mizoguchi H, Takeuchi H, Horiuchi H, Kawanokuchi J, Jin S, Mizuno T, Suzumura A

Behav Brain Res. 2014 Jul 15; 268:88-93. Epub 2014 Apr 05. PMID: 24713151. Abstract

Might be useful for treating autoimmune optic neuritis, based on experiments in mice

(63)

Suppression of Experimental Autoimmune Optic Neuritis by the Novel Agent Fingolimod.

An X, Kezuka T, Usui Y, Matsunaga Y, Matsuda R, Yamakawa N, Goto H

J Neuroophthalmol. 2013 Apr 19. PMID: 23609767. Abstract

Might be useful for treating neonatal brain injury, based on experiments in a neonatal model of oxygen toxicity

(290)

Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia.

Serdar M, Herz J, Kempe K, Lumpe K, Reinboth BS, Sizonenko SV, Hou X, Herrmann R, Hadamitzky M, Heumann R, et al.

Brain Behav Immun. 2015 Oct 12. PMID: 26456693. Abstract

Might be useful as a therapy to help extinguish aversive memories (for example, in post-traumatic stress disorder), based on experiments in mice

(146)

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, et al.

Nat Neurosci. 2014 Jul; 17(7):971-80. Epub 2014 May 25. PMID: 24859201. Abstract

Alleviates pre-existing cardiac hypertrophy and fibrosis in a mouse model by negatively regulating nuclear factor of activated T cells and periostin

(93)

A novel immunomodulator, FTY-720 reverses existing cardiac hypertrophy and fibrosis from pressure overload by targeting NFAT (nuclear factor of activated T-cells) signaling and periostin.

Liu W, Zi M, Tsui H, Chowdhury SK, Zeef L, Meng Q-J, Travis M, Prehar S, Berry A, Hanley NA, et al.

Circ Heart Fail. 2013 Jul; 6(4):833-44. Epub 2013 Jun 10. PMID: 23753531. Abstract

Might be useful, in combination with tamoxifen, for treating estrogen receptor-α negative breast cancer, based on experiments in mice and cell lines

(247)

The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.

Hait NC, Avni D, Yamada A, Nagahashi M, Aoyagi T, Aoki H, Dumur CI, Zelenko Z, Gallagher EJ, Leroith D, et al.

Oncogenesis. 2015; 4:e156. PMID: 26053034. Abstract

Might be useful, when applied topically, for treating cutaneous inflammation, as shown by studies in mice and humans

(336)

Topical Application of Fingolimod Perturbs Cutaneous Inflammation.

Sun WY, Dimasi DP, Pitman MR, Zhuang YZ, Heddle R, Pitson SM, Grimbaldeston MA, Bonder CS

J Immunol. 2016 Mar 21. PMID: 27001955. Abstract

Might be cardioprotective during myocardial infarction, based on experiments in a porcine model of ischemia-reperfusion

(324)

The Sphingosine 1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Post-Infarction Left Ventricular Remodeling in a Porcine Model of Ischemia-Reperfusion.

Santos-Gallego CG, Vahl TP, Goliasch G, Picatoste B, Arias T, Ishikawa K, Njerve IU, Sanz J, Narula J, Sengupta P, et al.

Circulation. 2016 Jan 29. PMID: 26826180. Abstract

Might be useful for treating colitis-associated colon cancer, based on experiments in mice

(52)

Sphingosine-1-Phosphate Links Persistent STAT3 Activation, Chronic Intestinal Inflammation, and Development of Colitis-Associated Cancer.

Liang J, Nagahashi M, Kim EY, Harikumar KB, Yamada A, Huang W-C, Hait NC, Allegood JC, Price MM, Avni D, et al.

Cancer Cell. 2013 Jan 14; 23(1):107-20. Epub 2012 Dec 27. PMID: 23273921. Abstract

Might be useful for treating thyroid cancer, based on experiments with thyroid cancer cell lines

(330)

FTY720 (Fingolimod) attenuates basal and sphingosine 1-phosphate-evoked thyroid cancer cell invasion.

Kalhori V, Magnusson M, Asghar M Y, Pulli I, Törnquist K

Endocr Relat Cancer. 2016 Mar 2. PMID: 26935838. Abstract

Might reduce symptoms of depression independently of its effect on MS symptoms, based on experiments in mice

(257)

FTY720 ameliorates Dry Eye Disease in NOD mice: Involvement of leukocytes inhibition and goblet cells regeneration in ocular surface tissue.

Di Nuzzo L, Orlando R, Tognoli C, Di Pietro P, Bertini G, Miele J, Bucci D, Motolese M, Scaccianoce S, Caruso A, et al.

Pharmacol Res Perspect. 2015 Jun; 3(3):e00135. Epub 2015 May 24. PMID: 26171219. Abstract

Might be useful for treating dry eye disease, based on experiments in mice

(308)

Xiao W, Xu G-T, Zhang J, Zhang J, Zhang Y, Ye W

Exp Eye Res. 2015 Sep; 138:145-52. Epub 2015 Jul 14. PMID: 26187517. Abstract

Inhibits neuroinflammation and decreases the length, frequency, and severity of spontaneous convulsions in a rat model of epilepsy

(38)

Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model.

Gao F, Liu Y, Li X, Wang Y, Wei D, Jiang W

Pharmacol Biochem Behav. 2012 Aug 31; 103(2):187-196. PMID: 22960129. Abstract

Might be useful for improving motor function in Huntington's disease, based on experiments in mice

(107)

FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease.

Di Pardo A, Amico E, Favellato M, Castrataro R, Fucile S, Squitieri F, Maglione V

Hum Mol Genet. 2013 Dec 18. Epub 2013 Dec 02. PMID: 24301680. Abstract

Might be useful for improving hippocampal synaptic plasticity and memory in Huntington's disease, based on experiments in mice

(260)

Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation.

Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J

Hum Mol Genet. 2015 Jun 10. Epub 2015 Jun 10. PMID: 26063761. Abstract

Might be useful for treating Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL), but not for Ph negative ALL, based on human ALL xenograft experiments

(51)

Disparate in vivo efficacy of FTY720 in xenograft models of Philadelphia positive and negative B-lineage acute lymphoblastic leukemia.

Wallington-Beddoe CT, Don AS, Hewson J, Qiao Q, Papa RA, Lock RB, Bradstock KF, Bendall LJ

PLoS One. 2012; 7(5):e36429. Epub 2012 May 03. PMID: 22570713. Abstract

Limits metastatic melanoma in mice

(133)

FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system.

Pereira FV, Arruda DC, Figueiredo CR, Massaoka MH, Matsuo AL, Bueno V, Rodrigues EG

Clinics (Sao Paulo). 2013 Jul; 68(7):1018-27. PMID: 23917669. Abstract

Might be useful for treating myeloproliferative neoplasms, based on experiments in mice

(85)

Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies.

Oaks JJ, Santhanam R, Walker CJ, Roof S, Harb JG, Ferenchak G, Eisfeld A K, Van Brocklyn JR, Briesewitz R, Saddoughi SA, et al.

Blood. 2013 Aug 7. PMID: 23926298. Abstract

Might be useful for drug development for acute myeloid leukemia, M2 subtype, based on experiments with cells and mouse models

(165)

FTY720 induces apoptosis of m2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels.

Chen L, Luo L-F, Lu J, Li L, Liu Y-F, Wang J, Liu H, Song H, Jiang H, Chen S-J, et al.

PLoS One. 2014; 9(7):e103033. Epub 2014 Jul 22. PMID: 25050888. Abstract

Inhibits neuroblastoma growth by interfering with the sphingolipid pathway in a pre-clinical model

(94)

FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway.

Li M-H, Hla T, Ferrer F

Pediatr Blood Cancer. 2013 Sep; 60(9):1418-23. Epub 2013 May 23. PMID: 23704073. Abstract

Might be useful for reducing chemotherapy-induced painful peripheral neuropathy, based on experiments in rats

(162)

The Development and Maintenance of Paclitaxel-Induced Neuropathic Pain Requires Activation of the Sphingosine 1-Phosphate Receptor Subtype 1.

Janes K, Little JW, Li C, Bryant L, Chen C, Chen Z, Kamocki K, Doyle T, Snider A, Esposito E, et al.

J Biol Chem. 2014 May 29. PMID: 24876379. Abstract

Might be useful for treating obstruction-induced renal injury, based on experiments in mice

(131)

Treatment with the Immunomodulator FTY720 (Fingolimod) Significantly Reduces Renal Inflammation in Murine Unilateral Ureteral Obstruction.

Thangada S, Shapiro LH, Silva C, Yamase H, Hla T, Ferrer FA

J Urol. 2014 Mar 25. PMID: 24679864. Abstract

Might be useful for treating proteinuric nephropathy, based in experiments in a rat model

(275)

FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway.

Xu M, Liu D, Ding L-hong, Ma K-ling, Wu M, Lv L-li, Wen Y, Liu H, Tang R-ning, Liu B-cheng

Acta Pharmacol Sin. 2014 Dec; 35(12):1537-45. Epub 2014 Nov 17. PMID: 25399649. Abstract

By reducing reactive astrogliosis, might be useful for treating spinal cord injury, based on experiments involving local delivery of fingolimod in animal models

(332)

Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis.

Wang J, Wang J, Lu P, Cai Y, Wang Y, Hong L, Ren H, Heng B C, Liu H, Zhou J, et al.

Biomaterials. 2015 Sep; 62:76-87. Epub 2015 May 15. PMID: 26036174. Abstract

Exhibits strong, selective activity against Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which cause human African trypanosomiasis

(305)

Identification and Characterization of FTY720 for the Treatment of Human African Trypanosomiasis.

Jones AJ, Kaiser M, Avery VM

Antimicrob Agents Chemother. 2015 Dec 14. PMID: 26666915. Abstract

Administration:

First oral treatment for RRMS available in US

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

0.5 mg orally once daily (information provided by the manufacturer)

(18)

Gilenya prescribing information

Novartis

Accessed on 4 Jan 2012 from http://www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf.

(226)

Efficacy of lower fingolimod doses in the treatment of MS.

Yamout B, Zeineddine MM, Khoury SJ

Mult Scler Relat Disord. 2014 Nov; 3(6):758. Epub 2014 Nov 21. PMID: 25891604. Abstract

(263)

Safety and efficacy of reduced fingolimod dosage treatment.

Yamout BI, Zeineddine MM, Sawaya RA, Khoury SJ

J Neuroimmunol. 2015 Aug 15; 285:13-5. Epub 2015 May 15. PMID: 26198913. Abstract

Label has been updated to say that all patients should have an electrocardiogram before the first dose, according to information from the manufacturer (April, 2012)

(26)

Novartis updates US label on Gilenya® following discussions with the FDA

Novartis, 20 Apr 2012

Accessed on 16 May 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1604414.shtml.

Contraindicated in the presence of specific cardiac conditions, according to information from the manufacturer

(26)

Novartis updates US label on Gilenya® following discussions with the FDA

Novartis, 20 Apr 2012

Accessed on 16 May 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1604414.shtml.

Contraindicated in the presence of certain cardiac conditions, which were found to be present in 9.2% of individuals with MS in a retrospective cohort study involving 136,542 hospital discharges

(163)

Frequency and economic impact of comorbid cardiac conditions with multiple sclerosis.

Franklin MA, Happe LE, Dillman R, Marshall LZ

J Manag Care Pharm. 2014 Aug; 20(8):795-9. PMID: 25062072. Abstract

(266)

FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs

US Food and Drug Administration, 4 Aug 2015

Accessed on 11 Aug 2015 from http://www.fda.gov/Drugs/DrugSafety/ucm456919.htm.

(309)

New EMA Advice for PML Prevention With Fingolimod in MS

Anderson P, Medscape, 18 Dec 2015

Accessed on 22 Dec 2015 from http://www.medscape.com/viewarticle/856208.

(151)

Fingolimod in a patient with heart failure on the background of pulmonary arterial hypertension and coronary artery disease.

Thomas K, Schrötter H, Halank M, Ziemssen T

BMC Neurol. 2014; 14(1):126. Epub 2014 Jun 07. PMID: 24906818. Abstract

Drug-drug interactions are not observed with a combined oral contraceptive (ethinylestradiol/levonorgestrel)

(29)

Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results.

David OJ, Ocwieja M, Meiser K, Emotte C, Jakab A, Wemer J, den Daas I, Schmouder R

Int J Clin Pharmacol Ther. 2012 Jun 26. PMID: 22735460. Abstract

Negative effects:

Associated with amenorrhea in three cases

(119)

Fingolimod-associated amenorrhea: a report of three cases.

Alroughani R

Mult Scler. 2014 Feb 10. PMID: 24515730. Abstract

Fingolimod-induced deterioration of asthma has been observed in an individual with RRMS

(145)

Fingolimod-induced asthma deterioration in a patient with relapsing-remitting multiple sclerosis.

van Rossum J, Looysen E, Daniels J, Killestein J

Mult Scler. 2014 May 27. PMID: 24866203. Abstract

Associated with a life-threatening asthma attack after 6 months of treatment in an individual

(164)

Life-threatening asthma attack during prolonged fingolimod treatment: case report.

Zecca C, Caporro M, Györik S, Gobbi C

Patient Prefer Adherence. 2014; 8:987-9. Epub 2014 Jul 14. PMID: 25053881. Abstract

Atrioventricular block

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Treatment initiation was associated with atrioventricular conduction delays in a low percentage (0% to 1%, depending on the dose and type of delay) of study participants, which generally were well tolerated, as shown by analysis of pooled data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials

(328)

First-dose effects of fingolimod: Pooled safety data from three phase 3 studies.

DiMarco JP, O'Connor P, Cohen JA, Reder AT, Zhang-Auberson L, Tang D, Collins W, Kappos L

Mult Scler Relat Disord. 2014 Sep; 3(5):629-38. Epub 2014 Jun 17. PMID: 26265275. Abstract

Intermittent atrioventricular block occurred in one individual with MS after initiation of treatment; this effect was hypothesized to be related to demyelinationg lesions in the spinal cord causing autonomic nervous system dysfunction, perhaps enhanced by fingolimod's parasympathetic effects

(170)

Intermittent Atrioventricular Block following Fingolimod Initiation.

Gialafos E, Gerakoulis S, Grigoriou A, Haina V, Kilidireas C, Stamboulis E, Andreadou E

Case Rep Neurol Med. 2014; 2014:191305. Epub 2014 Aug 05. PMID: 25161784. Abstract

Severe autoimmune hemolytic anemia has been reported in one patient receiving fingolimod

(77)

Severe auto-immune hemolytic anemia in a fingolimod-treated multiple sclerosis patient.

Lysandropoulos AP, Benghiat F

Mult Scler. 2013 Jul 1. PMID: 23817558. Abstract

Bradycardia

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Treatment initiation was associated with symptomatic bradycardia in 0.6% (0.5 mg dose) and 2.1% (1.25 mg dose) of study participants, which generally resolved spontaneously, as shown by analysis of pooled data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials

(328)

First-dose effects of fingolimod: Pooled safety data from three phase 3 studies.

DiMarco JP, O'Connor P, Cohen JA, Reder AT, Zhang-Auberson L, Tang D, Collins W, Kappos L

Mult Scler Relat Disord. 2014 Sep; 3(5):629-38. Epub 2014 Jun 17. PMID: 26265275. Abstract

Fingolimod-associated bradycardia is usually asymptomatic and spontaneously resolves, but symptomatic bradycardia (33 beats per minute) has occurred in one case after a single dose of fingolimod, which required treatment and a week for recovery

(90)

Prolonged and symptomatic bradycardia following a single dose of fingolimod.

Faber H, Fischer H-J, Weber F

Mult Scler. 2013 Jan; 19(1):126-8. Epub 2012 Jun 22. PMID: 22729989. Abstract

The first dose is associated with bradycardia in some individuals; such cardiac responses can be predicted by measures that assess autonomic balance

(153)

The autonomic balance predicts cardiac responses after the first dose of fingolimod.

Rossi S, Rocchi C, Studer V, Motta C, Lauretti B, Germani G, Macchiarulo G, Marfia G, Centonze D

Mult Scler. 2014 Jun 23. PMID: 24957049. Abstract

Deliberate overdose (14 mg, with 2 g phenoxymethylpenicillin) resulted in delayed bradycardia and hypotension (21 hours after ingestion)

(100)

Deliberate Fingolimod Overdose Presenting with Delayed Hypotension and Bradycardia Responsive to Atropine.

Stephenson M, Wong A, Rotella JA, Crump N, Kerr F, Greene SL

J Med Toxicol. 2013 Nov 1. PMID: 24178903. Abstract

Symptomatic bradycardia after the first dose was found to occur in a higher proportion of individuals (6.7%) in real-life medical settings than in the FREEDOMS clinical trial (in which the rate was <1%), based on a review of data from 180 individuals with MS in Brazil

(178)

The real-life experience with cardiovascular complications in the first dose of fingolimod for multiple sclerosis.

Fragoso Y D, Arruda C C, Arruda W O, Brooks J B B, Damasceno A, de Damasceno C A A, Finkelsztejn A, Finkelsztejn J, da Gama P D, Giacomo M C B, et al.

Arq Neuropsiquiatr. 2014 Sep; 72(9):712-4. PMID: 25252236. Abstract

Cardiac effects associated with the first dose are not affected by concomitant use of selective serotonin-reuptake inhibitors, as shown in a posthoc analysis involving >3300 individuals with relapsing MS

(242)

Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors.

Bermel RA, Hashmonay R, Meng X, Randhawa S, von Rosenstiel P, Sfikas N, Kantor D

Mult Scler Relat Disord. 2015 May; 4(3):273-80. Epub 2015 Apr 13. PMID: 26008945. Abstract

Bradyarrhythmia

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

In general, adverse cardiologic events were found to be limited over the long term (mean followup time, 1.5 years) in a study of 212 individuals with relapsing MS; one individual exhibited atrial fibrillation that required treatment and 5 exhibited persistent increases in blood pressure

(238)

Long term cardiac safety and tolerability of Fingolimod in Multiple Sclerosis: A post-marketing study.

Paolicelli D, Manni A, Direnzo V, D'Onghia M, Tortorella C, Zoccolella S, Trojano M

J Clin Pharmacol. 2015 Apr 23. PMID: 25903516. Abstract

Associated with a maximum heart rate reduction of 8 (0.5 mg dose) or 11 (1.25 mg dose) beats per minute 4 to 5 hours after the first dose, as shown by analysis of pooled data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials

(328)

First-dose effects of fingolimod: Pooled safety data from three phase 3 studies.

DiMarco JP, O'Connor P, Cohen JA, Reder AT, Zhang-Auberson L, Tang D, Collins W, Kappos L

Mult Scler Relat Disord. 2014 Sep; 3(5):629-38. Epub 2014 Jun 17. PMID: 26265275. Abstract

Causes prolonged heart-rate slowing upon initiation in some cases; in a study of 21 people with RRMS, 7 displayed this symptom; these individuals also exhibited some autonomic cardiovascular dysfunction before fingolimod initiation, suggesting that MS lesions can affect heart rate re-acceleration when fingolimod begins

(254)

Central Autonomic Dysfunction Delays Recovery of Fingolimod Induced Heart Rate Slowing.

Hilz MJ, Intravooth T, Moeller S, Wang R, Lee D-H, Koehn J, Linker RA

PLoS One. 2015; 10(7):e0132139. Epub 2015 Jul 06. PMID: 26147106. Abstract

Initially (at day 1) associated with an increase in cardiac parasympathetic regulation (prolonging the RR interval and increasing heart rate variability), but later (at month 3) is associated with a change toward sympathetic regulation (largely the opposite of parasympathetic regulation), based on a prospective study of 27 individuals with RRMS

(281)

Effect of fingolimod on cardiac autonomic regulation in patients with multiple sclerosis.

Simula S, Laitinen T, Laitinen TM, Tarkiainen T, Hartikainen P, Hartikainen JEK

Mult Scler. 2015 Sep 11. PMID: 26362903. Abstract

Breathing problems

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

Cancers (?)

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

Skin cancer (?)

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

May increase risk for basal cell carcinoma; as of December 2015, 151 cases have been reported in individuals taking fingolimod

(309)

New EMA Advice for PML Prevention With Fingolimod in MS

Anderson P, Medscape, 18 Dec 2015

Accessed on 22 Dec 2015 from http://www.medscape.com/viewarticle/856208.

Disseminated cryptococcosis has been reported in an individual with MS who was treated with fingolimod

(274)

Disseminated cryptococcosis in a patient with multiple sclerosis treated with fingolimod.

Huang D

Neurology. 2015 Aug 19. PMID: 26291283. Abstract

Primary cutaneous cryptococcus has been reported in an individual with MS who was treated with fingolimod

(317)

Primary Cutaneous Cryptococcus in a Patient With Multiple Sclerosis Treated With Fingolimod.

Forrestel AK, Modi BG, Longworth S, Wilck MB, Micheletti RG

JAMA Neurol. 2016 Jan 11:1-2. PMID: 26751160. Abstract

Cryptococcal meningoencephalitis has been reported in an individual with MS who was treated with fingolimod

(289)

Cryptococcal Meningoencephalitis in a Patient With Multiple Sclerosis Treated With Fingolimod.

Achtnichts L, Obreja O, Conen A, Fux CA, Nedeltchev K

JAMA Neurol. 2015 Oct 1; 72(10):1203-5. PMID: 26457631. Abstract

Possibly associated with ecchymotic angioedema-like cutaneous lesions

(272)

Occurrence of ecchymotic angioedema-like cutaneous lesions as a possible side effect of fingolimod.

Masera S, Chiavazza C, Mattioda A, Superti G, Beggiato E, Crosasso P, Broganelli P, Pinessi L, Cavalla P

Mult Scler. 2014 Oct; 20(12):1666-7. Epub 2014 Mar 06. PMID: 24603883. Abstract

Fatigue

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Potentially associated with glioblastoma in an individual with RRMS; the glioblastoma was diagnosed within 3 years of fingolimod initiation

(333)

Glioblastoma following treatment with fingolimod for relapsing-remitting multiple sclerosis.

Sharim J, Tashjian R, Golzy N, Pouratian N

J Clin Neurosci. 2016 Mar 9. PMID: 26970935. Abstract

Headache

(269)

Outcomes of switching directly to oral fingolimod from injectable therapies: Results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis.

Fox E, Edwards K, Burch G, Wynn DR, Laganke C, Crayton H, Hunter SF, Huffman C, Kim E, Pestreich L, et al.

Mult Scler Relat Disord. 2014 Sep; 3(5):607-19. Epub 2014 Jul 04. PMID: 26265273. Abstract

Hypertension

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Hypothyroidism has been reported in an individual with MS during fingolimod treatment

(197)

Hypothyroidism in multiple sclerosis patient during fingolimod treatment.

Flores J, Rito Y, Torres G, Jung H, Treviño-Frenk I, Corona T

J Neurol Sci. 2014 Nov 13. PMID: 25491264. Abstract

Infections (particularly herpes virus infections)

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

Associated with reactivation of herpes virus leading to severe herpes simplex encephalitis in one case

(271)

Reactivation of herpesvirus under fingolimod: A case of severe herpes simplex encephalitis.

Pfender N, Jelcic I, Linnebank M, Schwarz U, Martin R

Neurology. 2015 Jun 9; 84(23):2377-8. Epub 2015 May 08. PMID: 25957334. Abstract

Kaposi sarcoma has been reported in an individual with RRMS receiving fingolimod

(232)

Kaposi sarcoma in a patient with relapsing-remitting multiple sclerosis receiving fingolimod.

Tully T, Barkley A, Silber E

Neurology. 2015 Apr 15. PMID: 25878178. Abstract

Visceral leishmaniasis infection has been reported in an individual with MS treated with fingolimod

(325)

Visceral leishmaniasis infection in a fingolimod-treated multiple sclerosis patient.

Artemiadis A, Nikolaou G, Kolokythopoulos D, Tegos N, Terentiou A, Triantafyllou N, Papanastasiou I

Mult Scler. 2014 Nov 28. PMID: 25432949. Abstract

Acute lymphoblastic leukemia occurred in an individual with RRMS treated with fingolimod, although whether there was a causal relationship is not known

(285)

Acute Lymphoblastic Leukemia in a Man Treated With Fingolimod for Relapsing Multiple Sclerosis.

Cohan S, Godwin J, Gaedeke L

J Investig Med High Impact Case Rep. 2015 Jan-Mar; 3(1):2324709615575551. Epub 2015 Mar 09. PMID: 26425635. Abstract

Liver problems

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

Increased alanine aminotransferase, a measure of hepatocellular injury

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Associated with lymphomatoid papulosis, a benign subtype of cutaneous T-cell lymphoma that can become malignant, in an individual with MS

(265)

Lymphomatoid papulosis: A cutaneous lymphoproliferative disorder in a patient on fingolimod for multiple sclerosis.

Samaraweera A P, Cohen SN, Akay EM, Evangelou N

Mult Scler. 2015 Jul 28. Epub 2015 Jul 28. PMID: 26219664. Abstract

Lymphomatoid papulosis type D has been reported in an individual with MS treated with fingolimod

(344)

Lymphomatoid papulosis type D in a fingolimod-treated multiple sclerosis patient.

Matoula T, Nikolaou V, Marinos L, Katsavos S, Nasis G, Economidi A, Karampidou K, Stratigos A, Antoniou C

Mult Scler. 2016 Apr 6. PMID: 27053634. Abstract

Lymphopenia

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Fingolimod-induced lymphopenia risk may be increased in individuals with low initial lymphocyte counts and in women with low body mass index

(187)

Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia.

Warnke C, Dehmel T, Ramanujam R, Holmen C, Nordin N, Wolfram K, Leussink VI, Hartung H-P, Olsson T, Kieseier BC

Neurology. 2014 Oct 31. PMID: 25361781. Abstract

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

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

(61)

Ophthalmic Evaluations in Clinical Studies of Fingolimod (FTY720) in Multiple Sclerosis.

Zarbin MA, Jampol LM, Jager RD, Reder AT, Francis G, Collins W, Tang D, Zhang X

Ophthalmology. 2013 Mar 23. PMID: 23531349. Abstract

Fingolimod-associated macular edema has been successfully managed with topical anti-inflammatory drugs in one case

(82)

Management of fingolimod-associated macular edema.

Chui J, Herkes GK, Chang A

JAMA Ophthalmol. 2013 May; 131(5):694-6. PMID: 23538612. Abstract

Fingolimod-associated bilateral macular edema has been successfully treated by sub-Tenon injection of triamcinolone without the discontinuation of fingolimod in one case

(88)

Fingolimod-associated macular edema: resolution by sub-tenon injection of triamcinolone with continued fingolimod use.

Minuk A, Belliveau MJ, Almeida DRP, Dorrepaal SJ, Gale JS

JAMA Ophthalmol. 2013 Jun; 131(6):802-4. PMID: 23599188. Abstract

Fingolimod-associated macular edema has been successfully treated with intravitreal triamcinolone in two cases in which topical nonsteroidal anti-inflammatories were not successful; fingolimod use continued

(126)

Successful treatment of fingolimod-associated macular edema with intravitreal triamcinolone with continued fingolimod use.

Thoo S, Cugati S, Lee A, Chen C

Mult Scler. 2014 Apr 2. PMID: 24696055. Abstract

Cystoid macular edema

(49)

Cystoid macular edema associated with fingolimod use for multiple sclerosis.

Afshar AR, Fernandes JK, Patel RD, Ksiazek SM, Sheth VS, Reder AT, Hariprasad SM

JAMA Ophthalmol. 2013 Jan 1; 131(1):103-7. PMID: 23307220. Abstract

Associated with cystoid macular edema, which in one case did not resolve even after early detection and discontinuation of fingolimod

(105)

Cystoid macular oedema after fingolimod treatment in multiple sclerosis.

Asensio-Sánchez VM, Trujillo-Guzmán L, Ramoa-Osorio R

Arch Soc Esp Oftalmol. 2012 Oct 17. PMID: 24269406. Abstract

Associated with macular hemorrhage in one MS patient

(78)

Fingolimod Therapy and Macular Hemorrhage.

Bhatti TM, Freedman MS, Mahmoud TH

J Neuroophthalmol. 2013 Jul 10. PMID: 23845997. Abstract

Associated with bilateral cystoid macular edema in one individual

(44)

Early bilateral cystoid macular oedema secondary to fingolimod in multiple sclerosis.

Liu L, Cuthbertson F

Case Report Med. 2012; 2012:134636. Epub 2012 Sep 13. PMID: 23056052. Abstract

Associated with bilateral cystoid macular edema after cataract surgery in one individual with RRMS

(241)

Postoperative cystoid macular oedema in a patient on fingolimod.

Fan Gaskin J C-C, Coote M

BMJ Case Rep. 2015; 2015. PMID: 25969500. Abstract

Superficial spreading malignant melanoma has been reported in an individual with MS treated with fingolimod

(296)

Superficial spreading malignant melanoma in a patient on fingolimod therapy for multiple sclerosis.

Haebich G, Mughal A, Tofazzal N

Clin Exp Dermatol. 2015 Nov 18. PMID: 26577239. Abstract

Prolonged, extensive molluscum contagiosum virus infection has been reported in an individual with RRMS treated with fingolimod

(326)

Extensive molluscum contagiosum virus infection in a young adult receiving fingolimod.

Behle V, Wobser M, Goebeler M, Stoevesandt J

Mult Scler. 2016 Feb 9. PMID: 26860987. Abstract

Causes neural tube defects in embryos when administered to pregnant mice

(316)

Elevated Nuclear and Cytoplasmic FTY720-Phosphate in Mouse Embryonic Fibroblasts Suggests the Potential for Multiple Mechanisms in FTY720-Induced Neural Tube Defects.

Gardner NM, Riley RT, Showker JL, Voss KA, Sachs AJ, Maddox JR, Gelineau-van Waes JB

Toxicol Sci. 2015 Dec 29. PMID: 26719367. Abstract

Linked with the development of paroxysmal atrial fibrillation in one individual with MS

(117)

Paroxysmal atrial fibrillation after initiation of fingolimod for multiple sclerosis treatment.

Rolf L, Muris A-H, Damoiseaux J, van Daele M, Hupperts R

Neurology. 2014 Feb 12. PMID: 24523479. Abstract

Associated with retinal hemorrhages in an individual with MS

(292)

Retinal hemorrhages following fingolimod treatment for multiple sclerosis; a case report.

Ueda N, Saida K

BMC Ophthalmol. 2015; 15(1):135. Epub 2015 Oct 19. PMID: 26481728. Abstract

Associated with posterior reversible encephalopathy syndrome in an individual with MS

(220)

A case of posterior reversible encephalopathy syndrome associated with gilenya(®) (fingolimod) treatment for multiple sclerosis.

Lindå H, von Heijne A

Front Neurol. 2015; 6:39. Epub 2015 Mar 04. PMID: 25788891. Abstract

Progressive multifocal leukoencephalopathy has been reported in an individual with MS who had been taking fingolimod for 7 months (who had not been treated with natalizumab) (July 2013)

(83)

Patient taking Novartis MS pill developed rare disease

Reuters, 30 Jul 2013

Accessed on 8 Aug 2013 from http://www.reuters.com/article/2013/07/30/novartis-gilenya-idUSL6N0G02A520130730.

(91)

FDA Drug Safety Communication: FDA investigating rare brain infection in patient taking Gilenya (fingolimod)

US Food and Drug Administration, 29 Aug 2013

Accessed on 13 Sep 2013 from http://www.fda.gov/Drugs/DrugSafety/ucm366529.htm.

Whether there is fingolimod-associated risk of progressive multifocal leukoencephalopathy (PML) is unclear; one individual who was reported to have PML without previous natalizumab exposure may have had neuromyelitis optica (NMO), not MS, and the brain lesions may have been caused by NMO, not PML (meeting report, September 2014)

(180)

PML in MS Patients Making Natalizumab-to-Fingolimod Switch

Jeffrey S, Medscape, 25 Sep 2014

Accessed on 30 Sep 2014 from http://www.medscape.com/viewarticle/832307.

Progressive multifocal leukoencephalopathy has been reported in an individual with relapsing MS who had been taking fingolimod for over 4 years, according to a notice on the Novartis Web site (16 February 2015)

(214)

Gilenya Safety Update

Novartis, 16 Feb 2015

Accessed on 10 Mar 2015 from http://www.novartis.com/newsroom/product-related-info-center/gilenya-safety-update.shtml.

Progressive multifocal leukoencephalopathy (PML)-immune reconstitution inflammatory syndrome was diagnosed in an individual after the discontinuation of natalizumab (at which time PML was missed by MRI) and the initiation of fingolimod

(199)

PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation.

Killestein J, Vennegoor A, van Golde AEL, Bourez RLJH, Wijlens MLB, Wattjes MP

Case Rep Neurol Med. 2014; 2014:307872. Epub 2014 Nov 23. PMID: 25506447. Abstract

To date, 11 cases of progressive multifocal leukoencephalopathy have been identified in individuals with MS previously treated with natalizumab and then treated with fingolimod; in 5 cases, PML began before fingolimod treatment began (based on retrospective review of MRI), whereas in 4 cases, PML was reported 3 weeks to 6 months after fingolimod treatment began (meeting report, September 2014)

(180)

PML in MS Patients Making Natalizumab-to-Fingolimod Switch

Jeffrey S, Medscape, 25 Sep 2014

Accessed on 30 Sep 2014 from http://www.medscape.com/viewarticle/832307.

(266)

FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs

US Food and Drug Administration, 4 Aug 2015

Accessed on 11 Aug 2015 from http://www.fda.gov/Drugs/DrugSafety/ucm456919.htm.

A third case of progressive multifocal leukoencephalopathy has been reported in an individual with RRMS being treated with fingolimod who had not previously been treated with natalizumab; the individual had previously received chemotherapy and radiation (19 August 2015)

(273)

Another Case of PML with Gilenya Reported by Novartis

Ciccone A, Neurology Advisor, 19 Aug 2015

Accessed on 25 Aug 2015 from http://www.neurologyadvisor.com/neuromuscular-disorders/gilenya-novartis-multiple-sclerosis-pml/article/433640/.

Tumefactive demyelinating lesions occurred after initiation of fingolimod in a patient with active disease

(81)

Tumefactive multiple sclerosis lesions under fingolimod treatment.

Kinney MO, McDonnell G, Wattjes MP, Visser F, van Oosten BW

Neurology. 2013 Jul 23; 81(4):403. PMID: 23877798. Abstract

Associated with the development of a giant cavitating brain lesion (due to an active demyelinating inflammatory process) in an individual with MS; after cessation of therapy, the disease was very active

(158)

Tumefactive demyelination and a malignant course in an MS patient during and following fingolimod therapy.

Hellmann MA, Lev N, Lotan I, Mosberg-Galili R, Inbar E, Luckman J, Fichman-Horn S, Yakimov M, Steiner I

J Neurol Sci. 2014 Jun 17. PMID: 25001515. Abstract

Possibly associated with repeated tumefactive demyelinating lesions in one individual

(111)

Tumefactive MS lesions under fingolimod: A case report and literature review.

Pilz G, Harrer A, Wipfler P, Oppermann K, Sellner J, Fazekas F, Trinka E, Kraus J

Neurology. 2013 Oct 4. PMID: 24097813. Abstract

Associated with emerging tumefactive MS after changing treatment from interferon beta in one case

(278)

Emerging tumefactive MS after switching therapy from interferon-beta to fingolimod: A case report.

Harirchian M, Taalimi A, Siroos B

Mult Scler Relat Disord. 2015 Sep; 4(5):400-2. PMID: 26346786. Abstract

Urinary tract infections

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Varicella-zoster virus encephalitis and vasculopathy have been reported in one patient receiving fingolimod

(40)

Varicella-zoster virus encephalitis and vasculopathy in a patient treated with fingolimod.

Ratchford JN, Costello K, Reich DS, Calabresi PA

Neurology. 2012 Oct 3. PMID: 23035072. Abstract

Severe varicella-zoster virus reactivation has been reported in an individual receiving fingolimod

(41)

Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod.

Gross C M, Baumgartner A, Rauer S, Stich O

Neurology. 2012 Oct 3. PMID: 23035074. Abstract

Associated with recurrent varicella in an individual with MS, who also received steroids

(101)

Recurrent Varicella following Steroids and Fingolimod in a Multiple Sclerosis Patient.

Ferraro D, De Biasi S, Vitetta F, Simone A, Federzoni L, Borghi V, Cossarizza A, Nichelli P, Sola P

J Neuroimmune Pharmacol. 2013 Oct 27. Epub 2013 Oct 27. PMID: 24163092. Abstract

Rates of varicella-zoster virus infections are higher in individuals treated with fingolimod versus placebo (11 versus 6 per 1000 patient-years), based on analysis of clinical trial results, and comparable results are seen in the postmarketing setting

(193)

Varicella-Zoster Virus Infections in Patients Treated With Fingolimod: Risk Assessment and Consensus Recommendations for Management.

Arvin AM, Wolinsky JS, Kappos L, Morris MI, Reder AT, Tornatore C, Gershon A, Gershon M, Levin MJ, Bezuidenhoudt M, et al.

JAMA Neurol. 2014 Nov 24. PMID: 25419615. Abstract

Risk of herpes zoster development was found to be 40 per 1000 patient-years among 32 fingolimod-treated individuals with MS in Japan

(337)

The risk of varicella zoster virus infection in multiple sclerosis patients treated with fingolimod.

Tanaka M

Rinsho Shinkeigaku. 2016 Mar 24. PMID: 27010095. Abstract

Varicella-zoster virus encephalitis occurred in an immunized individual during treatment with fingolimod

(239)

VZV encephalitis that developed in an immunized patient during fingolimod therapy.

Issa NP, Hentati A

Neurology. 2015 Jan 6; 84(1):99-100. Epub 2014 Nov 21. PMID: 25416038. Abstract

Caused peripheral vascular adverse effects in an individual with MS

(277)

Fingolimod-Associated Peripheral Vascular Adverse Effects.

Russo M, Guarneri C, Mazzon E, Sessa E, Bramanti P, Calabrò R S

Mayo Clin Proc. 2015 Sep 5. PMID: 26349949. Abstract

Associated with reversible cerebral vasoconstriction syndrome, which occurred three months after childbirth, in an individual with RRMS

(270)

Reversible cerebral vasoconstriction syndrome associated with fingolimod treatment in relapsing-remitting multiple sclerosis three months after childbirth.

Kraemer M, Weber R, Herold M, Berlit P

Mult Scler. 2015 Aug 17. PMID: 26283695. Abstract

Appeared to exacerbate ventricular arrhythmia in an individual with MS

(307)

Ventricular arrhythmia in a male MS patient on fingolimod.

van Pesch V, Marchandise S, Elsankari S, Sindic C

Acta Neurol Belg. 2015 Mar; 115(1):77-9. Epub 2014 Apr 08. PMID: 24710722. Abstract

Associated with ventricular tachycardia in one individual, such that the episode occurred within one month of fingolimod initiation

(221)

Ventricular tachycardia on chronic fingolimod treatment for multiple sclerosis.

Castillo-Trivino T, Lopetegui I, Alarcón-Duque J A, de Munain A L, Olascoaga J

J Neurol Neurosurg Psychiatry. 2015 Apr 2. PMID: 25835036. Abstract

Decreases left ventricular systolic function, as shown in a study involving 53 individuals with MS, an effect that does not result in clinical consequences in the absence of other cardiac problems

(246)

Fingolimod effects on left ventricular function in multiple sclerosis.

Racca V, Di Rienzo M, Cavarretta R, Toccafondi A, Vaini E, Ferratini M, Rovaris M

Mult Scler. 2015 Jun 3. PMID: 26041795. Abstract

Not associated with an increased risk of serious cardiovascular events, malignancies, or infections (including herpes infections and serious infections), based on integrated long-term safety data from Phase II and III studies

(233)

Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings.

Kappos L, Cohen J, Collins W, de Vera A, Zhang-Auberson L, Ritter S, von Rosenstiel P, Francis G

Mult Scler Relat Disord. 2014 Jul; 3(4):494-504. Epub 2014 Mar 25. PMID: 25877062. Abstract

Concomitant use of either fingolimod or natalizumab is not associated with complications of Dengue fever in individuals with MS, as shown in a study of 15 individuals

(340)

Dengue fever in patients with multiple sclerosis taking fingolimod or natalizumab.

Fragoso Y D, da Gama P D, Gomes S, Khouri J M N, da Matta A P C, Mendes M F, Stella C R A V

Mult Scler Relat Disord. 2016 Mar; 6:64-5. Epub 2016 Jan 28. PMID: 27063625. Abstract

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

(34)

Withdrawal of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six cases.

Hakiki B, Portaccio E, Giannini M, Razzolini L, Pastò L, Amato M P

Mult Scler. 2012 Jul 24. PMID: 22829326. Abstract

Withdrawal has led to rebound activity during pregnancy

(79)

Rebound of disease activity during pregnancy after withdrawal of fingolimod.

Sempere AP, Berenguer-Ruiz L, Feliu-Rey E

Eur J Neurol. 2013 Aug; 20(8):e109-10. PMID: 23829238. Abstract

Suspension of treatment led to rebound in a pediatric-onset patient

(65)

Rebound after Fingolimod suspension in a pediatric-onset multiple sclerosis patient.

Piscolla E, Hakiki B, Pastò L, Razzolini L, Portaccio E, Amato MP

J Neurol. 2013 May 5. PMID: 23645219. Abstract

Discontinuation led to severe disease reactivation in one individual, potentially due to immune reconstitution inflammatory syndrome

(185)

Multiple sclerosis reactivation postfingolimod cessation: Is it IRIS?

Alroughani R, Almulla A, Lamdhade S, Thussu A

BMJ Case Rep. 2014; 2014. PMID: 25320259. Abstract

Discontinuation led to severe disease reactivation 2 to 4 months later in 4 cases

(237)

Severe disease reactivation in four patients with relapsing-remitting multiple sclerosis after fingolimod cessation.

Berger B, Baumgartner A, Rauer S, Mader I, Luetzen N, Farenkopf U, Stich O

J Neuroimmunol. 2015 May 15; 282:118-22. Epub 2015 Apr 07. PMID: 25903738. Abstract

Cessation of therapy was associated with tumefactive demyelinating lesions in 3 individuals who had been free of clinical and radiological disease activity during therapy

(295)

Tumefactive multiple sclerosis lesions in two patients after cessation of fingolimod treatment.

Faissner S, Hoepner R, Lukas C, Chan A, Gold R, Ellrichmann G

Ther Adv Neurol Disord. 2015 Sep; 8(5):233-8. PMID: 26557898. Abstract

Commercial:

Clinical trials have been sponsored by Novartis Pharma

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Marketed by Novartis

(1)

Novartis gains FDA approval for Gilenya(TM), a novel first-line multiple sclerosis treatment shown to significantly reduce relapses and delay disability progression

Novartis, 22 Sep 2010

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2010/1445917.shtml.

Licensed from Mitsubishi Tanabe Pharma Corporation

(16)

Novartis receives European Commission approval for Gilenya®, the first oral multiple sclerosis treatment for use in the EU

Novartis

Accessed on 4 Jan 2012 from http://www.novartis.com/newsroom/media-releases/en/2011/1498377.shtml.

(120)

Mapi Pharma granted United States patent covering the process for the preparation of fingolimod for multiple sclerosis

Market Watch, The Wall Street Journal, 18 Feb 2014

(141)

Novartis: CHMP Issues Positive Opinion To Expand EU Label For Gilenya In RRMS

RTT News, 29 Apr 2014

Accessed on 19 May 2014 from http://www.rttnews.com/2309584/novartis-chmp-issues-positive-opinion-to-expand-eu-label-for-gilenya-in-rrms.aspx?type=qf&utm_source=google&utm_campaign=sitemap.

; extended license has been approved by the European Commission (June, 2014)

(148)

Fingolimod (Gilenya) eligibility extended by NHS England

MS Trust, 12 Jun 2014

Accessed on 12 Jun 2014 from http://www.mstrust.org.uk/news/article.jsp?id=6381.

(154)

MS Trust, 2 July 2014

Accessed on 3 July 2014 from http://www.mstrust.org.uk/news/article.jsp?id=6400.

Endorsed by the Scottish Medicines Consortium for treating rapidly evolving, severe RRMS (October, 2014)

(184)

Novartis MS pill heads stream of SMC approvals

McKee S, PharmaTimes, 13 Oct 2014

Accessed on 21 Oct 2014 from http://www.pharmatimes.com/Article/14-10-13/Novartis_MS_pill_heads_stream_of_SMC_approvals.aspx.

Generic version Neskler has been approved by the Russian Ministry of Health (November 2014)

(318)

Biointegrator announced that it has successfully launched Neskler® - a first generic of Gilenya® in Russia and EuroAsian Economic Union

ChemRar, 11 Jan 2016

Accessed on 19 Jan 2016 from http://www.chemrar.ru/eng/press/press.php?ELEMENT_ID=20580.

(318)

Biointegrator announced that it has successfully launched Neskler® - a first generic of Gilenya® in Russia and EuroAsian Economic Union

ChemRar, 11 Jan 2016

Accessed on 19 Jan 2016 from http://www.chemrar.ru/eng/press/press.php?ELEMENT_ID=20580.

Key Clinical Trials

Placebo-controlled Trials:

Trial name:

TOFINGO (meeting report, October 2013; publ May 2015)

(97)

Shorter washout reduces MS relapse switching off natalizumab

Hughes S, Medscape, 7 Oct 2013

Accessed on 10 Oct 2013 from http://www.medscape.com/viewarticle/812174.

(244)

Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.

Kappos L, Radue E-W, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung H-P, Derfuss T, Naegelin Y, et al.

Neurology. 2015 May 29. Epub 1969 Dec 31. PMID: 26024899. Abstract

Phase:

Phase IV trial

(244)

Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.

Kappos L, Radue E-W, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung H-P, Derfuss T, Naegelin Y, et al.

Neurology. 2015 May 29. Epub 1969 Dec 31. PMID: 26024899. Abstract

Study Design:

Company-sponsored, multicenter, randomized, double-blind, placebo-controlled trial to determine the optimum timing for beginning fingolimod treatment after discontinuation of natalizumab; individuals who had been treated with natalizumab for at least 6 months (and had reason to discontinue such as positive JC virus antibody status, a risk for progressive multifocal leukoencephalopathy) were randomized to the following regimens: a washout period of 8 weeks followed by 24 weeks of fingolimod, a washout period of 12 weeks (no therapy for 8 weeks followed by 4 weeks of placebo) followed by 20 weeks of fingolimod, or a washout period of 16 weeks (no therapy for 8 weeks followed by 8 weeks of placebo) followed by 16 weeks of fingolimod; the primary outcome was the number of active T2 lesions during the washout and first 8 weeks of fingolimod; brain MRIs were obtained at baseline and weeks 8, 12, 16, 20, and 24

(97)

Shorter washout reduces MS relapse switching off natalizumab

Hughes S, Medscape, 7 Oct 2013

Accessed on 10 Oct 2013 from http://www.medscape.com/viewarticle/812174.

(244)

Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.

Kappos L, Radue E-W, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung H-P, Derfuss T, Naegelin Y, et al.

Neurology. 2015 May 29. Epub 1969 Dec 31. PMID: 26024899. Abstract

Disease Stage:

RRMS

(244)

Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.

Kappos L, Radue E-W, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung H-P, Derfuss T, Naegelin Y, et al.

Neurology. 2015 May 29. Epub 1969 Dec 31. PMID: 26024899. Abstract

Enrollment/Number of Patients:

142, with 112 completing the trial

(97)

Shorter washout reduces MS relapse switching off natalizumab

Hughes S, Medscape, 7 Oct 2013

Accessed on 10 Oct 2013 from http://www.medscape.com/viewarticle/812174.

(244)

Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.

Kappos L, Radue E-W, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung H-P, Derfuss T, Naegelin Y, et al.

Neurology. 2015 May 29. Epub 1969 Dec 31. PMID: 26024899. Abstract

Duration:

32 weeks from the last natalizumab infusion

(244)

Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.

Kappos L, Radue E-W, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung H-P, Derfuss T, Naegelin Y, et al.

Neurology. 2015 May 29. Epub 1969 Dec 31. PMID: 26024899. Abstract

Status/Outcome:

8- and 12-week washout periods were associated with fewer active T2 lesions during washout and the first 8 weeks of fingolimod (2.1 and 1.7 versus 8.2 for the 16-week washout) and a higher percentage of relapse-free individuals (88% and 91% versus 84% for the 16-week washout) during the 24 weeks since the last natalizumab treatment

(97)

Shorter washout reduces MS relapse switching off natalizumab

Hughes S, Medscape, 7 Oct 2013

Accessed on 10 Oct 2013 from http://www.medscape.com/viewarticle/812174.

(244)

Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS.

Kappos L, Radue E-W, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung H-P, Derfuss T, Naegelin Y, et al.

Neurology. 2015 May 29. Epub 1969 Dec 31. PMID: 26024899. Abstract

Trial name:

Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting Multiple Sclerosis (FREEDOMS II) (press releases, 2012-2015; publ 2014, 2015)

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

(43)

Efficacy and safety of fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis (FREEDOMS II)

ClinicalTrials.gov, 2 Aug 2012

Accessed on 16 Oct 2012 from http://clinicaltrials.gov/ct2/show/results/NCT00355134.

(59)

New analysis shows Novartis drug Gilenya® significantly reduced rate of brain volume loss across three large Phase III studies

Novartis, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1686799.shtml.

(96)

New data show Novartis' Gilenya® reduced brain volume loss by one third and confirm brain volume loss link with disability in MS patients

Novartis, 4 Oct 2013

Accessed on 4 Oct 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1733406.shtml.

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

(138)

New data at AAN to confirm efficacy of Novartis' Gilenya® across four key measures of MS disease activity, including brain volume loss

GlobeNewswire, 23 Apr 2014

Accessed on 17 May 2014 from http://www.nasdaq.com/press-release/new-data-at-aan-to-confirm-efficacy-of-novartis-gilenya-across-four-key-measures-of-ms-disease-20140423-00020.

(171)

New data confirm high efficacy of Gilenya® in achieving 'no evidence of disease activity (NEDA)' based on four key measures of MS

Novartis, 12 Sep 2014

Accessed on 16 Sep 2014 from http://www.novartis.com/newsroom/media-releases/en/2014/1855482.shtml.

(179)

Efficacy and Safety of Fingolimod in Hispanic Patients with Multiple Sclerosis: Pooled Clinical Trial Analyses.

Chinea Martinez AR, Correale J, Coyle PK, Meng X, Tenenbaum N

Adv Ther. 2014 Sep 23. Epub 2014 Sep 23. PMID: 25245812. Abstract

(223)

Data at AAN showed Gilenya® high efficacy in achieving 'no evidence of disease activity' in previously-treated highly-active MS patients

Novartis, 21 Apr 2015

Accessed on 21 Apr 2015 from http://www.novartis.com/newsroom/media-releases/en/2015/1912676.shtml.

(253)

Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis.

Derfuss T, Bergvall NK, Sfikas N, Tomic DL

Curr Med Res Opin. 2015 Jun 29:1-16. PMID: 26121423. Abstract

Phase:

Phase III trial

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

(43)

Efficacy and safety of fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis (FREEDOMS II)

ClinicalTrials.gov, 2 Aug 2012

Accessed on 16 Oct 2012 from http://clinicaltrials.gov/ct2/show/results/NCT00355134.

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

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 and the secondary endpoints the percentage brain volume change and time to disability progression

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

(43)

Efficacy and safety of fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis (FREEDOMS II)

ClinicalTrials.gov, 2 Aug 2012

Accessed on 16 Oct 2012 from http://clinicaltrials.gov/ct2/show/results/NCT00355134.

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

; in 2009, individuals assigned to the 1.25 mg dose were switched in a blinded fashion to the 0.5 mg dose after review of other data

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Disease Stage:

RRMS

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

(43)

Efficacy and safety of fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis (FREEDOMS II)

ClinicalTrials.gov, 2 Aug 2012

Accessed on 16 Oct 2012 from http://clinicaltrials.gov/ct2/show/results/NCT00355134.

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Enrollment/Number of Patients:

1083

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Duration:

24 months

(43)

Efficacy and safety of fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis (FREEDOMS II)

ClinicalTrials.gov, 2 Aug 2012

Accessed on 16 Oct 2012 from http://clinicaltrials.gov/ct2/show/results/NCT00355134.

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

Status/Outcome:

FIngolimod 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

(43)

Efficacy and safety of fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis (FREEDOMS II)

ClinicalTrials.gov, 2 Aug 2012

Accessed on 16 Oct 2012 from http://clinicaltrials.gov/ct2/show/results/NCT00355134.

; posthoc 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]

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

; over 2 years, fingolimod decreased the rate of brain volume loss by 33% as compared to placebo

(59)

New analysis shows Novartis drug Gilenya® significantly reduced rate of brain volume loss across three large Phase III studies

Novartis, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1686799.shtml.

; fingolimod was associated with a mean percentage brain volume change from baseline of -0.86 versus -1.28 for placebo

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

; fingolimod was not associated with a change in confirmed disability progression

(128)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial.

Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, et al.

Lancet Neurol. 2014 Mar 27. PMID: 24685276. Abstract

; fingolimod-associated reductions in ARR occurred across baseline disease activity, previous treatment, age, and gender

(59)

New analysis shows Novartis drug Gilenya® significantly reduced rate of brain volume loss across three large Phase III studies

Novartis, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1686799.shtml.

; analysis of results from FREEDOMS, FREEDOMS II, and TRANSFORMS showed that progression of disability correlates with brain volume loss

(96)

New data show Novartis' Gilenya® reduced brain volume loss by one third and confirm brain volume loss link with disability in MS patients

Novartis, 4 Oct 2013

Accessed on 4 Oct 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1733406.shtml.

; analyses of pooled data from FREEDOMS and FREEDOMS II showed that more individuals treated with fingolimod versus placebo displayed rates of brain volume loss that were similar to rates in individuals without MS

(138)

New data at AAN to confirm efficacy of Novartis' Gilenya® across four key measures of MS disease activity, including brain volume loss

GlobeNewswire, 23 Apr 2014

Accessed on 17 May 2014 from http://www.nasdaq.com/press-release/new-data-at-aan-to-confirm-efficacy-of-novartis-gilenya-across-four-key-measures-of-ms-disease-20140423-00020.

; analysis of FREEDOMS and FREEDOMS II data showed that individuals treated with fingolimod (0.5 mg) are more likely than those in the placebo group to show no evidence of disease activity on the basis of 4 measures (no relapses, MRI lesions, progression of disabilty, or MS-related brain volume loss) (at 2 years, 19.7% of the treated group versus 5.3% for the placebo group at a particular mean rate threshold for brain volume loss)

(171)

New data confirm high efficacy of Gilenya® in achieving 'no evidence of disease activity (NEDA)' based on four key measures of MS

Novartis, 12 Sep 2014

Accessed on 16 Sep 2014 from http://www.novartis.com/newsroom/media-releases/en/2014/1855482.shtml.

(299)

Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis.

Kappos L, De Stefano N, Freedman MS, Cree BAC, Radue E-W, Sprenger T, Sormani M P, Smith T, Häring DA, Meier D P, et al.

Mult Scler. 2015 Nov 19. PMID: 26585439. Abstract

; posthoc analysis of data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials indicated that fingolimod (0.5 mg) reduced the ARR by 52% (relative to placebo) and 35% (relative to interferon beta-1a) [with ARRs of 0.22 (fingolimod), 0.46 (placebo) or 0.34 (interferon beta-1a)] in Hispanic individuals; furthermore, the safety profile in this group was similar to that of the whole study population

(179)

Efficacy and Safety of Fingolimod in Hispanic Patients with Multiple Sclerosis: Pooled Clinical Trial Analyses.

Chinea Martinez AR, Correale J, Coyle PK, Meng X, Tenenbaum N

Adv Ther. 2014 Sep 23. Epub 2014 Sep 23. PMID: 25245812. Abstract

; posthoc analysis of data from FREEDOMS, FREEDOMS II, TRANSFORMS, and their extensions indicated that disease severity at baseline, and new disease activity during the studies, correlated with the rate of brain volume loss during these trials

(206)

Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis.

Radue E-W, Barkhof F, Kappos L, Sprenger T, Häring DA, de Vera A, von Rosenstiel P, Bright JR, Francis G, Cohen JA

Neurology. 2015 Jan 28. PMID: 25632085. Abstract

; analysis of FREEDOMS and FREEDOMS II data showed that, over 2 years, individuals with highly-active relapsing disease (who had been previously treated with an injectable drug) in the fingolimod group were 6 times more likely than those in the placebo group to show no evidence of disease activity on the basis of 4 measures (no relapses, MRI lesions, progression of disabilty, or MS-related brain volume loss)

(223)

Data at AAN showed Gilenya® high efficacy in achieving 'no evidence of disease activity' in previously-treated highly-active MS patients

Novartis, 21 Apr 2015

Accessed on 21 Apr 2015 from http://www.novartis.com/newsroom/media-releases/en/2015/1912676.shtml.

; posthoc analysis of data from FREEDOMS and FREEDOMS II indicated that fingolimod was effective in individuals with highly active RRMS despite previous disease-modifying therapy, such that fingolimod was associated with a reduction in (i) the ARR by 48%, (ii) the risk of 3-month and 6-month confirmed disability progression by 34% and 45%, and (iii) brain volume loss by 46%, in this group

(253)

Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis.

Derfuss T, Bergvall NK, Sfikas N, Tomic DL

Curr Med Res Opin. 2015 Jun 29:1-16. PMID: 26121423. Abstract

; analysis of pooled data from FREEDOMS, FREEDOMS II, and their extensions indicated that during year 1, 27.1% of participants receiving fingolimod exhibited no evidence of disease activity over 4 measures versus 9.1% on placebo; switching to fingolimod from placebo after year 2 increased the frequency of such participants from 12.7% to 27.4%

(288)

Long-term efficacy of Gilenya® reinforced by new 'no evidence of disease activity' (NEDA-4) analysis in MS patients over seven years

Novartis, 8 Oct 2015

Accessed on 13 Oct 2015 from https://www.novartis.com/news/media-releases/long-term-efficacy-gilenya®-reinforced-new-no-evidence-disease-activity-neda-4.

; posthoc analysis of pooled data from FREEDOMS and FREEDOMS II from individuals receiving 0.5 mg fingolimod or placebo showed that fingolimod's effects on relapses, MRI, cognition, brain volume loss, and disability were apparent within 6 months after initiation; at 3 months, effects on ARR were apparent (0.32 versus 0.52) and from day 48 onwards, a delay in time to first relapse was apparent

(302)

Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis.

Kappos L, Radue E-W, Chin P, Ritter S, Tomic D, Lublin F

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645392. Abstract

Trial name:

FTY720 in Patients With Primary Progressive Multiple Sclerosis (INFORMS) (press release, December 2014; meeting report, October 2015; publ January 2016)

(19)

FTY720 in patients with primary progressive multiple sclerosis (INFORMS)

ClinicalTrials.gov

Accessed on 4 Jan 2012 from http://clinicaltrials.gov/ct2/show/record/NCT00731692.

(196)

Novartis provides update on fingolimod Phase III trial in primary progressive MS (PPMS)

Novartis, 1 Dec 2014

Accessed on 2 Dec 2014 from http://www.novartis.com/newsroom/media-releases/en/2014/1875463.shtml.

(287)

Neurology Advisor, 7 Oct 2015

Accessed on 13 Oct 2015 from http://www.neurologyadvisor.com/ectrims-2015/fingolimod-effect-primary-progressive-multiple-sclerosis/article/443534/.

(323)

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung H-P, Montalban X, Uitdehaag B M, et al.

Lancet. 2016 Jan 27. Epub 1969 Dec 31. PMID: 26827074. Abstract

Phase:

Phase III trial

(19)

FTY720 in patients with primary progressive multiple sclerosis (INFORMS)

ClinicalTrials.gov

Accessed on 4 Jan 2012 from http://clinicaltrials.gov/ct2/show/record/NCT00731692.

(323)

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung H-P, Montalban X, Uitdehaag B M, et al.

Lancet. 2016 Jan 27. Epub 1969 Dec 31. PMID: 26827074. Abstract

Study Design:

Industry-sponsored, multinational, double-blind, randomized, placebo-controlled, parallel-group trial to evaluate the effect of fingolimod (initially 1.25 mg per day, switched to 0.5 mg per day in 2009 following a protocol amendment) on a composite primary endpoint that measured disability progression

(19)

FTY720 in patients with primary progressive multiple sclerosis (INFORMS)

ClinicalTrials.gov

Accessed on 4 Jan 2012 from http://clinicaltrials.gov/ct2/show/record/NCT00731692.

(323)

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung H-P, Montalban X, Uitdehaag B M, et al.

Lancet. 2016 Jan 27. Epub 1969 Dec 31. PMID: 26827074. Abstract

Disease Stage:

PPMS

(19)

FTY720 in patients with primary progressive multiple sclerosis (INFORMS)

ClinicalTrials.gov

Accessed on 4 Jan 2012 from http://clinicaltrials.gov/ct2/show/record/NCT00731692.

(323)

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung H-P, Montalban X, Uitdehaag B M, et al.

Lancet. 2016 Jan 27. Epub 1969 Dec 31. PMID: 26827074. Abstract

Enrollment/Number of Patients:

970

(196)

Novartis provides update on fingolimod Phase III trial in primary progressive MS (PPMS)

Novartis, 1 Dec 2014

Accessed on 2 Dec 2014 from http://www.novartis.com/newsroom/media-releases/en/2014/1875463.shtml.

(323)

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung H-P, Montalban X, Uitdehaag B M, et al.

Lancet. 2016 Jan 27. Epub 1969 Dec 31. PMID: 26827074. Abstract

Duration:

≥36 months

(19)

FTY720 in patients with primary progressive multiple sclerosis (INFORMS)

ClinicalTrials.gov

Accessed on 4 Jan 2012 from http://clinicaltrials.gov/ct2/show/record/NCT00731692.

(323)

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung H-P, Montalban X, Uitdehaag B M, et al.

Lancet. 2016 Jan 27. Epub 1969 Dec 31. PMID: 26827074. Abstract

Status/Outcome:

Fingolimod did not slow progression of disease as measured by a combination of disability measures as compared with placebo

(196)

Novartis provides update on fingolimod Phase III trial in primary progressive MS (PPMS)

Novartis, 1 Dec 2014

Accessed on 2 Dec 2014 from http://www.novartis.com/newsroom/media-releases/en/2014/1875463.shtml.

(323)

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung H-P, Montalban X, Uitdehaag B M, et al.

Lancet. 2016 Jan 27. Epub 1969 Dec 31. PMID: 26827074. Abstract

; fingolimod did not affect atrophy of the brain or spinal cord (meeting report, October 2015)

(287)

Neurology Advisor, 7 Oct 2015

Accessed on 13 Oct 2015 from http://www.neurologyadvisor.com/ectrims-2015/fingolimod-effect-primary-progressive-multiple-sclerosis/article/443534/.

Trial name:

Saida et al., Mult. Scler., September 2012 trial

(113)

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis.

Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J

Mult Scler. 2012 Sep; 18(9):1269-77. Epub 2012 Feb 21. PMID: 22354739. Abstract

Phase:

Phase II trial

(113)

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis.

Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J

Mult Scler. 2012 Sep; 18(9):1269-77. Epub 2012 Feb 21. PMID: 22354739. Abstract

Study Design:

Randomized, double-blind, parallel-group, placebo-controlled trial to examine the effects of fingolimod (0.5 mg or 1.25 mg per day) on gadolinium-enhanced lesions at months 3 and 6 (with the percentage of participants free from such lesions the primary endpoint) and the proportion of participants with relapses over 6 months (secondary endpoint) in Japanese individuals

(113)

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis.

Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J

Mult Scler. 2012 Sep; 18(9):1269-77. Epub 2012 Feb 21. PMID: 22354739. Abstract

Disease Stage:

Relapsing MS

(113)

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis.

Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J

Mult Scler. 2012 Sep; 18(9):1269-77. Epub 2012 Feb 21. PMID: 22354739. Abstract

Enrollment/Number of Patients:

171 began the trial; 147 completed it

(113)

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis.

Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J

Mult Scler. 2012 Sep; 18(9):1269-77. Epub 2012 Feb 21. PMID: 22354739. Abstract

Duration:

6 months

(113)

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis.

Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J

Mult Scler. 2012 Sep; 18(9):1269-77. Epub 2012 Feb 21. PMID: 22354739. Abstract

Status/Outcome:

Results were consistent with those from trials involving primarily Caucasian populations; fingolimod was associated with a greater proportion of participants with no gadolinium-enhanced lesions [70% (0.5 mg dose group) and 86% (1.25 mg dose group) versus 40% (placebo group)] but not with a significant change in the proportion of relapse-free participants

(113)

A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis.

Saida T, Kikuchi S, Itoyama Y, Hao Q, Kurosawa T, Nagato K, Tang D, Zhang-Auberson L, Kira J

Mult Scler. 2012 Sep; 18(9):1269-77. Epub 2012 Feb 21. PMID: 22354739. Abstract

Trial name:

FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) (publ 2010, 2012-2015; press releases, 2013-2015)

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

(30)

Impact of Fingolimod Therapy on Magnetic Resonance Imaging Outcomes in Patients With Multiple SclerosisImpact of Fingolimod Therapy in Multiple Sclerosis.

Radue E-W, O'Connor P, Polman CH, Hohlfeld R, Calabresi P, Selmaj K, Mueller-Lenke N, Agoropoulou C, Holdbrook F, de Vera A, et al.

Arch Neurol. 2012 Jul 2:1-11. PMID: 22751847. Abstract

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

(59)

New analysis shows Novartis drug Gilenya® significantly reduced rate of brain volume loss across three large Phase III studies

Novartis, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1686799.shtml.

(96)

New data show Novartis' Gilenya® reduced brain volume loss by one third and confirm brain volume loss link with disability in MS patients

Novartis, 4 Oct 2013

Accessed on 4 Oct 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1733406.shtml.

(129)

Fingolimod Therapy in Early Multiple Sclerosis: An Efficacy Analysis of the TRANSFORMS and FREEDOMS Studies by Time Since First Symptom.

Agius M, Meng X, Chin P, Grinspan A, Hashmonay R

CNS Neurosci Ther. 2014 Mar 31. PMID: 24684973. Abstract

(138)

New data at AAN to confirm efficacy of Novartis' Gilenya® across four key measures of MS disease activity, including brain volume loss

GlobeNewswire, 23 Apr 2014

Accessed on 17 May 2014 from http://www.nasdaq.com/press-release/new-data-at-aan-to-confirm-efficacy-of-novartis-gilenya-across-four-key-measures-of-ms-disease-20140423-00020.

(171)

New data confirm high efficacy of Gilenya® in achieving 'no evidence of disease activity (NEDA)' based on four key measures of MS

Novartis, 12 Sep 2014

Accessed on 16 Sep 2014 from http://www.novartis.com/newsroom/media-releases/en/2014/1855482.shtml.

(179)

Efficacy and Safety of Fingolimod in Hispanic Patients with Multiple Sclerosis: Pooled Clinical Trial Analyses.

Chinea Martinez AR, Correale J, Coyle PK, Meng X, Tenenbaum N

Adv Ther. 2014 Sep 23. Epub 2014 Sep 23. PMID: 25245812. Abstract

(253)

Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis.

Derfuss T, Bergvall NK, Sfikas N, Tomic DL

Curr Med Res Opin. 2015 Jun 29:1-16. PMID: 26121423. Abstract

Phase:

Phase III trial

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

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 (ARR) (primary endpoint) and the time to disability progression and the number of gadolinium-enhancing lesions (secondary endpoints)

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

; MRI scans were obtained at 0, 6, 12, and 24 months

(30)

Impact of Fingolimod Therapy on Magnetic Resonance Imaging Outcomes in Patients With Multiple SclerosisImpact of Fingolimod Therapy in Multiple Sclerosis.

Radue E-W, O'Connor P, Polman CH, Hohlfeld R, Calabresi P, Selmaj K, Mueller-Lenke N, Agoropoulou C, Holdbrook F, de Vera A, et al.

Arch Neurol. 2012 Jul 2:1-11. PMID: 22751847. Abstract

Disease Stage:

RRMS

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

Enrollment/Number of Patients:

1272 (with 1033 completing study)

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

Duration:

24 months

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

Status/Outcome:

Fingolimod caused a relative reduction in the ARR 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

(6)

A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al.

N Engl J Med. 2010 Feb 4; 362(5):387-401. Epub 2010 Jan 20. PMID: 20089952. Abstract

; 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

(30)

Impact of Fingolimod Therapy on Magnetic Resonance Imaging Outcomes in Patients With Multiple SclerosisImpact of Fingolimod Therapy in Multiple Sclerosis.

Radue E-W, O'Connor P, Polman CH, Hohlfeld R, Calabresi P, Selmaj K, Mueller-Lenke N, Agoropoulou C, Holdbrook F, de Vera A, et al.

Arch Neurol. 2012 Jul 2:1-11. PMID: 22751847. Abstract

; posthoc 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]

(42)

New analysis indicates that Novartis drug Gilenya shows significant early effect on reducing brain volume loss at 6 months

Novartis, 12 Oct 2012

Accessed on 16 Oct 2012 from http://www.novartis.com/newsroom/media-releases/en/2012/1648172.shtml.

; over 2 years, fingolimod decreased the rate of brain volume loss by 35% as compared to placebo

(59)

New analysis shows Novartis drug Gilenya® significantly reduced rate of brain volume loss across three large Phase III studies

Novartis, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1686799.shtml.

; continuous treatment over 4 years (as shown by collective data from the FREEDOMS trial and its extension study) was associated with as much as one third less brain volume loss than treatment with placebo for 2 years followed by fingolimod for 2 years, and a lower rate of brain volume loss was associated with being disease free

(96)

New data show Novartis' Gilenya® reduced brain volume loss by one third and confirm brain volume loss link with disability in MS patients

Novartis, 4 Oct 2013

Accessed on 4 Oct 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1733406.shtml.

; furthermore, analysis of results from FREEDOMS, FREEDOMS II, and TRANSFORMS showed that progression of disability correlates with brain volume loss

(96)

New data show Novartis' Gilenya® reduced brain volume loss by one third and confirm brain volume loss link with disability in MS patients

Novartis, 4 Oct 2013

Accessed on 4 Oct 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1733406.shtml.

; posthoc subgroup analyses showed that in individuals with early MS (who exhibited their first symptom <3 years before randomization), fingolimod reduced the ARR by 67.4% as compared with placebo; in individuals who exhibited their first symptom ≥3 years before randomization, the reduction was 51.4%

(129)

Fingolimod Therapy in Early Multiple Sclerosis: An Efficacy Analysis of the TRANSFORMS and FREEDOMS Studies by Time Since First Symptom.

Agius M, Meng X, Chin P, Grinspan A, Hashmonay R

CNS Neurosci Ther. 2014 Mar 31. PMID: 24684973. Abstract

(138)

New data at AAN to confirm efficacy of Novartis' Gilenya® across four key measures of MS disease activity, including brain volume loss

GlobeNewswire, 23 Apr 2014

Accessed on 17 May 2014 from http://www.nasdaq.com/press-release/new-data-at-aan-to-confirm-efficacy-of-novartis-gilenya-across-four-key-measures-of-ms-disease-20140423-00020.

(171)

New data confirm high efficacy of Gilenya® in achieving 'no evidence of disease activity (NEDA)' based on four key measures of MS

Novartis, 12 Sep 2014

Accessed on 16 Sep 2014 from http://www.novartis.com/newsroom/media-releases/en/2014/1855482.shtml.

(299)

Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis.

Kappos L, De Stefano N, Freedman MS, Cree BAC, Radue E-W, Sprenger T, Sormani M P, Smith T, Häring DA, Meier D P, et al.

Mult Scler. 2015 Nov 19. PMID: 26585439. Abstract

(179)

Efficacy and Safety of Fingolimod in Hispanic Patients with Multiple Sclerosis: Pooled Clinical Trial Analyses.

Chinea Martinez AR, Correale J, Coyle PK, Meng X, Tenenbaum N

Adv Ther. 2014 Sep 23. Epub 2014 Sep 23. PMID: 25245812. Abstract

(206)

Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis.

Radue E-W, Barkhof F, Kappos L, Sprenger T, Häring DA, de Vera A, von Rosenstiel P, Bright JR, Francis G, Cohen JA

Neurology. 2015 Jan 28. PMID: 25632085. Abstract

; an analysis of 992 participants showed that the treatment effect on the number of relapses during the first year and the yearly percentage brain volume change over 2 years independently predict the treatment effect on progression of disability

(208)

Fingolimod effect on brain volume loss independently contributes to its effect on disability.

Sormani M, De Stefano N, Francis G, Sprenger T, Chin P, Radue E, Kappos L

Mult Scler. 2015 Feb 6. PMID: 25662353. Abstract

; analysis of 36 participants showed reduced median levels of neurofilament light chain subunit (a marker of axonal injury) in the cerebrospinal fluid for fingolimod but not placebo at 12 months, and this reduction correlated with better relapse and MRI results

(218)

Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis.

Kuhle J, Disanto G, Lorscheider J, Stites T, Chen Y, Dahlke F, Francis G, Shrinivasan A, Radue E-W, Giovannoni G, et al.

Neurology. 2015 Mar 25. PMID: 25809304. Abstract

(223)

Data at AAN showed Gilenya® high efficacy in achieving 'no evidence of disease activity' in previously-treated highly-active MS patients

Novartis, 21 Apr 2015

Accessed on 21 Apr 2015 from http://www.novartis.com/newsroom/media-releases/en/2015/1912676.shtml.

; posthoc analysis of FREEDOMS and its extension indicated that there is a relationship between the categorical change in the T2 lesion volume (T2LV) and disability over 24 and 48 months, such that participants with increased T2LV display greater changes in the Expanded Disability Status Scale score and the MS Functional Composite score and less time to confirmed disability progression; fingolimod treatment was associated with stable or decreased LV more so than placebo

(228)

Categorical change in T2 lesion volume and clinical outcomes in the Phase III FREEDOMS and its extension study, evaluating fingolimod in patients with relapsing-remitting multiple sclerosis.

Jeffery D, Cantogno EVD, Meier DP, Meinel M, Chin P, Shamim A

Mult Scler Relat Disord. 2014 Nov; 3(6):752-3. Epub 2014 Nov 21. PMID: 25891591. Abstract

; posthoc subgroup analysis indicated that the efficacy of fingolimod was similar regardless of previous treatment

(234)

Impact of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod: Subgroup analyses of the Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study.

Kremenchutzky M, O'Connor P, Hohlfeld R, Zhang-Auberson L, von Rosenstiel P, Meng X, Grinspan A, Hashmonay R, Kappos L

Mult Scler Relat Disord. 2014 May; 3(3):341-9. Epub 2013 Nov 05. PMID: 25876471. Abstract

(253)

Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis.

Derfuss T, Bergvall NK, Sfikas N, Tomic DL

Curr Med Res Opin. 2015 Jun 29:1-16. PMID: 26121423. Abstract

(288)

Long-term efficacy of Gilenya® reinforced by new 'no evidence of disease activity' (NEDA-4) analysis in MS patients over seven years

Novartis, 8 Oct 2015

Accessed on 13 Oct 2015 from https://www.novartis.com/news/media-releases/long-term-efficacy-gilenya®-reinforced-new-no-evidence-disease-activity-neda-4.

(302)

Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis.

Kappos L, Radue E-W, Chin P, Ritter S, Tomic D, Lublin F

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645392. Abstract

Trial name:

Efficacy and Safety of FTY720 in Patients With Relapsing Multiple Sclerosis (publ 2006)

(20)

Efficacy and safety of FTY720 in patients with relapsing multiple sclerosis

ClinicalTrials.gov.

Accessed on 4 Jan 2012 from http://clinicaltrials.gov/show/NCT00333138.

Phase:

Phase II trial

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Study Design:

Industry-sponsored, double-blind, placebo-controlled, proof-of-concept trial to test the effects of daily oral fingolimod (5.0 mg or 1.25 mg dose) on the number of gadolinium-enhanced lesions and on the annualized relapse rate (ARR)

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Disease Stage:

RRMS

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Enrollment/Number of Patients:

281 (with 255 completing core study and 227 completing extension study)

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Duration:

6-month core study and 6-month extension study

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Status/Outcome:

Both doses of fingolimod reduced in the number of gadolinium-enhanced lesions and the ARR compared with placebo (ARR for 1.25 mg dose, 0.35; for 5.0 mg dose, 0.36; for placebo, 0.77)

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Trial name:

Kahan et al., N. Engl. J. Med., Oct 2003 trial

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

Phase:

Phase I trial

(11)

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, et al.

N Engl J Med. 2006 Sep 14; 355(11):1124-40. PMID: 16971719. Abstract

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)

(13)

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

Kahan BD, Karlix JL, Ferguson RM, Leichtman AB, Mulgaonkar S, Gonwa TA, Skerjanec A, Schmouder RL, Chodoff L

Transplantation. 2003 Oct 15; 76(7):1079-84. PMID: 14557756. Abstract

Disease Stage:

Not MS; stable renal transplant patients

(13)

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

Kahan BD, Karlix JL, Ferguson RM, Leichtman AB, Mulgaonkar S, Gonwa TA, Skerjanec A, Schmouder RL, Chodoff L

Transplantation. 2003 Oct 15; 76(7):1079-84. PMID: 14557756. Abstract

Enrollment/Number of Patients:

(13)

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

Kahan BD, Karlix JL, Ferguson RM, Leichtman AB, Mulgaonkar S, Gonwa TA, Skerjanec A, Schmouder RL, Chodoff L

Transplantation. 2003 Oct 15; 76(7):1079-84. PMID: 14557756. Abstract

Duration:

28 days

(13)

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

Kahan BD, Karlix JL, Ferguson RM, Leichtman AB, Mulgaonkar S, Gonwa TA, Skerjanec A, Schmouder RL, Chodoff L

Transplantation. 2003 Oct 15; 76(7):1079-84. PMID: 14557756. Abstract

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

(13)

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

Kahan BD, Karlix JL, Ferguson RM, Leichtman AB, Mulgaonkar S, Gonwa TA, Skerjanec A, Schmouder RL, Chodoff L

Transplantation. 2003 Oct 15; 76(7):1079-84. PMID: 14557756. Abstract

Head-to-Head Trials:

Trial name:

Barbin et al., Neurology, January 2016 study

(322)

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Barbin L, Rousseau C, Jousset N, Casey R, Debouverie M, Vukusic S, De Sèze J, Brassat D, Wiertlewski S, Brochet B, et al.

Neurology. 2016 Jan 29. PMID: 26826205. Abstract

Phase:

Observational study

(322)

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Barbin L, Rousseau C, Jousset N, Casey R, Debouverie M, Vukusic S, De Sèze J, Brassat D, Wiertlewski S, Brochet B, et al.

Neurology. 2016 Jan 29. PMID: 26826205. Abstract

Study Design:

Multicenter, observational, French study to compare the effects of natalizumab and fingolimod on relapses and MRI outcomes, with statistical analysis done using both logistic regression and propensity scores

(322)

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Barbin L, Rousseau C, Jousset N, Casey R, Debouverie M, Vukusic S, De Sèze J, Brassat D, Wiertlewski S, Brochet B, et al.

Neurology. 2016 Jan 29. PMID: 26826205. Abstract

Disease Stage:

RRMS

(322)

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Barbin L, Rousseau C, Jousset N, Casey R, Debouverie M, Vukusic S, De Sèze J, Brassat D, Wiertlewski S, Brochet B, et al.

Neurology. 2016 Jan 29. PMID: 26826205. Abstract

Enrollment/Number of Patients:

629 (326 treated with natalizumab and 303 with fingolimod)

(322)

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Barbin L, Rousseau C, Jousset N, Casey R, Debouverie M, Vukusic S, De Sèze J, Brassat D, Wiertlewski S, Brochet B, et al.

Neurology. 2016 Jan 29. PMID: 26826205. Abstract

Duration:

2 years

(322)

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Barbin L, Rousseau C, Jousset N, Casey R, Debouverie M, Vukusic S, De Sèze J, Brassat D, Wiertlewski S, Brochet B, et al.

Neurology. 2016 Jan 29. PMID: 26826205. Abstract

Status/Outcome:

The group receiving natalizumab had a lower proportion of participants with ≥1 relapse than the group receiving fingolimod at year 1 (confounder-adjusted proportion, 21.1% versus 30.4%) and year 2 (30.9% versus 41.7%) as well as a lower proportion with new T2 and gadolinium-enhancing lesions at both 1 and 2 years

(322)

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Barbin L, Rousseau C, Jousset N, Casey R, Debouverie M, Vukusic S, De Sèze J, Brassat D, Wiertlewski S, Brochet B, et al.

Neurology. 2016 Jan 29. PMID: 26826205. Abstract

Trial name:

Safety and Efficacy of Oral Fingolimod Versus Interferon Beta-1a in Pediatric Patients With Multiple Sclerosis (PARADIGMS) (recruiting as of May 2014)

(138)

New data at AAN to confirm efficacy of Novartis' Gilenya® across four key measures of MS disease activity, including brain volume loss

GlobeNewswire, 23 Apr 2014

Accessed on 17 May 2014 from http://www.nasdaq.com/press-release/new-data-at-aan-to-confirm-efficacy-of-novartis-gilenya-across-four-key-measures-of-ms-disease-20140423-00020.

(139)

Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

ClinicalTrials.gov, 6 May 2014

Accessed on 17 May 2014 from http://www.clinicaltrials.gov/ct2/show/NCT01892722.

Phase:

Phase III trial

(139)

Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

ClinicalTrials.gov, 6 May 2014

Accessed on 17 May 2014 from http://www.clinicaltrials.gov/ct2/show/NCT01892722.

Study Design:

Company-sponsored, double-blind, randomized, multicenter, active-controlled study to examine the safety and effectiveness of oral fingolimod versus intramuscular interferon beta-1a in pediatric patients, such that participants either receive weekly interferon beta-1a injections and daily placebo capsules or daily fingolimod capsules (0.5 mg or 0.25 mg depending on body weight) and weekly placebo injections, with the frequency of relapses the primary outcome measure

(139)

Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

ClinicalTrials.gov, 6 May 2014

Accessed on 17 May 2014 from http://www.clinicaltrials.gov/ct2/show/NCT01892722.

Disease Stage:

Relapsing MS

(139)

Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

ClinicalTrials.gov, 6 May 2014

Accessed on 17 May 2014 from http://www.clinicaltrials.gov/ct2/show/NCT01892722.

Enrollment/Number of Patients:

190 (estimated)

(139)

Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

ClinicalTrials.gov, 6 May 2014

Accessed on 17 May 2014 from http://www.clinicaltrials.gov/ct2/show/NCT01892722.

Duration:

24 months

(139)

Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

ClinicalTrials.gov, 6 May 2014

Accessed on 17 May 2014 from http://www.clinicaltrials.gov/ct2/show/NCT01892722.

Status/Outcome:

Estimated study completion date, May 2017

(139)

Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis

ClinicalTrials.gov, 6 May 2014

Accessed on 17 May 2014 from http://www.clinicaltrials.gov/ct2/show/NCT01892722.

Trial name:

Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) (publ 2010, 2013, 2014)

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

(59)

New analysis shows Novartis drug Gilenya® significantly reduced rate of brain volume loss across three large Phase III studies

Novartis, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1686799.shtml.

(64)

Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS.

Cohen JA, Barkhof F, Comi G, Izquierdo G, Khatri B, Montalban X, Pelletier J, Eckert B, Häring DA, Francis G

J Neurol. 2013 Apr 30. PMID: 23632946. Abstract

(72)

New data at ENS show Novartis drug Gilenya benefited patients by improving all four key measures of multiple sclerosis

Novartis, 5 Jun 2013

Accessed on 8 Jun 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1707070.shtml.

(96)

New data show Novartis' Gilenya® reduced brain volume loss by one third and confirm brain volume loss link with disability in MS patients

Novartis, 4 Oct 2013

Accessed on 4 Oct 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1733406.shtml.

(129)

Fingolimod Therapy in Early Multiple Sclerosis: An Efficacy Analysis of the TRANSFORMS and FREEDOMS Studies by Time Since First Symptom.

Agius M, Meng X, Chin P, Grinspan A, Hashmonay R

CNS Neurosci Ther. 2014 Mar 31. PMID: 24684973. Abstract

(136)

The influence of patient demographics, disease characteristics and treatment on brain volume loss in Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), a phase 3 study of fingolimod in multiple scl

Barkhof F, de Jong R, Sfikas N, de Vera A, Francis G, Cohen J, on behalf of the TRANSFORMS study group

Mult Scler. 2014 May 8. PMID: 24812043. Abstract

(175)

Are Natalizumab and Fingolimod Analogous Second-Line Options for the Treatment of Relapsing-Remitting Multiple Sclerosis? A Clinical Practice Observational Study.

Gajofatto A, Bianchi M R, Deotto L, Benedetti M D

Eur Neurol. 2014 Sep 6; 72(3-4):173-180. Epub 2014 Sep 06. PMID: 25226868. Abstract

Phase:

Phase III trial

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

Study Design:

Industry-sponsored, 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); the primary endpoint was the annualized relapse rate (ARR) and secondary endpoints included the number of new or enlarged lesions and progression of disability

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

Disease Stage:

RRMS

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

Enrollment/Number of Patients:

1292 (with 1153 completing study)

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

Duration:

12 months

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

Status/Outcome:

Fingolimod was associated with a lower 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

(8)

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al.

N Engl J Med. 2010 Feb 4; 362(5):402-15. Epub 2010 Jan 20. PMID: 20089954. Abstract

; over 1 year, fingolimod decreased the rate of brain volume loss by -32% as compared to interferon beta-1a

(59)

New analysis shows Novartis drug Gilenya® significantly reduced rate of brain volume loss across three large Phase III studies

Novartis, 21 Mar 2013

Accessed on 25 Mar 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1686799.shtml.

; 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

(64)

Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS.

Cohen JA, Barkhof F, Comi G, Izquierdo G, Khatri B, Montalban X, Pelletier J, Eckert B, Häring DA, Francis G

J Neurol. 2013 Apr 30. PMID: 23632946. Abstract

; additional data showed that fingolimod was associated with improvements in disability progression

(72)

New data at ENS show Novartis drug Gilenya benefited patients by improving all four key measures of multiple sclerosis

Novartis, 5 Jun 2013

Accessed on 8 Jun 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1707070.shtml.

; a higher percentage of patients on fingolimod were free of disease after 1 year as compared to those on interferon beta-1a

(72)

New data at ENS show Novartis drug Gilenya benefited patients by improving all four key measures of multiple sclerosis

Novartis, 5 Jun 2013

Accessed on 8 Jun 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1707070.shtml.

; analysis of results from FREEDOMS, FREEDOMS II, and TRANSFORMS showed that progression of disability correlates with brain volume loss

(96)

New data show Novartis' Gilenya® reduced brain volume loss by one third and confirm brain volume loss link with disability in MS patients

Novartis, 4 Oct 2013

Accessed on 4 Oct 2013 from http://www.novartis.com/newsroom/media-releases/en/2013/1733406.shtml.

; posthoc subgroup analyses showed that in individuals with early MS (who exhibited their first symptom <3 years before randomization), fingolimod reduced the ARR by 73.4% as compared with interferon beta-1a; in individuals who exhibited their first symptom ≥3 years before randomization, the reduction was 45.4%

(129)

Fingolimod Therapy in Early Multiple Sclerosis: An Efficacy Analysis of the TRANSFORMS and FREEDOMS Studies by Time Since First Symptom.

Agius M, Meng X, Chin P, Grinspan A, Hashmonay R

CNS Neurosci Ther. 2014 Mar 31. PMID: 24684973. Abstract

; fingolimod was associated with reduced loss of brain volume over 12 months as compared with interferon beta-1a in all subgroups examined, including those with and without baseline gadolinium-enhancing lesions; the number of gadolinium-enhancing T1 lesions at baseline was the factor that was most predictive of the percentage brain volume change

(136)

Barkhof F, de Jong R, Sfikas N, de Vera A, Francis G, Cohen J, on behalf of the TRANSFORMS study group

Mult Scler. 2014 May 8. PMID: 24812043. Abstract

(179)

Efficacy and Safety of Fingolimod in Hispanic Patients with Multiple Sclerosis: Pooled Clinical Trial Analyses.

Chinea Martinez AR, Correale J, Coyle PK, Meng X, Tenenbaum N

Adv Ther. 2014 Sep 23. Epub 2014 Sep 23. PMID: 25245812. Abstract

(206)

Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis.

Radue E-W, Barkhof F, Kappos L, Sprenger T, Häring DA, de Vera A, von Rosenstiel P, Bright JR, Francis G, Cohen JA

Neurology. 2015 Jan 28. PMID: 25632085. Abstract

; participants in the fingolimod group were two times more likely than those in the interferon beta-1a group to show no evidence of disease activity on the basis of 4 measures (no relapses, MRI lesions, progression of disabilty, or MS-related brain volume loss)

(223)

Data at AAN showed Gilenya® high efficacy in achieving 'no evidence of disease activity' in previously-treated highly-active MS patients

Novartis, 21 Apr 2015

Accessed on 21 Apr 2015 from http://www.novartis.com/newsroom/media-releases/en/2015/1912676.shtml.

; posthoc subgroup analysis indicated that fingolimod reduced the ARR more than interferon beta-1a regardless of previous interferon beta treatment or the duration or efficacy of previous treatment

(225)

Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing-Remitting Multipl

Khatri BO, Pelletier J, Kappos L, Hartung H-P, Comi G, Barkhof F, von Rosenstiel P, Meng X, Grinspan A, Hashmonay R, et al.

Mult Scler Relat Disord. 2014 May; 3(3):355-63. Epub 2013 Dec 12. PMID: 25876473. Abstract

Other Trials:

Trial name:

Koch-Henriksen et al., Mult. Scler., April 2016 study

(342)

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod.

Koch-Henriksen N, Magyari M, Sellebjerg F, Sørensen P S

Mult Scler. 2016 Apr 7. Epub 1969 Dec 31. PMID: 27055806. Abstract

Phase:

Observational/open-label study

(342)

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod.

Koch-Henriksen N, Magyari M, Sellebjerg F, Sørensen P S

Mult Scler. 2016 Apr 7. Epub 1969 Dec 31. PMID: 27055806. Abstract

Study Design:

Real-life observational study in Denmark to compare clinical disease activity between individuals treated with natalizumab versus fingolimod; individuals who began treatment either of these drug as their first second-line treatment between July 2011 and March 2015 were prospectively recorded in the Danish MS Treatment Register and the two groups were 1:1 propensity score matched

(342)

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod.

Koch-Henriksen N, Magyari M, Sellebjerg F, Sørensen P S

Mult Scler. 2016 Apr 7. Epub 1969 Dec 31. PMID: 27055806. Abstract

Disease Stage:

RRMS

(342)

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod.

Koch-Henriksen N, Magyari M, Sellebjerg F, Sørensen P S

Mult Scler. 2016 Apr 7. Epub 1969 Dec 31. PMID: 27055806. Abstract

Enrollment/Number of Patients:

928 (464 in each group) after propensity score matching

(342)

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod.

Koch-Henriksen N, Magyari M, Sellebjerg F, Sørensen P S

Mult Scler. 2016 Apr 7. Epub 1969 Dec 31. PMID: 27055806. Abstract

Duration:

N/A

(342)

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod.

Koch-Henriksen N, Magyari M, Sellebjerg F, Sørensen P S

Mult Scler. 2016 Apr 7. Epub 1969 Dec 31. PMID: 27055806. Abstract

Status/Outcome:

Differences in clinical disease activity were not found between the two treatment arms: for natalizumab, the annualized relapse rate (ARR) was 0.296 and the mean time to first relapse was 2.55 years; for fingolimod, the ARR was 0.307 and the mean time to first relapse was 2.56 years; Expanded Disability Status Scale score change did not differ between the groups

(342)

A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod.

Koch-Henriksen N, Magyari M, Sellebjerg F, Sørensen P S

Mult Scler. 2016 Apr 7. Epub 1969 Dec 31. PMID: 27055806. Abstract

Trial name:

Correia et al., Mult. Scler. Relat. Disord., March 2016 study

(341)

The effectiveness of fingolimod in a Portuguese real-world population.

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes C, Macário MC, Sousa L

Mult Scler Relat Disord. 2016 Mar; 6:41-8. Epub 2016 Jan 12. PMID: 27063621. Abstract

Phase:

Retrospective study

(341)

The effectiveness of fingolimod in a Portuguese real-world population.

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes C, Macário MC, Sousa L

Mult Scler Relat Disord. 2016 Mar; 6:41-8. Epub 2016 Jan 12. PMID: 27063621. Abstract

Study Design:

Retrospective study to examine the safety and efficacy of fingolimod in a real-world Portuguese population

(341)

The effectiveness of fingolimod in a Portuguese real-world population.

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes C, Macário MC, Sousa L

Mult Scler Relat Disord. 2016 Mar; 6:41-8. Epub 2016 Jan 12. PMID: 27063621. Abstract

Disease Stage:

RRMS

(341)

The effectiveness of fingolimod in a Portuguese real-world population.

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes C, Macário MC, Sousa L

Mult Scler Relat Disord. 2016 Mar; 6:41-8. Epub 2016 Jan 12. PMID: 27063621. Abstract

Enrollment/Number of Patients:

104

(341)

The effectiveness of fingolimod in a Portuguese real-world population.

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes C, Macário MC, Sousa L

Mult Scler Relat Disord. 2016 Mar; 6:41-8. Epub 2016 Jan 12. PMID: 27063621. Abstract

Duration:

≥6 months; mean treatment duration, 21.06 months

(341)

The effectiveness of fingolimod in a Portuguese real-world population.

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes C, Macário MC, Sousa L

Mult Scler Relat Disord. 2016 Mar; 6:41-8. Epub 2016 Jan 12. PMID: 27063621. Abstract

Status/Outcome:

In individuals in whom first-line therapy had failed (n=56), the annualized relapse rate (ARR) was reduced by 68.5% and the Expanded Disability Status Scale score was reduced (from 2.5 to 2.0); in treatment-naive individuals (n=7), the ARR was reduced by 94.9%; adverse events occurred in 56.7% of individuals, but none of these events were serious

(341)

The effectiveness of fingolimod in a Portuguese real-world population.

Correia I, Batista S, Marques IB, Sousa M, Ferreira R, Nunes C, Macário MC, Sousa L

Mult Scler Relat Disord. 2016 Mar; 6:41-8. Epub 2016 Jan 12. PMID: 27063621. Abstract

Trial name:

Alping et al., Ann. Neurol., March 2016 study

(338)

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, et al.

Ann Neurol. 2016 Mar 31. PMID: 27038238. Abstract

Phase:

Observational/open-label study

(338)

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, et al.

Ann Neurol. 2016 Mar 31. PMID: 27038238. Abstract

Study Design:

Observational study to compare the outcomes for individuals switching, because of positive anti-JC virus antibody status, from natalizumab to either rituximab or fingolimod at three Swidish centers (which had different preferences for rituximab and fingolimod)

(338)

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, et al.

Ann Neurol. 2016 Mar 31. PMID: 27038238. Abstract

Disease Stage:

RRMS

(338)

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, et al.

Ann Neurol. 2016 Mar 31. PMID: 27038238. Abstract

Enrollment/Number of Patients:

256 (previously stable on natalizumab), with 55% switching to fingolimod

(338)

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, et al.

Ann Neurol. 2016 Mar 31. PMID: 27038238. Abstract

Duration:

1.5 years after natalizumab cessation

(338)

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, et al.

Ann Neurol. 2016 Mar 31. PMID: 27038238. Abstract

Status/Outcome:

Clinical relapses were experienced by 1.8% of individuals who switched to rituximab and 17.6% of individuals who switched to fingolimod within 1.5 years of natalizumab cessation

(338)

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, Axelsson M, Malmeström C, Fink K, Lycke J, et al.

Ann Neurol. 2016 Mar 31. PMID: 27038238. Abstract

Trial name:

Chevalier et al., PLoS One, March 2016 study

(334)

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

Chevalier J, Chamoux C, Hammès F, Chicoye A

PLoS One. 2016; 11(3):e0150703. Epub 2016 Mar 17. PMID: 26987055. Abstract

Phase:

Economic analysis

(334)

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

Chevalier J, Chamoux C, Hammès F, Chicoye A

PLoS One. 2016; 11(3):e0150703. Epub 2016 Mar 17. PMID: 26987055. Abstract

Study Design:

Industry-funded study using a Markov model to estimate the cost-effectiveness of dimethyl fumarate versus interferon beta-1a (44 microg or 30 microg), interferon beta-1b (250 microg), teriflunomide, glatiramer acetate, and fingolimod from a French societal perspective; event probabilities were taken from pivotal dimethyl fumarate clinical trials and the London Ontario Dataset

(334)

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

Chevalier J, Chamoux C, Hammès F, Chicoye A

PLoS One. 2016; 11(3):e0150703. Epub 2016 Mar 17. PMID: 26987055. Abstract

Disease Stage:

RRMS

(334)

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

Chevalier J, Chamoux C, Hammès F, Chicoye A

PLoS One. 2016; 11(3):e0150703. Epub 2016 Mar 17. PMID: 26987055. Abstract

Enrollment/Number of Patients:

Theoretical cohort, 1000 people

(334)

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

Chevalier J, Chamoux C, Hammès F, Chicoye A

PLoS One. 2016; 11(3):e0150703. Epub 2016 Mar 17. PMID: 26987055. Abstract

Duration:

30-year time horizon in simulation

(334)

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

Chevalier J, Chamoux C, Hammès F, Chicoye A

PLoS One. 2016; 11(3):e0150703. Epub 2016 Mar 17. PMID: 26987055. Abstract

Status/Outcome:

Dimethyl fumarate and interferon beta-1a (44 microg) were found to be the best options, dominating the other therapies with respect to quality-adjusted life years and cost; from a societal perspective, the incremental cost-effectiveness ratio of dimethyl fumarate versus interferon beta-1a (44 microg) was €13,110 per quality-adjusted life year

(334)

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

Chevalier J, Chamoux C, Hammès F, Chicoye A

PLoS One. 2016; 11(3):e0150703. Epub 2016 Mar 17. PMID: 26987055. Abstract

Trial name:

Spelman et al., Eur. J. Neurol., January 2016 study

(319)

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, Horakova D, Duquette P, Izquierdo G, Grand'maison F, et al.

Eur J Neurol. 2016 Jan 19. PMID: 26782663. Abstract

Phase:

Observational study

(319)

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, Horakova D, Duquette P, Izquierdo G, Grand'maison F, et al.

Eur J Neurol. 2016 Jan 19. PMID: 26782663. Abstract

Study Design:

Study to compare the risk of early relapse and disease progression in individuals with stable disease on injectable therapy (glatiramer acetate, interferon beta-1a, or interferon beta-1b) who switch to oral therapy (dimethyl fumarate, fingolimod, or teriflunomide) versus individuals who remain on injectable therapy, using data from the MSBase Registry, an international, longitudinal, observational registry that prospectively collects MS-related information

(319)

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, Horakova D, Duquette P, Izquierdo G, Grand'maison F, et al.

Eur J Neurol. 2016 Jan 19. PMID: 26782663. Abstract

Disease Stage:

RRMS

(319)

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, Horakova D, Duquette P, Izquierdo G, Grand'maison F, et al.

Eur J Neurol. 2016 Jan 19. PMID: 26782663. Abstract

Enrollment/Number of Patients:

792 (396 individuals who switched to oral therapy propensity-matched 1:1 with 396 individuals who stayed on injectable therapy)

(319)

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, Horakova D, Duquette P, Izquierdo G, Grand'maison F, et al.

Eur J Neurol. 2016 Jan 19. PMID: 26782663. Abstract

Duration:

≥12 months stability on injectable treatment pre-baseline and ≥6 months post-baseline

(319)

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, Horakova D, Duquette P, Izquierdo G, Grand'maison F, et al.

Eur J Neurol. 2016 Jan 19. PMID: 26782663. Abstract

Status/Outcome:

Switching to oral therapy was not associated with a change in the rate of disability progression or in the proportion of individuals experiencing ≥1 relapse in the 6 month period post-baseline

(319)

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Spelman T, Mekhael L, Burke T, Butzkueven H, Hodgkinson S, Havrdova E, Horakova D, Duquette P, Izquierdo G, Grand'maison F, et al.

Eur J Neurol. 2016 Jan 19. PMID: 26782663. Abstract

Trial name:

Rasenack et al., PLoS One, January 2016 study

(315)

Efficacy and Safety of Fingolimod in an Unselected Patient Population.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RLP, Sprenger T, Derfuss T

PLoS One. 2016; 11(1):e0146190. Epub 2016 Jan 06. PMID: 26734938. Abstract

Phase:

Retrospective study

(315)

Efficacy and Safety of Fingolimod in an Unselected Patient Population.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RLP, Sprenger T, Derfuss T

PLoS One. 2016; 11(1):e0146190. Epub 2016 Jan 06. PMID: 26734938. Abstract

Study Design:

Retrospective, nonrandomized, open-label, observational study to examine the effects of fingolimod in clinical practice

(315)

Efficacy and Safety of Fingolimod in an Unselected Patient Population.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RLP, Sprenger T, Derfuss T

PLoS One. 2016; 11(1):e0146190. Epub 2016 Jan 06. PMID: 26734938. Abstract

Disease Stage:

RRMS

(315)

Efficacy and Safety of Fingolimod in an Unselected Patient Population.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RLP, Sprenger T, Derfuss T

PLoS One. 2016; 11(1):e0146190. Epub 2016 Jan 06. PMID: 26734938. Abstract

Enrollment/Number of Patients:

105

(315)

Efficacy and Safety of Fingolimod in an Unselected Patient Population.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RLP, Sprenger T, Derfuss T

PLoS One. 2016; 11(1):e0146190. Epub 2016 Jan 06. PMID: 26734938. Abstract

Duration:

1 year

(315)

Efficacy and Safety of Fingolimod in an Unselected Patient Population.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RLP, Sprenger T, Derfuss T

PLoS One. 2016; 11(1):e0146190. Epub 2016 Jan 06. PMID: 26734938. Abstract

Status/Outcome:

Fingolimod was associated with a 44% reduction in the annualized relapse rate (similar to results from Phase III trials) and an increase from 11% to 38% in the fraction of individuals with no evidence of disease activity; the effectiveness and safety of fingolimod was similar in those who had undergone previous treatment(s) or with comorbidities and participants in general

(315)

Efficacy and Safety of Fingolimod in an Unselected Patient Population.

Rasenack M, Rychen J, Andelova M, Naegelin Y, Stippich C, Kappos L, Lindberg RLP, Sprenger T, Derfuss T

PLoS One. 2016; 11(1):e0146190. Epub 2016 Jan 06. PMID: 26734938. Abstract

Trial name:

Mauskopf et al., J. Med. Econ., December 2015 study

(310)

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States.

Mauskopf J, Fay M, Iyer R, Sarda S, Livingston T

J Med Econ. 2015 Dec 26:1-36. PMID: 26707273. Abstract

Phase:

Economic analysis

(310)

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States.

Mauskopf J, Fay M, Iyer R, Sarda S, Livingston T

J Med Econ. 2015 Dec 26:1-36. PMID: 26707273. Abstract

Study Design:

Industry-sponsored study that used a Markov model to compare the cost-effectiveness of delayed-release dimethyl fumarate to that of glatiramer acetate and fingolimod over a 20-year time horizon from a US payer perspective; clinical trial data were used to estimate efficacy and safety

(310)

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States.

Mauskopf J, Fay M, Iyer R, Sarda S, Livingston T

J Med Econ. 2015 Dec 26:1-36. PMID: 26707273. Abstract

Disease Stage:

Relapsing forms of MS

(310)

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States.

Mauskopf J, Fay M, Iyer R, Sarda S, Livingston T

J Med Econ. 2015 Dec 26:1-36. PMID: 26707273. Abstract

Enrollment/Number of Patients:

N/A

(310)

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States.

Mauskopf J, Fay M, Iyer R, Sarda S, Livingston T

J Med Econ. 2015 Dec 26:1-36. PMID: 26707273. Abstract

Duration:

N/A

(310)

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States.

Mauskopf J, Fay M, Iyer R, Sarda S, Livingston T

J Med Econ. 2015 Dec 26:1-36. PMID: 26707273. Abstract

Status/Outcome:

According to this model, relative to once-daily glatiramer acetate and fingolimod, dimethyl fumarate increases quality-adjusted life-years (by +0.450 and +0.359, respectively) and decreases 20-year costs (by -$70,644 and -$32,958, respectively)

(310)

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States.

Mauskopf J, Fay M, Iyer R, Sarda S, Livingston T

J Med Econ. 2015 Dec 26:1-36. PMID: 26707273. Abstract

Trial name:

Braune et al., J. Neurol., December 2015 study

(303)

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Braune S, Lang M, Bergmann A, NeuroTransData Study Group

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645389. Abstract

Phase:

Observational/open-label study

(303)

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Braune S, Lang M, Bergmann A, NeuroTransData Study Group

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645389. Abstract

Study Design:

Observational cohort study in Germany to examine the efficacy of fingolimod in individuals for whom earlier injectable disease modifying therapy (iDMT) failed (fingolimod is registered in Europe for treatment of RRMS if other DMTs fail); individuals either switched to fingolimod or to another iDMT and a propensity-score matched group comparison was done

(303)

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Braune S, Lang M, Bergmann A, NeuroTransData Study Group

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645389. Abstract

Disease Stage:

RRMS

(303)

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Braune S, Lang M, Bergmann A, NeuroTransData Study Group

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645389. Abstract

Enrollment/Number of Patients:

433 (with 300 switching to fingolimod and 133 to a second iDMT)

(303)

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Braune S, Lang M, Bergmann A, NeuroTransData Study Group

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645389. Abstract

Duration:

>2 years

(303)

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Braune S, Lang M, Bergmann A, NeuroTransData Study Group

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645389. Abstract

Status/Outcome:

Compared to a second iDMT, fingolimod was associated with a reduced annualized relapse rate (0.21 versus 0.33), a reduced percentage of individuals with progression of the Expanded Disability Status Scale (EDSS) score (15.10 versus 31.00%), and an increased percentage who were free of relapse and progression of the EDSS score (64.4 versus 46.5%)

(303)

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Braune S, Lang M, Bergmann A, NeuroTransData Study Group

J Neurol. 2015 Dec 8. Epub 2015 Dec 08. PMID: 26645389. Abstract

Trial name:

Yamout et al., J. Neuroimmunol., December 2015 study

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Phase:

Retrospective medical record review

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Study Design:

Retrospective review to examine the efficacy and safety of fingolimod in a real-world setting; individuals were identified who were treated during the period between October 2011 and January 2015 at an academic center in Lebanon

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Disease Stage:

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Enrollment/Number of Patients:

122

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Duration:

Variable

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Status/Outcome:

Fingolimod was associated with a decrease in the annualized relapse rate from 1.16 to 0.29; 66.3% of individuals exhibited no new T2 or enhancing lesions; 62.3% experienced some form of adverse event, primarily lymphopenia, an increase in liver enzymes, fatigue, and urinary tract infections, but the first dose was uneventful for 98.8% of individuals

(300)

Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East.

Yamout BI, Zeineddine MM, Tamim H, Khoury SJ

J Neuroimmunol. 2015 Dec 15; 289:93-7. Epub 2015 Oct 26. PMID: 26616877. Abstract

Trial name:

Rotstein et al., Neurol. Neuroimmunol. Neuroinflamm., October 2015 study

(297)

Effect of vitamin D on MS activity by disease-modifying therapy class.

Rotstein DL, Healy BC, Malik MT, Carruthers RL, Musallam AJ, Kivisakk P, Weiner HL, Glanz B, Chitnis T

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e167. Epub 2015 Oct 29. PMID: 26568968. Abstract

Phase:

Observational/open-label study

(297)

Effect of vitamin D on MS activity by disease-modifying therapy class.

Rotstein DL, Healy BC, Malik MT, Carruthers RL, Musallam AJ, Kivisakk P, Weiner HL, Glanz B, Chitnis T

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e167. Epub 2015 Oct 29. PMID: 26568968. Abstract

Study Design:

Observational study to examine the relationship between vitamin D status, measured as serum 25-hydroxyvitamin D (25[OH]D) concentration adjusted for season, and disease activity (time to relapse or the development of a new gadolinium-enhancing lesion) in individuals treated with interferon beta-1a, interferon beta-1b, glatiramer acetate, or fingolimod

(297)

Effect of vitamin D on MS activity by disease-modifying therapy class.

Rotstein DL, Healy BC, Malik MT, Carruthers RL, Musallam AJ, Kivisakk P, Weiner HL, Glanz B, Chitnis T

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e167. Epub 2015 Oct 29. PMID: 26568968. Abstract

Disease Stage:

RRMS

(297)

Effect of vitamin D on MS activity by disease-modifying therapy class.

Rotstein DL, Healy BC, Malik MT, Carruthers RL, Musallam AJ, Kivisakk P, Weiner HL, Glanz B, Chitnis T

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e167. Epub 2015 Oct 29. PMID: 26568968. Abstract

Enrollment/Number of Patients:

324 from the Comprehensive Longitudinal Investigation of MS at Brigham and Women's Hospital (CLIMB) Study

(297)

Effect of vitamin D on MS activity by disease-modifying therapy class.

Rotstein DL, Healy BC, Malik MT, Carruthers RL, Musallam AJ, Kivisakk P, Weiner HL, Glanz B, Chitnis T

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e167. Epub 2015 Oct 29. PMID: 26568968. Abstract

Duration:

One blood draw within 18 months of beginning treatment, and a second 3 to 18 months after the first

(297)

Effect of vitamin D on MS activity by disease-modifying therapy class.

Rotstein DL, Healy BC, Malik MT, Carruthers RL, Musallam AJ, Kivisakk P, Weiner HL, Glanz B, Chitnis T

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e167. Epub 2015 Oct 29. PMID: 26568968. Abstract

Status/Outcome:

Generally, higher 25(OH)D levels were associated with reduced disease activity, but some differences were seen between treatment groups

(297)

Effect of vitamin D on MS activity by disease-modifying therapy class.

Rotstein DL, Healy BC, Malik MT, Carruthers RL, Musallam AJ, Kivisakk P, Weiner HL, Glanz B, Chitnis T

Neurol Neuroimmunol Neuroinflamm. 2015 Dec; 2(6):e167. Epub 2015 Oct 29. PMID: 26568968. Abstract

Trial name:

Tramacere et al., Cochrane Database Syst. Rev., September 2015 study

(283)

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Tramacere I, Giovane C D, Salanti G, D'Amico R, Filippini G

Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381. PMID: 26384035. Abstract

Phase:

Retrospective clinical trial analysis

(283)

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Tramacere I, Giovane C D, Salanti G, D'Amico R, Filippini G

Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381. PMID: 26384035. Abstract

Study Design:

Retrospective network meta-analysis to compare the benefits of alemtuzumab, azathioprine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1a (Avonex, Rebif), pegylated interferon beta-1a, interferon beta-1b, laquinimod, mitoxantrone, natalizumab, and teriflunomide; data were extracted from 39 randomized controlled trials that compared one or more of the 15 drugs used as monotherapy to placebo or another drug

(283)

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Tramacere I, Giovane C D, Salanti G, D'Amico R, Filippini G

Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381. PMID: 26384035. Abstract

Disease Stage:

Adults with RRMS

(283)

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Tramacere I, Giovane C D, Salanti G, D'Amico R, Filippini G

Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381. PMID: 26384035. Abstract

Enrollment/Number of Patients:

25,113 individuals were randomized in the studies included in the analyses

(283)

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Tramacere I, Giovane C D, Salanti G, D'Amico R, Filippini G

Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381. PMID: 26384035. Abstract

Duration:

Median duration of studies, 24 months

(283)

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Tramacere I, Giovane C D, Salanti G, D'Amico R, Filippini G

Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381. PMID: 26384035. Abstract

Status/Outcome:

Alemtuzumab was found to be the most protective against relapses during the first 24 months of therapy (moderate quality evidence); the next most protective were found to be mitoxantrone (very low quality evidence), natalizumab (high quality evidence), and fingolimod (moderate quality evidence); mitoxantrone (low quality evidence) was found to be the most effective at delaying disability worsening, followed by alemtuzumab (low quality evidence) and natalizumab (moderate quality evidence); these results must be interpreted conservatively because few trials have been performed for most of the drugs

(283)

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

Tramacere I, Giovane C D, Salanti G, D'Amico R, Filippini G

Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381. PMID: 26384035. Abstract

Trial name:

Lattanzi et al., J. Neurol. Sci., September 2015 study

(282)

Prediction of disability progression in fingolimod-treated patients.

Lattanzi S, Danni M, Cerqua R, Taffi R, Provinciali L, Silvestrini M

J Neurol Sci. 2015 Sep 6. PMID: 26362335. Abstract

Phase:

Observational/open-label study

(282)

Prediction of disability progression in fingolimod-treated patients.

Lattanzi S, Danni M, Cerqua R, Taffi R, Provinciali L, Silvestrini M

J Neurol Sci. 2015 Sep 6. PMID: 26362335. Abstract

Study Design:

Observational study to examine whether there is an association between early disease activity during treatment with fingolimod and disease progression; the modified Rio score (MRS) was used to assess early disease activity

(282)

Prediction of disability progression in fingolimod-treated patients.

Lattanzi S, Danni M, Cerqua R, Taffi R, Provinciali L, Silvestrini M

J Neurol Sci. 2015 Sep 6. PMID: 26362335. Abstract

Disease Stage:

RRMS

(282)

Prediction of disability progression in fingolimod-treated patients.

Lattanzi S, Danni M, Cerqua R, Taffi R, Provinciali L, Silvestrini M

J Neurol Sci. 2015 Sep 6. PMID: 26362335. Abstract

Enrollment/Number of Patients:

(282)

Prediction of disability progression in fingolimod-treated patients.

Lattanzi S, Danni M, Cerqua R, Taffi R, Provinciali L, Silvestrini M

J Neurol Sci. 2015 Sep 6. PMID: 26362335. Abstract

Duration:

≥36 months of followup, with ≥12 months of fingolimod treatment

(282)

Prediction of disability progression in fingolimod-treated patients.

Lattanzi S, Danni M, Cerqua R, Taffi R, Provinciali L, Silvestrini M

J Neurol Sci. 2015 Sep 6. PMID: 26362335. Abstract

Status/Outcome:

Early disease activity was associated with disease progression, such that individuals with MRS = 0 or 1 after 1 year of treatment had a risk of disability progression of 21.1% during the next 2 years and those with an MRS ≥2 had a risk of disability progression of 80%

(282)

Prediction of disability progression in fingolimod-treated patients.

Lattanzi S, Danni M, Cerqua R, Taffi R, Provinciali L, Silvestrini M

J Neurol Sci. 2015 Sep 6. PMID: 26362335. Abstract

Trial name:

Iaffaldano et al., Brain, September 2015 study

(280)

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Iaffaldano P, Lucisano G, Pozzilli C, Brescia Morra V, Ghezzi A, Millefiorini E, Patti F, Lugaresi A, Zimatore G B, Marrosu M G, et al.

Brain. 2015 Sep 11. PMID: 26362907. Abstract

Phase:

Observational/open-label study

(280)

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Iaffaldano P, Lucisano G, Pozzilli C, Brescia Morra V, Ghezzi A, Millefiorini E, Patti F, Lugaresi A, Zimatore G B, Marrosu M G, et al.

Brain. 2015 Sep 11. PMID: 26362907. Abstract

Study Design:

Observational, multicenter, prospectively acquired cohort study to examine the effects of fingolimod versus interferon beta or glatiramer acetate in individuals (in the Italian iMedWeb registry) who had discontinued natalizumab; the risk of relapse was first estimated during the washout and new therapy periods using Poisson regression analyses in separated models; individuals who switched to fingolimod or interferon beta/glatiramer acetate were also propensity score-matched before further modeling

(280)

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Iaffaldano P, Lucisano G, Pozzilli C, Brescia Morra V, Ghezzi A, Millefiorini E, Patti F, Lugaresi A, Zimatore G B, Marrosu M G, et al.

Brain. 2015 Sep 11. PMID: 26362907. Abstract

Disease Stage:

Relapsing MS

(280)

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Iaffaldano P, Lucisano G, Pozzilli C, Brescia Morra V, Ghezzi A, Millefiorini E, Patti F, Lugaresi A, Zimatore G B, Marrosu M G, et al.

Brain. 2015 Sep 11. PMID: 26362907. Abstract

Enrollment/Number of Patients:

613

(280)

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Iaffaldano P, Lucisano G, Pozzilli C, Brescia Morra V, Ghezzi A, Millefiorini E, Patti F, Lugaresi A, Zimatore G B, Marrosu M G, et al.

Brain. 2015 Sep 11. PMID: 26362907. Abstract

Duration:

12-month followup

(280)

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Iaffaldano P, Lucisano G, Pozzilli C, Brescia Morra V, Ghezzi A, Millefiorini E, Patti F, Lugaresi A, Zimatore G B, Marrosu M G, et al.

Brain. 2015 Sep 11. PMID: 26362907. Abstract

Status/Outcome:

The risk of relapse after switching drugs was greater in those with a washout period >3 months, with more relapses before and during natalizumab therapy, and with comorbidities; the risk of an initial relapse after switching treatments was lower in individuals treated with fingolimod versus interferon beta/glatiramer acetate, although the time to 3-month confirmed disability was similar between groups

(280)

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Iaffaldano P, Lucisano G, Pozzilli C, Brescia Morra V, Ghezzi A, Millefiorini E, Patti F, Lugaresi A, Zimatore G B, Marrosu M G, et al.

Brain. 2015 Sep 11. PMID: 26362907. Abstract

Trial name:

Totaro et al., Mult. Scler. Int., July 2015 study

(267)

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A

Mult Scler Int. 2015; 2015:763418. Epub 2015 Jul 22. PMID: 26266049. Abstract

Phase:

Observational/open-label study

(267)

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A

Mult Scler Int. 2015; 2015:763418. Epub 2015 Jul 22. PMID: 26266049. Abstract

Study Design:

Prospective, observational, multicenter, postmarketing study to examine the efficacy of fingolimod in a real-world setting in Central and Southern Italy, with efficacy endpoints including the fraction of participants free from all disease activity, relapses, disability progression, and MRI activity

(267)

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A

Mult Scler Int. 2015; 2015:763418. Epub 2015 Jul 22. PMID: 26266049. Abstract

Disease Stage:

RRMS

(267)

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A

Mult Scler Int. 2015; 2015:763418. Epub 2015 Jul 22. PMID: 26266049. Abstract

Enrollment/Number of Patients:

142

(267)

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A

Mult Scler Int. 2015; 2015:763418. Epub 2015 Jul 22. PMID: 26266049. Abstract

Duration:

1 to 33 month followup (mean, 14.95 months)

(267)

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A

Mult Scler Int. 2015; 2015:763418. Epub 2015 Jul 22. PMID: 26266049. Abstract

Status/Outcome:

Consistent with previous studies that showed efficacy of fingolimod, 41.9% of participants were free from any disease activity, 88.1% did not exhibit clinical relapse, 69.0% did not show disability progression, and 81.7% were free from gadolinium enhancing lesions

(267)

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Totaro R, Di Carmine C, Costantino G, Fantozzi R, Bellantonio P, Fuiani A, Mundi C, Ruggieri S, Marini C, Carolei A

Mult Scler Int. 2015; 2015:763418. Epub 2015 Jul 22. PMID: 26266049. Abstract

Trial name:

Warrender-Sparkes et al., Mult. Scler., July 2015 study

(261)

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, et al.

Mult Scler. 2015 Jul 21. PMID: 26199347. Abstract

Phase:

Observational study

(261)

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, et al.

Mult Scler. 2015 Jul 21. PMID: 26199347. Abstract

Study Design:

Multivariable conditional risk set survival analysis using data from MSBASIS, an observational, prospective sub-study of the MSBase registry, to examine the effects of fingolimod on treatment persistence, as well as to identify factors that predict treatment discontinuation

(261)

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, et al.

Mult Scler. 2015 Jul 21. PMID: 26199347. Abstract

Disease Stage:

(261)

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, et al.

Mult Scler. 2015 Jul 21. PMID: 26199347. Abstract

Enrollment/Number of Patients:

2640 (who began immunomodulatory therapy)

(261)

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, et al.

Mult Scler. 2015 Jul 21. PMID: 26199347. Abstract

Duration:

N/A

(261)

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, et al.

Mult Scler. 2015 Jul 21. PMID: 26199347. Abstract

Status/Outcome:

The introduction of fingolimod increased the likelihood of discontinuing injectable treatments; fingolimod accounted for 42.3% of switches to other treatments and the switch was likely to be made because of convenience; those treated with fingolimod showed improved persistence compared to those treated with other therapies; factors associated with increased treatment discontinuation rates included female sex, country of residence, younger age, higher Expanded Disability Status Scale scores, and relapse activity

(261)

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

Warrender-Sparkes M, Spelman T, Izquierdo G, Trojano M, Lugaresi A, Grand'maison F, Havrdova E, Horakova D, Boz C, Oreja-Guevara C, et al.

Mult Scler. 2015 Jul 21. PMID: 26199347. Abstract

Trial name:

Ordoñez-Boschetti et al., Adv. Ther., July 2015 study (FIRST LATAM)

(259)

Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study.

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R

Adv Ther. 2015 Jul; 32(7):626-35. Epub 2015 Jul 14. PMID: 26170105. Abstract

Phase:

Observational/open label study

(259)

Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study.

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R

Adv Ther. 2015 Jul; 32(7):626-35. Epub 2015 Jul 14. PMID: 26170105. Abstract

Study Design:

Open-label, single-arm, multicenter study to examine the safety and tolerability of fingolimod in individuals from Latin America; in contrast to Phase III trials, individuals with controlled diabetes, cardiac or pulmonary conditions, higher baseline Expanded Disability Status Scale scores, or older age could enroll

(259)

Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study.

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R

Adv Ther. 2015 Jul; 32(7):626-35. Epub 2015 Jul 14. PMID: 26170105. Abstract

Disease Stage:

RRMS

(259)

Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study.

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R

Adv Ther. 2015 Jul; 32(7):626-35. Epub 2015 Jul 14. PMID: 26170105. Abstract

Enrollment/Number of Patients:

162, with 138 from Latin American countries

(259)

Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study.

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R

Adv Ther. 2015 Jul; 32(7):626-35. Epub 2015 Jul 14. PMID: 26170105. Abstract

Duration:

16 weeks

(259)

Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study.

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R

Adv Ther. 2015 Jul; 32(7):626-35. Epub 2015 Jul 14. PMID: 26170105. Abstract

Status/Outcome:

The first dose was tolerated well and, on the whole, the safety and tolerability profile was similar to that seen in Phase III trials

(259)

Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study.

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R

Adv Ther. 2015 Jul; 32(7):626-35. Epub 2015 Jul 14. PMID: 26170105. Abstract

Trial name:

Klotz et al., BMC Neurol., June 2015 study (ToFingo-Successor)

(248)

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

Klotz L, Grützke B, Eveslage M, Deppe M, Gross CC, Kirstein L, Posevitz-Fejfar A, Schneider-Hohendorf T, Schwab N, Meuth SG, et al.

BMC Neurol. 2015; 15:96. Epub 2015 Jun 23. PMID: 26099927. Abstract

Phase:

Observational/open label study

(248)

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

Klotz L, Grützke B, Eveslage M, Deppe M, Gross CC, Kirstein L, Posevitz-Fejfar A, Schneider-Hohendorf T, Schwab N, Meuth SG, et al.

BMC Neurol. 2015; 15:96. Epub 2015 Jun 23. PMID: 26099927. Abstract

Study Design:

Investigator-initiated, partly industry-supported, exploratory, open-label, monocentric study to examine immune cell migration and function and disease activity during a switch from natalizumab to fingolimod; participants who were receiving natalizumab treatment will receive a final natalizumab infusion, followed by an 8-week washout period and a 24-week period of fingolimod treatment

(248)

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

Klotz L, Grützke B, Eveslage M, Deppe M, Gross CC, Kirstein L, Posevitz-Fejfar A, Schneider-Hohendorf T, Schwab N, Meuth SG, et al.

BMC Neurol. 2015; 15:96. Epub 2015 Jun 23. PMID: 26099927. Abstract

Disease Stage:

RRMS

(248)

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

Klotz L, Grützke B, Eveslage M, Deppe M, Gross CC, Kirstein L, Posevitz-Fejfar A, Schneider-Hohendorf T, Schwab N, Meuth SG, et al.

BMC Neurol. 2015; 15:96. Epub 2015 Jun 23. PMID: 26099927. Abstract

Enrollment/Number of Patients:

(248)

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

Klotz L, Grützke B, Eveslage M, Deppe M, Gross CC, Kirstein L, Posevitz-Fejfar A, Schneider-Hohendorf T, Schwab N, Meuth SG, et al.

BMC Neurol. 2015; 15:96. Epub 2015 Jun 23. PMID: 26099927. Abstract

Duration:

32 weeks

(248)

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

Klotz L, Grützke B, Eveslage M, Deppe M, Gross CC, Kirstein L, Posevitz-Fejfar A, Schneider-Hohendorf T, Schwab N, Meuth SG, et al.

BMC Neurol. 2015; 15:96. Epub 2015 Jun 23. PMID: 26099927. Abstract

Status/Outcome:

Recruitment began in April 2014

(248)

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

Klotz L, Grützke B, Eveslage M, Deppe M, Gross CC, Kirstein L, Posevitz-Fejfar A, Schneider-Hohendorf T, Schwab N, Meuth SG, et al.

BMC Neurol. 2015; 15:96. Epub 2015 Jun 23. PMID: 26099927. Abstract

Trial name:

Maruszczak et al., J. Med. Econ., June 2015 study

(245)

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England.

Maruszczak MJ, Montgomery SM, Griffiths MJS, Bergvall N, Adlard N

J Med Econ. 2015 Jun 9:1-24. PMID: 26055952. Abstract

Phase:

Economic analysis

(245)

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England.

Maruszczak MJ, Montgomery SM, Griffiths MJS, Bergvall N, Adlard N

J Med Econ. 2015 Jun 9:1-24. PMID: 26055952. Abstract

Study Design:

Industry-sponsored study to model and compare the cost-utility of fingolimod versus dimethyl fumarate in England in individuals with highly active RRMS, using data from pivotal clinical trials for both drugs; Expanded Disability Status Scale scores formed the basis for the cohort Markov model

(245)

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England.

Maruszczak MJ, Montgomery SM, Griffiths MJS, Bergvall N, Adlard N

J Med Econ. 2015 Jun 9:1-24. PMID: 26055952. Abstract

Disease Stage:

Highly active RRMS

(245)

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England.

Maruszczak MJ, Montgomery SM, Griffiths MJS, Bergvall N, Adlard N

J Med Econ. 2015 Jun 9:1-24. PMID: 26055952. Abstract

Enrollment/Number of Patients:

N/A

(245)

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England.

Maruszczak MJ, Montgomery SM, Griffiths MJS, Bergvall N, Adlard N

J Med Econ. 2015 Jun 9:1-24. PMID: 26055952. Abstract

Duration:

N/A

(245)

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England.

Maruszczak MJ, Montgomery SM, Griffiths MJS, Bergvall N, Adlard N

J Med Econ. 2015 Jun 9:1-24. PMID: 26055952. Abstract

Status/Outcome:

This analysis indicated that fingolimod continued to be to be cost-effective in highly active RRMS after the introduction of dimethyl fumarate; the incremental cost-effectiveness ratio for fingolimod versus dimethyl fumarate was determined to be £14,076 using UK list prices for both drugs

(245)

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England.

Maruszczak MJ, Montgomery SM, Griffiths MJS, Bergvall N, Adlard N

J Med Econ. 2015 Jun 9:1-24. PMID: 26055952. Abstract

Trial name:

Fragoso et al., Pediatr. Neurol., April 2015 study

(243)

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger than Age 18 Years.

Fragoso Y D, Alves-Leon S V, Barreira A A, Callegaro D, Ferreira M L B, Finkelsztejn A, Gomes S, Goncalves M V M, Moraes Machado M I, Marques V D, et al.

Pediatr Neurol. 2015 Apr 2. PMID: 26026897. Abstract

Phase:

Retrospective medical record review

(243)

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger than Age 18 Years.

Fragoso Y D, Alves-Leon S V, Barreira A A, Callegaro D, Ferreira M L B, Finkelsztejn A, Gomes S, Goncalves M V M, Moraes Machado M I, Marques V D, et al.

Pediatr Neurol. 2015 Apr 2. PMID: 26026897. Abstract

Study Design:

Study to describe the effects of fingolimod in individuals with MS who began treatment when they were younger than 18 years old; these individuals were identified in a Brazilian database

(243)

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger than Age 18 Years.

Fragoso Y D, Alves-Leon S V, Barreira A A, Callegaro D, Ferreira M L B, Finkelsztejn A, Gomes S, Goncalves M V M, Moraes Machado M I, Marques V D, et al.

Pediatr Neurol. 2015 Apr 2. PMID: 26026897. Abstract

Disease Stage:

Very active MS

(243)

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger than Age 18 Years.

Fragoso Y D, Alves-Leon S V, Barreira A A, Callegaro D, Ferreira M L B, Finkelsztejn A, Gomes S, Goncalves M V M, Moraes Machado M I, Marques V D, et al.

Pediatr Neurol. 2015 Apr 2. PMID: 26026897. Abstract

Enrollment/Number of Patients:

(243)

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger than Age 18 Years.

Fragoso Y D, Alves-Leon S V, Barreira A A, Callegaro D, Ferreira M L B, Finkelsztejn A, Gomes S, Goncalves M V M, Moraes Machado M I, Marques V D, et al.

Pediatr Neurol. 2015 Apr 2. PMID: 26026897. Abstract

Duration:

8.6 months (average time for use of fingolimod)

(243)

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger than Age 18 Years.

Fragoso Y D, Alves-Leon S V, Barreira A A, Callegaro D, Ferreira M L B, Finkelsztejn A, Gomes S, Goncalves M V M, Moraes Machado M I, Marques V D, et al.

Pediatr Neurol. 2015 Apr 2. PMID: 26026897. Abstract

Status/Outcome:

The efficacy and safety profile for fingolimod was good in these individuals, such that their degree of disability did not progress, and only one individual experienced a relapse, while on treatment; no major adverse events were described

(243)

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger than Age 18 Years.

Fragoso Y D, Alves-Leon S V, Barreira A A, Callegaro D, Ferreira M L B, Finkelsztejn A, Gomes S, Goncalves M V M, Moraes Machado M I, Marques V D, et al.

Pediatr Neurol. 2015 Apr 2. PMID: 26026897. Abstract

Trial name:

Frisell et al., Mult. Scler., April 2015 study

(235)

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

Frisell T, Forsberg L, Nordin N, Kiesel C, Alfredsson L, Askling J, Hillert J, Olsson T, Piehl F

Mult Scler. 2015 Apr 28. PMID: 25921036. Abstract

Phase:

Retrospective registry analysis

(235)

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

Frisell T, Forsberg L, Nordin N, Kiesel C, Alfredsson L, Askling J, Hillert J, Olsson T, Piehl F

Mult Scler. 2015 Apr 28. PMID: 25921036. Abstract

Study Design:

Retrospective analysis to examine differences in a real-world setting in baseline characteristics and drug discontinuation among individuals beginning treatment with natalizumab or fingolimod, who registered in a Swedish drug monitoring registry in 2011 to 2013

(235)

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

Frisell T, Forsberg L, Nordin N, Kiesel C, Alfredsson L, Askling J, Hillert J, Olsson T, Piehl F

Mult Scler. 2015 Apr 28. PMID: 25921036. Abstract

Disease Stage:

RRMS

(235)

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

Frisell T, Forsberg L, Nordin N, Kiesel C, Alfredsson L, Askling J, Hillert J, Olsson T, Piehl F

Mult Scler. 2015 Apr 28. PMID: 25921036. Abstract

Enrollment/Number of Patients:

1516 (natalizumab, 640 and fingolimod, 876, with 44% of those on fingolimod previously using natalizumab)

(235)

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

Frisell T, Forsberg L, Nordin N, Kiesel C, Alfredsson L, Askling J, Hillert J, Olsson T, Piehl F

Mult Scler. 2015 Apr 28. PMID: 25921036. Abstract

Duration:

Drug discontinuation at 1 year was monitored

(235)

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

Frisell T, Forsberg L, Nordin N, Kiesel C, Alfredsson L, Askling J, Hillert J, Olsson T, Piehl F

Mult Scler. 2015 Apr 28. PMID: 25921036. Abstract

Status/Outcome:

Those in the fingolimod group were older and more likely to be male than those in the natalizumab group; most [87% (natalizumab), 83% (fingolimod and natalizumab-naïve), and 76% (fingolimod after natalizumab)] continued on treatment after 1 year; individuals on fingolimod discontinued treatment because of adverse events more often than those on natalizumab

(235)

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

Frisell T, Forsberg L, Nordin N, Kiesel C, Alfredsson L, Askling J, Hillert J, Olsson T, Piehl F

Mult Scler. 2015 Apr 28. PMID: 25921036. Abstract

Trial name:

He et al., JAMA Neurol., February 2015 study

(207)

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis.

He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, Lugaresi A, Izquierdo G, Grammond P, Duquette P, et al.

JAMA Neurol. 2015 Feb 9:1-10. PMID: 25665031. Abstract

Phase:

Retrospective data analysis

(207)

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis.

He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, Lugaresi A, Izquierdo G, Grammond P, Duquette P, et al.

JAMA Neurol. 2015 Feb 9:1-10. PMID: 25665031. Abstract

Study Design:

Analysis of data from the MSBase registry to compare the effects of switching to fingolimod versus an injectable therapy (interferon beta or glatiramer acetate) on the annualized relapse rate (ARR), disability progression, and therapy persistence in individuals who were originally treated with an injectable disease-modifying therapy and who had had on-treatment disease activity ≤12 months before the switch; the new treatment was given for ≥3 months after the switch

(207)

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis.

He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, Lugaresi A, Izquierdo G, Grammond P, Duquette P, et al.

JAMA Neurol. 2015 Feb 9:1-10. PMID: 25665031. Abstract

Disease Stage:

RRMS

(207)

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis.

He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, Lugaresi A, Izquierdo G, Grammond P, Duquette P, et al.

JAMA Neurol. 2015 Feb 9:1-10. PMID: 25665031. Abstract

Enrollment/Number of Patients:

527 (379 in the interferon beta/glatiramer acetate group matched to 148 in the fingolimod group)

(207)

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis.

He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, Lugaresi A, Izquierdo G, Grammond P, Duquette P, et al.

JAMA Neurol. 2015 Feb 9:1-10. PMID: 25665031. Abstract

Duration:

13.1 months (median followup duration)

(207)

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis.

He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, Lugaresi A, Izquierdo G, Grammond P, Duquette P, et al.

JAMA Neurol. 2015 Feb 9:1-10. PMID: 25665031. Abstract

Status/Outcome:

Fingolimod was associated with a lower mean ARR (0.31 versus 0.42), a lower hazard of disability progression (hazard ratio, 0.53), and a lower hazard of treatment discontinuation (hazard ratio, 0.55) than were the injectable therapies

(207)

Comparison of Switch to Fingolimod or Interferon Beta/Glatiramer Acetate in Active Multiple Sclerosis.

He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, Lugaresi A, Izquierdo G, Grammond P, Duquette P, et al.

JAMA Neurol. 2015 Feb 9:1-10. PMID: 25665031. Abstract

Trial name:

Kalincik et al., Ann. Neurol., December 2014 study

(200)

Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, Izquierdo G, Rozsa C, Grammond P, Alroughani R, et al.

Ann Neurol. 2014 Dec 27. PMID: 25546031. Abstract

Phase:

Retrospective data analysis

(200)

Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, Izquierdo G, Rozsa C, Grammond P, Alroughani R, et al.

Ann Neurol. 2014 Dec 27. PMID: 25546031. Abstract

Study Design:

Analysis of data from the MSBase registry to compare the effects of switching to natalizumab versus fingolimod from interferon beta or glatiramer acetate (with the change in treatment made because of relapses or disability progression in the preceding 6-month period); subpopulations with comparable baseline characteristics were selected by using quasi-randomization with propensity score-based matching

(200)

Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, Izquierdo G, Rozsa C, Grammond P, Alroughani R, et al.

Ann Neurol. 2014 Dec 27. PMID: 25546031. Abstract

Disease Stage:

RRMS

(200)

Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, Izquierdo G, Rozsa C, Grammond P, Alroughani R, et al.

Ann Neurol. 2014 Dec 27. PMID: 25546031. Abstract

Enrollment/Number of Patients:

792, with 578 matched (natalizumab, 407; fingolimod, 171)

(200)

Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, Izquierdo G, Rozsa C, Grammond P, Alroughani R, et al.

Ann Neurol. 2014 Dec 27. PMID: 25546031. Abstract

Duration:

12 months (mean on-study followup)

(200)

Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, Izquierdo G, Rozsa C, Grammond P, Alroughani R, et al.

Ann Neurol. 2014 Dec 27. PMID: 25546031. Abstract

Status/Outcome:

Switching to natalizumab appeared more effective in decreasing the relapse rate and burden of short term disability than switching to fingolimod, such that the annualized relapse rate changed from 1.5 to 0.2 for natalizumab and from 1.3 to 0.4 for fingolimod and the rate of sustained disability regression was 2.8 times higher for natalizumab versus fingolimod, although the rate of sustained disability progression events was similar

(200)

Switch to natalizumab vs fingolimod in active relapsing-remitting multiple sclerosis.

Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, Izquierdo G, Rozsa C, Grammond P, Alroughani R, et al.

Ann Neurol. 2014 Dec 27. PMID: 25546031. Abstract

Trial name:

Nixon et al., Adv. Ther., November 2014 study

(194)

No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.

Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G

Adv Ther. 2014 Nov; 31(11):1134-54. Epub 2014 Nov 21. PMID: 25414048. Abstract

Phase:

Retrospective comparisons of trial data

(194)

No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.

Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G

Adv Ther. 2014 Nov; 31(11):1134-54. Epub 2014 Nov 21. PMID: 25414048. Abstract

Study Design:

Industry-sponsored, indirect comparisons of the efficacy of the oral therapies fingolimod, dimethyl fumarate, and teriflunomide, using statistical modeling approaches to control for differences in patient characteristics in Phase III trials of each of these drugs; the indirect relative risk of attaining no evidence of disease activity (NEDA) for fingolimod versus the other two therapies in an average participant in these trials was predicted by the models

(194)

No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.

Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G

Adv Ther. 2014 Nov; 31(11):1134-54. Epub 2014 Nov 21. PMID: 25414048. Abstract

Disease Stage:

RRMS

(194)

No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.

Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G

Adv Ther. 2014 Nov; 31(11):1134-54. Epub 2014 Nov 21. PMID: 25414048. Abstract

Enrollment/Number of Patients:

N/A

(194)

No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.

Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G

Adv Ther. 2014 Nov; 31(11):1134-54. Epub 2014 Nov 21. PMID: 25414048. Abstract

Duration:

N/A

(194)

No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.

Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G

Adv Ther. 2014 Nov; 31(11):1134-54. Epub 2014 Nov 21. PMID: 25414048. Abstract

Status/Outcome:

The probability of NEDA appeared to be higher for fingolimod than for dimethyl fumarate or teriflunomide in this analysis

(194)

No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis.

Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G

Adv Ther. 2014 Nov; 31(11):1134-54. Epub 2014 Nov 21. PMID: 25414048. Abstract

Trial name:

O'Day et al., J. Med. Econ., November 2014 study

(192)

Cost-effectiveness of natalizumab vs fingolimod for the treatment of relapsing-remitting multiple sclerosis: analyses in Sweden.

O'Day K, Meyer K, Stafkey-Mailey D, Watson C

J Med Econ. 2014 Nov 25:1-22. PMID: 25422991. Abstract

Phase:

Retrospective analysis

(192)

Cost-effectiveness of natalizumab vs fingolimod for the treatment of relapsing-remitting multiple sclerosis: analyses in Sweden.

O'Day K, Meyer K, Stafkey-Mailey D, Watson C

J Med Econ. 2014 Nov 25:1-22. PMID: 25422991. Abstract

Study Design:

Study to compare the cost-effectiveness of natalizumab versus fingolimod from a Swedish perspective, using data from the AFFIRM and FREEDOMS trials; the model considered costs of drug acquisition, administration and monitoring, and treatment of MS relapses

(192)

Cost-effectiveness of natalizumab vs fingolimod for the treatment of relapsing-remitting multiple sclerosis: analyses in Sweden.

O'Day K, Meyer K, Stafkey-Mailey D, Watson C

J Med Econ. 2014 Nov 25:1-22. PMID: 25422991. Abstract

Disease Stage:

RRMS and rapidly evolving severe disease

(192)

Cost-effectiveness of natalizumab vs fingolimod for the treatment of relapsing-remitting multiple sclerosis: analyses in Sweden.

O'Day K, Meyer K, Stafkey-Mailey D, Watson C

J Med Econ. 2014 Nov 25:1-22. PMID: 25422991. Abstract

Enrollment/Number of Patients:

N/A

(192)

Cost-effectiveness of natalizumab vs fingolimod for the treatment of relapsing-remitting multiple sclerosis: analyses in Sweden.

O'Day K, Meyer K, Stafkey-Mailey D, Watson C

J Med Econ. 2014 Nov 25:1-22. PMID: 25422991. Abstract

Duration:

Costs over a 2-year period were considered

(192)

Cost-effectiveness of natalizumab vs fingolimod for the treatment of relapsing-remitting multiple sclerosis: analyses in Sweden.

O'Day K, Meyer K, Stafkey-Mailey D, Watson C

J Med Econ. 2014 Nov 25:1-22. PMID: 25422991. Abstract

Status/Outcome:

When all individuals with RRMS were considered, treatment with fingolimod was found to cost less but treatment with natalizumab resulted in more relapses avoided (0.74 versus 0.59); when only individuals with rapidly evolving severe disease were considered, natalizumab dominated fingolimod; natalizumab was found to be cost-effective in >80% of the simulations in both groups of individuals at a willingness-to-pay threshold of 500,000 Swedish kronor per avoided relapse

(192)

Cost-effectiveness of natalizumab vs fingolimod for the treatment of relapsing-remitting multiple sclerosis: analyses in Sweden.

O'Day K, Meyer K, Stafkey-Mailey D, Watson C

J Med Econ. 2014 Nov 25:1-22. PMID: 25422991. Abstract

Trial name:

Bianco et al., Eur. Neurol., November 2014 study

(189)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab.

Bianco A, Patanella A K, Nociti V, Marti A, Frisullo G, Plantone D, De Fino C, Fetta A, Batocchi A P, Rossini P M, et al.

Eur Neurol. 2014 Nov 7; 73(1-2):57-65. Epub 2014 Nov 07. PMID: 25402749. Abstract

Phase:

Observational/open-label study

(189)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab.

Bianco A, Patanella A K, Nociti V, Marti A, Frisullo G, Plantone D, De Fino C, Fetta A, Batocchi A P, Rossini P M, et al.

Eur Neurol. 2014 Nov 7; 73(1-2):57-65. Epub 2014 Nov 07. PMID: 25402749. Abstract

Study Design:

Prospective, observational, single center study to examine the efficacy and safety of fingolimod (0.5 mg per day) in individuals with previous exposure to natalizumab

(189)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab.

Bianco A, Patanella A K, Nociti V, Marti A, Frisullo G, Plantone D, De Fino C, Fetta A, Batocchi A P, Rossini P M, et al.

Eur Neurol. 2014 Nov 7; 73(1-2):57-65. Epub 2014 Nov 07. PMID: 25402749. Abstract

Disease Stage:

RRMS

(189)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab.

Bianco A, Patanella A K, Nociti V, Marti A, Frisullo G, Plantone D, De Fino C, Fetta A, Batocchi A P, Rossini P M, et al.

Eur Neurol. 2014 Nov 7; 73(1-2):57-65. Epub 2014 Nov 07. PMID: 25402749. Abstract

Enrollment/Number of Patients:

71 (26 with previous exposure to natalizumab)

(189)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab.

Bianco A, Patanella A K, Nociti V, Marti A, Frisullo G, Plantone D, De Fino C, Fetta A, Batocchi A P, Rossini P M, et al.

Eur Neurol. 2014 Nov 7; 73(1-2):57-65. Epub 2014 Nov 07. PMID: 25402749. Abstract

Duration:

Mean duration, 21.75 months

(189)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab.

Bianco A, Patanella A K, Nociti V, Marti A, Frisullo G, Plantone D, De Fino C, Fetta A, Batocchi A P, Rossini P M, et al.

Eur Neurol. 2014 Nov 7; 73(1-2):57-65. Epub 2014 Nov 07. PMID: 25402749. Abstract

Status/Outcome:

Previous exposure to natalizumab did not affect neuroradiological outcomes, disability progression, or the rate of discontinuation because of adverse events; previous natalizumab exposure and fingolimod treatment duration independently predicted the annualized relapse rate during the first year of fingolimod therapy, but not during the long term

(189)

Second-Line Therapy with Fingolimod for Relapsing-Remitting Multiple Sclerosis in Clinical Practice: The Effect of Previous Exposure to Natalizumab.

Bianco A, Patanella A K, Nociti V, Marti A, Frisullo G, Plantone D, De Fino C, Fetta A, Batocchi A P, Rossini P M, et al.

Eur Neurol. 2014 Nov 7; 73(1-2):57-65. Epub 2014 Nov 07. PMID: 25402749. Abstract

Trial name:

Post-authorization Noninterventional German Safety Study of GilEnyA (PANGAEA) (2014-2016)

(230)

PANGAEA: Post-authorization Noninterventional German Safety Study of GilEnyA in relapsing-remitting multiple sclerosis (RRMS) patients: A 24-month interim analysis of a German five-year fingolimod registry study.

Ziemssen T, Diaz-Lorente M, Abdelkader M, Cornelissen C

Mult Scler Relat Disord. 2014 Nov; 3(6):751. Epub 2014 Nov 21. PMID: 25891587. Abstract

(249)

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

Ziemssen T, Kern R, Cornelissen C

BMC Neurol. 2015; 15:93. Epub 2015 Jun 18. PMID: 26084334. Abstract

(345)

Interim Report Released on Real-World Safety of Fingolimod for Relapsing MS

MPR, 17 Apr 2016

Accessed on 19 Apr 2016 from http://www.empr.com/aan-2016-multiple-sclerosis/interim-report-released-on-real-world-safety-of-fingolimod-for-relapsing-ms/article/487770/.

Phase:

Observational/open-label study

(230)

Ziemssen T, Diaz-Lorente M, Abdelkader M, Cornelissen C

Mult Scler Relat Disord. 2014 Nov; 3(6):751. Epub 2014 Nov 21. PMID: 25891587. Abstract

(249)

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

Ziemssen T, Kern R, Cornelissen C

BMC Neurol. 2015; 15:93. Epub 2015 Jun 18. PMID: 26084334. Abstract

Study Design:

Industry-supported, prospective, multicenter, non-interventional registry study to examine the safety and efficacy, as well as pharmacoeconomic aspects, of fingolimod use under real-world conditions

(230)

Ziemssen T, Diaz-Lorente M, Abdelkader M, Cornelissen C

Mult Scler Relat Disord. 2014 Nov; 3(6):751. Epub 2014 Nov 21. PMID: 25891587. Abstract

(249)

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

Ziemssen T, Kern R, Cornelissen C

BMC Neurol. 2015; 15:93. Epub 2015 Jun 18. PMID: 26084334. Abstract

Disease Stage:

RRMS

(230)

Ziemssen T, Diaz-Lorente M, Abdelkader M, Cornelissen C

Mult Scler Relat Disord. 2014 Nov; 3(6):751. Epub 2014 Nov 21. PMID: 25891587. Abstract

Enrollment/Number of Patients:

>4100 at the end of 2013

(230)

Ziemssen T, Diaz-Lorente M, Abdelkader M, Cornelissen C

Mult Scler Relat Disord. 2014 Nov; 3(6):751. Epub 2014 Nov 21. PMID: 25891587. Abstract

; 4051 in April 2016

(345)

Interim Report Released on Real-World Safety of Fingolimod for Relapsing MS

MPR, 17 Apr 2016

Accessed on 19 Apr 2016 from http://www.empr.com/aan-2016-multiple-sclerosis/interim-report-released-on-real-world-safety-of-fingolimod-for-relapsing-ms/article/487770/.

Duration:

5 years

(230)

Ziemssen T, Diaz-Lorente M, Abdelkader M, Cornelissen C

Mult Scler Relat Disord. 2014 Nov; 3(6):751. Epub 2014 Nov 21. PMID: 25891587. Abstract

(249)

The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice.

Ziemssen T, Kern R, Cornelissen C

BMC Neurol. 2015; 15:93. Epub 2015 Jun 18. PMID: 26084334. Abstract

Status/Outcome:

24-month interim analysis indicated that the benefit-to-risk profile of fingolimod that was seen in Phase III clinical trials was also observed in this study; all participants displayed a reduced annual relapse rate relative to baseline (for all participants, 0.4 at month 12 versus 1.5 at baseline), independent of any former treatment, and 73.7% of participants displayed a stable Expanded Disability Status Scale score at month 18

(230)

Ziemssen T, Diaz-Lorente M, Abdelkader M, Cornelissen C

Mult Scler Relat Disord. 2014 Nov; 3(6):751. Epub 2014 Nov 21. PMID: 25891587. Abstract

; 4-year interim analysis indicated that the safety profile of fingolimod is similar to that seen in Phase III clinical trials; 30.5% of participants had not experienced any adverse events (meeting report, April 2016)

(345)

Interim Report Released on Real-World Safety of Fingolimod for Relapsing MS

MPR, 17 Apr 2016

Accessed on 19 Apr 2016 from http://www.empr.com/aan-2016-multiple-sclerosis/interim-report-released-on-real-world-safety-of-fingolimod-for-relapsing-ms/article/487770/.

Trial name:

Limmroth et al., Mult. Scler. Relat. Disord., November 2014 study (START study)

(227)

Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose.

Limmroth V, Hoyer S, Schmidt S, Lang M, Ziemssen T

Mult Scler Relat Disord. 2014 Nov; 3(6):754. Epub 2014 Nov 21. PMID: 25891594. Abstract

Phase:

Observational/open-label study

(227)

Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose.

Limmroth V, Hoyer S, Schmidt S, Lang M, Ziemssen T

Mult Scler Relat Disord. 2014 Nov; 3(6):754. Epub 2014 Nov 21. PMID: 25891594. Abstract

Study Design:

Prospective, open-label study to characterize fingolimod's cardiac safety profile during treatment initiation

(227)

Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose.

Limmroth V, Hoyer S, Schmidt S, Lang M, Ziemssen T

Mult Scler Relat Disord. 2014 Nov; 3(6):754. Epub 2014 Nov 21. PMID: 25891594. Abstract

Disease Stage:

RRMS

(227)

Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose.

Limmroth V, Hoyer S, Schmidt S, Lang M, Ziemssen T

Mult Scler Relat Disord. 2014 Nov; 3(6):754. Epub 2014 Nov 21. PMID: 25891594. Abstract

Enrollment/Number of Patients:

Up to 7000

(227)

Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose.

Limmroth V, Hoyer S, Schmidt S, Lang M, Ziemssen T

Mult Scler Relat Disord. 2014 Nov; 3(6):754. Epub 2014 Nov 21. PMID: 25891594. Abstract

Duration:

1 week

(227)

Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose.

Limmroth V, Hoyer S, Schmidt S, Lang M, Ziemssen T

Mult Scler Relat Disord. 2014 Nov; 3(6):754. Epub 2014 Nov 21. PMID: 25891594. Abstract

Status/Outcome:

An interim analysis involving 599 participants found no Mobitz type II 2nd degree atrioventricular (AV) block; Mobitz type I 2nd degree block and 2:1 2nd degree AV block developed in 1.4% and 0.3% of participants, respectively

(227)

Good cardiac safety in patients with relapsing remitting multiple sclerosis upon first fingolimod dose.

Limmroth V, Hoyer S, Schmidt S, Lang M, Ziemssen T

Mult Scler Relat Disord. 2014 Nov; 3(6):754. Epub 2014 Nov 21. PMID: 25891594. Abstract

Trial name:

Zhang et al., CNS Drugs, October 2014 study

(186)

Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl Fumarate and Intramuscular Interferon-β1a in Relapsing-Remitting Multiple Sclerosis.

Zhang X, Hay JW, Niu X

CNS Drugs. 2014 Oct 19. PMID: 25326785. Abstract

Phase:

Economic analysis

(186)

Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl Fumarate and Intramuscular Interferon-β1a in Relapsing-Remitting Multiple Sclerosis.

Zhang X, Hay JW, Niu X

CNS Drugs. 2014 Oct 19. PMID: 25326785. Abstract

Study Design:

Study to compare the cost-effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and intramuscular interferon beta-1a from a US societal perspective using a Markov model; the incremental net monetary benefit (INMB) was the primary outcome; $150,000 (in 2012 US dollars) per quality-adjusted life year was assumed to be the base case INMB willingness-to-pay (WTP) threshold

(186)

Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl Fumarate and Intramuscular Interferon-β1a in Relapsing-Remitting Multiple Sclerosis.

Zhang X, Hay JW, Niu X

CNS Drugs. 2014 Oct 19. PMID: 25326785. Abstract

Disease Stage:

RRMS

(186)

Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl Fumarate and Intramuscular Interferon-β1a in Relapsing-Remitting Multiple Sclerosis.

Zhang X, Hay JW, Niu X

CNS Drugs. 2014 Oct 19. PMID: 25326785. Abstract

Enrollment/Number of Patients:

N/A

(186)

Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl Fumarate and Intramuscular Interferon-β1a in Relapsing-Remitting Multiple Sclerosis.

Zhang X, Hay JW, Niu X

CNS Drugs. 2014 Oct 19. PMID: 25326785. Abstract

Duration:

5 year time horizon

(186)

Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl Fumarate and Intramuscular Interferon-β1a in Relapsing-Remitting Multiple Sclerosis.

Zhang X, Hay JW, Niu X

CNS Drugs. 2014 Oct 19. PMID: 25326785. Abstract

Status/Outcome:

Dimethyl fumarate was the optimal treatment for >90% of the simulations across a wide range of WTP values; relative to intramuscular interferon beta-1a, fingolimod, teriflunomide, and dimethyl fumarate had INMBs that were estimated to be $36,567, $49,780, and $80,611, respectively, at a WTP of $150,000

(186)

Cost Effectiveness of Fingolimod, Teriflunomide, Dimethyl Fumarate and Intramuscular Interferon-β1a in Relapsing-Remitting Multiple Sclerosis.

Zhang X, Hay JW, Niu X

CNS Drugs. 2014 Oct 19. PMID: 25326785. Abstract

Trial name:

Hersh et al., Int. J. Neurosci., October 2014 study

(181)

Hersh CM, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA, Ontaneda D

Int J Neurosci. 2014 Oct 1:1-24. PMID: 25271798. Abstract

Phase:

Observational/open-label study

(181)

Hersh CM, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA, Ontaneda D

Int J Neurosci. 2014 Oct 1:1-24. PMID: 25271798. Abstract

Study Design:

Observational study to examine experience with fingolimod in a clinical practice setting during the first year of treatment with this drug

(181)

Hersh CM, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA, Ontaneda D

Int J Neurosci. 2014 Oct 1:1-24. PMID: 25271798. Abstract

Disease Stage:

(181)

Hersh CM, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA, Ontaneda D

Int J Neurosci. 2014 Oct 1:1-24. PMID: 25271798. Abstract

Enrollment/Number of Patients:

317, with followup data available for 306

(181)

Hersh CM, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA, Ontaneda D

Int J Neurosci. 2014 Oct 1:1-24. PMID: 25271798. Abstract

Duration:

12 months

(181)

Hersh CM, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA, Ontaneda D

Int J Neurosci. 2014 Oct 1:1-24. PMID: 25271798. Abstract

Status/Outcome:

76 individuals (24.8%) discontinued fingolimod at a mean of 248 days after beginning treatment (a higher proportion than during clinical trials), most often because of adverse effects or breakthrough disease; of those who remained on treatment, 267 (87.3%) were relapse free during the study

(181)