453
Views
28
CrossRef citations to date
0
Altmetric
Review

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

, , &

References

  • Melcon MO, Correale J, Melcon CM. Is it time for a new global classification of multiple sclerosis? J Neurol Sci 2014;344(1-2):171-81
  • Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the. 2013 revisions. Neurology 2014;83(3):278-86
  • Carrithers MD. Update on disease-modifying treatments for multiple sclerosis. Clin Ther 2014;36(12):1938-45
  • Scott LJ. Fingolimod: a review of its use in the management of relapsing remitting multiple sclerosis. CNS Drugs 2011;25(8):673-98
  • Tanasescu R, Constantinescu CS. Pharmacokinetic evaluation of fingolimod for the treatment of multiple sclerosis. Expert Opin Drug Metab Toxicol 2014;10(4):621-30
  • Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002;277(24):21453-7
  • Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355(11):1124-40
  • Comi G, O’Connor P, Montalban X, et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult Scler 2010;16(2):197-207
  • Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362(5):387-401
  • Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13(6):545-56
  • Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 2011;10(6):520-9
  • Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362(5):402-15
  • Devonshire V, Havrdova E, Radue EW, et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol 2012;11(5):420-8
  • Izquierdo G, O’Connor P, Montalban X, et al. Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis. Mult Scler 2013
  • Jeffrey D, et al. Brain volume change by quartile and disability progression in multiple sclerosis: a 4-year analysis of the phase 3 FREEDOMS trial and its extension. Abstract presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; 10-13 September 2014; Boston, Massachusetts. Abstract 36. Free communication FC2.3
  • Radue EW, Sprenger T, Chin P, et al. Consistent reduction in the annualized rate of brain volume loss across Phase 3 core and extension trials of fingolimod in relapsing multiple sclerosis. Neurology 2014;82(10 Suppl):P3.180
  • MS Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone. Available from: https://clinicaltrials.gov/ct2/show/NCT01633112
  • Fingolimod Versus Interferon Beta 1b in Cognitive Symptoms (Cognition). Available from: https://clinicaltrials.gov/ct2/show/NCT01333501
  • Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis. Available from: https://clinicaltrials.gov/ct2/show/NCT01892722
  • Min JH, Kim BJ, Lee KH. Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder. Mult Scler 2012;18:113-15
  • Jacob A, Hutchinson M, Elsone L, et al. Does natalizumab therapy worsen neuromyelitis optica? Neurology 2012;79:1065-6
  • Kornberg MD, Newsome SD. Unmasking and provoking severe disease activity in a patient with NMO spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2015;2(2):e66
  • Trebst C, Jarius S, Berthele A, et al. Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014;261(1):1-16
  • Cohen J, Von Rosenstiel P, Gottschalk R, et al. Long-Term Safety Of Fingolimod: Interim Evaluation Of Data From The LONGTERMS Trial. Neurology 2014;82(10 Suppl):P2.210
  • Poulsen RR, McClaskey CM, Rivkees SA, Wendler CC. The Sphingosine-1-phosphate receptor 1 mediates S1P action during cardiac development. BMC Dev Biol 2011;11:37
  • Willis MA, Cohen JA. Fingolimod therapy for multiple sclerosis. Semin Neurol 2013;33(1):37-44
  • U.S. Food and Drug Administration. (FDA) Center for Drug Evaluation and Research (CDER). Fingolimod Background Package (NDA 22–257). Available from: www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm216553.pdf
  • Lindsey JW, Haden-Pinneri K, Memon NB, Buja LM. Sudden unexpected death on fingolimod. Mult Scler 2012;18(10):1507-8
  • DiMarco JP, O’Connor P, Cohen JA, et al. First-dose effect of fingolimod: pooled safety data from two phase 3 studies (TRANSFORMS and FREEDOMS). Mult Scler 2010;16(Suppl 10):S290
  • Espinosa PS, Berger JR. Delayed fingolimod-associated asystole. Mult Scler 2011;17(11):1387-9
  • Gold R, Comi G, Palace J, et al. Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study. J Neurol 2014;261(2):267-76
  • Pfaff M, Powaga N, Akinci S, et al. Activation of the SPHK/S1P signalling pathway is coupled to muscarinic receptor-dependent regulation of peripheral airways. Respir Res 2005;6:48
  • Brinkmann V, Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol 2006;6(3):244-50
  • Johnson TA, Shames I, Keezer M, et al. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin Immunol 2010;137(1):15-20
  • U.S. Food and Drug Administration. (FDA) Center for Drug Evaluation and Research (CDER). Fingolimod Background Package (NDA 22–257). Available from: www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm216553.pdf
  • Collins W, Cohen J, O’ Connor P, et al. Long-term safety of oral fingolimod (FTY720) in relapsing multiple sclerosis: integrated analyses of phase 1 and phase 3 studies (P843). Mult Scler 2010;16(Suppl 10):S295
  • di Nuzzo L, Orlando R, Nasca C, Nicoletti F. Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis. Drug Des Devel Ther 2014;8:555-68
  • Novartis. Gilenya (Fingolimod) Safety Information Update (Released April 13, 2012). Available from: www.novartis.com/downloads/newsroom/product-related-info-center/statement-PML.pdf [Last accessed 15 May 2012]
  • Jeffrey S. PML in MS Patients Making Natalizumab-to-Fingolimod Switch. MS Boston 2014. The 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting, Boston, Massachusetts; September 10 – 13, 2014; Abstract FC3.1
  • Nolan R, Gelfand JM, Green AJ. Fingolimod treatment in multiple sclerosis leads to increased macular volume. Neurology 2013;80(2):139-44
  • Dinkin M, Paul F. Higher macular volume in patients with MS receiving fingolimod: positive outcome or side effect? Neurology 2013;80(2):128-9
  • Lu E, Wang BW, Alwan S, et al. A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis. CNS Drugs 2014;28(2):89-94
  • Karlsson G, Francis G, Koren G, et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology 2014;82(8):674-80
  • Cohen M, Maillart E, Tourbah A, et al. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol 2014;71(4):436-41
  • Hoepner R, Havla J, Eienbröker C, et al. Predictors for multiple sclerosis relapses after switching from natalizumab to fingolimod. Mult Scler 2014;20(13):1714-20
  • Laroni A, Brogi D, Milesi V, et al. Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab interruption. Mult Scler 2013;19:1236-7
  • Jokubaitis VG, Li V, Kalincik T, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 2014;82(14):1204-11
  • Comi G, Gold R, Dahlke F, et al. Relapses in patients treated with fingolimod after previous exposure to natalizumab. Mult Scler 2015;21(6):786-90
  • Kalincik T, Horakova D, Spelman T, et al. Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis. Ann Neurol 2015;77(3):425-35
  • Bar-Or A, Pachner A, Menguy-Vacheron F, et al. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs 2014;74(6):659-74
  • Fox RI, Herrmann ML, Frangou CG, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 1999;93(3):198-208
  • Garnock-Jones KP. Teriflunomide: a review of its use in relapsing multiple sclerosis. CNS Drugs 2013;27(12):1103-23
  • O’Connor P, Li D, Freedman M, et al. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006;66:894-900
  • O’Connor P, Wolinsky J, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303
  • O’Connor P, Lublin F, Wolinsky J, et al. Effect of teriflunomide on relapses leading to healthcare resource use: results from the TEMSO study. Mult Scler 2011;17(Suppl 17):S95, P250
  • O´Connor P, Wolinsky J, Confavreux C, et al. Extension of a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses: clinical and MRI data 5 years after initial randomisation. Mult Scler 2011;17(Suppl 17):S414, P924
  • Confavreux C, Li D, Freedman M, et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult Scler 2012;18:1278-89
  • Miller A, Kappos L, Comi G, et al. Teriflunomide efficacy and safety in patients with relapsing multiple sclerosis: results from TOWER, a second pivotal phase 3 placebo-controlled study. Neurology 2013;80:S01.004
  • Confavreux C, O’Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13(3):247-56
  • Leist T, Freedman M, Kappos L, et al. Pooled safety data from three placebo-controlled teriflunomide studies. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 2013, Copenhagen
  • Vermersch P, Czlonkowska A, Grimaldi L, et al. Evaluation of patient satisfaction from the TENERE study: a comparison of teriflunomide and subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis. J Neurol 2012;259(Suppl 1):1-236
  • Miller AE, Wolinsky JS, Kappos L, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13(10):977-86
  • Freedman M, Wolinsky J, Wamil B, et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: a randomized phase II trial. Neurology 2012;78:1877-85
  • Freedman M, Wolinsky J, Wamil B, et al. Oral teriflunomide plus glatiramer acetate in relapsing multiple sclerosis. Int J MS Care 2011;13:17
  • Efficacy, Safety and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS). Available from: https://clinicaltrials.gov/ct2/show/NCT02201108
  • Freedman MS. Teriflunomide in relapsing multiple sclerosis: therapeutic utility. Ther Adv Chronic Dis 2013;4(5):192-205
  • White H. A heteroskedasticity consistent covariance matrix estimator and a direct test for heteroscedasticity. Econometrica 1980;817-30
  • Warnatz K, Peter HH, Schumacher M, et al. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Ann Rheum Dis 2003;62(1):50-7
  • Rahmlow M, Shuster EA, Dominik J, et al. Leflunomide-associated progressive multifocal leukoencephalopathy. Arch Neurol 2008;65(11):1538-9
  • Oh J, O’Connor PW. Teriflunomide in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord 2014;7(5):239-52
  • Brent R. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 2001;63:106-12
  • Fukushima R, Kanamori S, Hirashiba M, et al. Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reproduc Toxicol 2007;24(3-4):310-16
  • Kieseier B, Stuve O, Benamor M, et al. Updated pregnancy outcomes from the teriflunomide clinical development programme: retrospective analysis of the teriflunomide CT database. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 2013, Copenhagen
  • Ruggieri S, Tortorella C, Gasperini C. Pharmacology and clinical efficacy of dimethyl fumarate (BG-12) for treatment of relapsing-remitting multiple sclerosis. Ther Clin Risk Manag 2014;10:229-39
  • Litjens NH, Burggraaf J, van Strijen E, et al. Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol 2004;58:429-32
  • Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134:678-92
  • Scannevin RH, Chollate S, Jung MY, et al. Fumarates promotecytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 2012;341:274-84
  • Metz I, Traffehn S, Straßburger-Krogias K, et al. Glial cells express nuclear nrf2 after fumarate treatment for multiple sclerosis and psoriasis. Neurol Neuroimmunol Neuroinflamm 2015;2(3):e99
  • Ghoreschi K, Brück J, Kellerer C, Deng C. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 2011;208(11):2291-303
  • Treumer F, Zhu K, Gläser R, Mrowietz U. Dimethyl fumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol 2003;121(6):1383-8
  • Bomprezzi R. Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview. Adv Neurol Disord 2015;8(1):20-30
  • Salmen A, Gold R. Mode of action and clinical studies with fumarates in multiple sclerosis. Exp Neurol 2014;262(Pt A):52-6
  • Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 2006;13(6):604-10
  • Kappos L, Gold R, Miller DH, et al. BG-12 Phase IIb Study Investigators Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo controlled phase IIb study. Lancet 2008;372:1463-72
  • MacManus DG, Miller DH, Kappos L, et al. BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis. J Neurol 2011;258:449-55
  • Gold R, Kappos L, Arnold DL, et al. DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367(12):1098-107
  • Fox RJ, Miller DH, Phillips JT, et al. CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367(12):1087-97
  • Miller DH, Fox RJ, Phillips JT, et al. Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study. Neurology 2015;84(11):1145-52
  • A Study Evaluating the Effectiveness of Tecfidera™ (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC). Available from: https://clinicaltrials.gov/ct2/show/NCT01930708
  • Gastrointestinal Tolerability Study Of Dimethyl Fumarate (DMF) In Participants With Relapsing-Remitting Multiple Sclerosis In Germany (TOLERATE). Available from: https://clinicaltrials.gov/ct2/show/NCT02125604
  • Phase 4 Study of Effect of Aspirin on Flushing in Dimethyl Fumarate (DMF)-Treated Participants With Relapsing-Remitting Multiple Sclerosis (RRMS) (ASSURE). Available from: https://clinicaltrials.gov/ct2/show/NCT02090413
  • Study to Evaluate Fatigue in Participants With Relapsing Remitting Multiple Sclerosis When Treated With BG00012 or Standard of Care (TECNERGY). Available from: https://clinicaltrials.gov/ct2/show/NCT02090348
  • Strassburger-Krogias K, Ellrichmann G, Krogias C, et al. Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study. Ther Adv Neurol Disord 2014;7(5):232-8
  • Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol 1999;141:424-9
  • Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol 2003;149:363-9
  • Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med 2013;368:1657-8
  • van Oosten BW, Killestein J, Barkhof F, et al. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med 2013;368:1658-9
  • Sweetser MT, Dawson KT, Bozic C. Manufacturer’s response to case reports of PML. N Engl J Med 2013;368:1659-61
  • Schwab N, Ulzheimer JC, Fox RJ, et al. Fatal PML associated with efalizumab therapy: insights into integrin aLβ2 in JC virus control. Neurology 2012;78:458-67
  • Nieuwkamp DJ, Murk JL, van Oosten BW, et al. PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N Engl J Med 2015;372(15):1474-6
  • Rosenkranz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med 2015;372:1476-8
  • Phillips JT, Fox R, Selmaj K, et al. Safety and tolerability of oral BG-12 (dimethyl fumarate) in relapsing–remitting multiple sclerosis (RRMS): interim results from ENDORSE Extension Study (P01.162). Neurology 2013;80: (Meeting Abstracts 1):P01.162
  • Haggiag S, Ruggieri S, Gasperini C. Efficacy and safety of laquinimod in multiple sclerosis: current status. Ther Adv Neurol Disord 2013;6(6):343-52
  • Noseworthy J, Wolinsky J, Lublin F, et al. Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology 2000;54:1726-33
  • Wolinsky J, Narayana P, Noseworthy J, et al. Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators. Neurology 2000;54:1734-41
  • Jönsson S, Andersson G, Fex T, et al. Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship. J Med Chem 2014;47:2075-88
  • Brunmark C, Runström A, Ohlsson L, et al. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol 2002;130:163-72
  • Yang J, Xu L, Xiao B, et al. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol 2004;156:3-9
  • Toubi E, Nussbaum S, Staun-Ram E, et al. Laquinimod modulates B cells and their regulatory effects on T cells in multiple sclerosis. J Neuroimmunol 2012;251:45-54
  • Wegner C, Stadelmann C, Pförtner R, et al. Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 2010;227:133-43
  • Zou L, Abbas N, Volkmann I, et al. Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue. Neuropharmacology 2002;42:731-9
  • Aharoni R, Saada R, Eilam R, et al. Oral treatment with laquinimod augments regulatory T-cells and brain-derived neurotrophic factor expression and reduces injury in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 2012;251:14-24
  • Ruffini F, Rossi S, Bergamaschi A, et al. Laquinimod prevents inflammation-induced synaptic alterations occurring in experimental autoimmune encephalomyelitis. Mult Scler 2013;19:1084-94
  • Gurevich M, Gritzman T, Orbach R, et al. Laquinimod suppress antigen presentation in relapsing–remitting multiple sclerosis: in vitro high-throughput gene expression study. J Neuroimmunol 2010;221:87-94
  • Thöne J, Ellrichmann G, Seubert S, et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Pathol 2012;180(1):267-74
  • Jolivel V, Luessi F, Masri J, et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain 2013;136:1048-66
  • Sühs K. Effects of laquinimod on axon degeneration in autoimmune optic neuritis. Mult Scler 2007;13(S7–S273):P835
  • Polman C, Barkhof F, Sandberg-Wollheim M, Laquinimod in Relapsing MS Study Group. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 2005;64:987-91
  • Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;371:2085-92
  • Comi G, Abramsky O, Arbizu T, et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult Scler 2010;16:1360-6
  • Comi G, Abramsky O, Arbizu T, et al. Long-term open extension of oral laquinimod in patients with relapsing multiple sclerosis shows favourable safety and sustained low relapse rate and MRI activity. Mult Scler 2009;15(Suppl):S127
  • Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med 2012a;366:1000-9
  • Vollmer T, Soelberg Sorensen P, Arnold D. on behalf of the BRAVO Study Group. A placebo-controlled and active comparator phase III trial (BRAVO) for relapsing-remitting multiple sclerosis. In: 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, Amsterdam, The Netherlands, 19–22 October 2011
  • Filippi M, Rocca MA, Pagani E, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry 2014;85(8):851-8
  • Comi G, Jeffery D, Kappos L, et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: clinical effects at 36 months in the open-label extension phase of the ALLEGRO study. Mult Scler 2012b;18(Suppl):P560
  • Comi G, Jeffrey D, Kappos L, et al. Comparison of early and delayed oral laquinimod in patients with relapsing-remitting multiple sclerosis: effects on disability progression at 36 months in the ALLEGRO Trial (S41.004). Neurology 2013;80; Meeting Abstracts 1
  • Vollmer T, Sorensen PS, Selmaj K, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol 2014;261(4):773-83
  • Comi G, Ladkani D, Vollmer T, et al. Mediation of the effect of laquinimod on disability progression in relapsing-remitting multiple sclerosis (RRMS). Neurology 2014;82(10 Suppl):P3.195
  • The Efficacy and Safety and Tolerability of Laquinimod in Subjects With Relapsing Remitting Multiple Sclerosis (RRMS) (CONCERTO). Available from: https://clinicaltrials.gov/ct2/show/NCT01707992
  • An Open Label Extension of the LAQ/5062 and LAQ/5063 Studies to Assess the Long Term Safety and Tolerability of Laquinimod 0.6 mg in RRMS Patients. Available from: https://clinicaltrials.gov/ct2/show/NCT00745615
  • A Study To Evaluate the Long-Term Safety, Tolerability and Effect on Disease Course. Available from: https://clinicaltrials.gov/ct2/show/NCT00988052
  • A Study to Evaluate the Long-term Safety, Tolerability and Effect of Daily Oral Laquinimod 0.6 mg on Disease Course in Subjects With Relapsing Multiple Sclerosis. Available from: https://clinicaltrials.gov/ct2/show/NCT01047319
  • A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5 mg/day (Experimental Drug) as Compared to Placebo. Available from: https://clinicaltrials.gov/ct2/show/NCT02284568
  • Leist TP, Weissert R. Cladribine: mode of action and implications for treatment of multiple sclerosis. Clin Neuropharmacol 2011;34(1):28-35
  • Sipe JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005;5(6):721-7
  • Sigal DS, Miller HJ, Schram ED, Saven A. Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood 2010;116(16):2884-96
  • Hartung HP, Aktas O, Kieseier B, Giancarlo Comi GC. Development of oral cladribine for the treatment of multiple sclerosis. J Neurol 2010;257(2):163-70
  • Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA 1996;93(4):1716-20
  • Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;34(8914):9-13
  • Giovannoni G, Comi G, Cook S, et al. CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362(5):416-26
  • Giovannoni G, Cook S, Rammohan K, et al. CLARITY study group. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol 2011;10(4):329-37
  • Havrdova E, Galetta S, Stefoski D, Comi G. Freedom from disease activity in multiple sclerosis. Neurology 2010;74(Suppl 3):S3-7
  • Stangel M, Penner IK, Kallmann BA, et al. Towards the implementation of ‘no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord 2015;8(1):3-13
  • Leist TP, Comi G, Cree BA, Coyle PK; oral cladribine for early MS (ORACLE MS) Study Group. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol 2014;13(3):257-67
  • Lau C, Narotsky MG, Lui D, et al. Exposure-disease continuum for 2-chloro-2’-deoxyadenosine (2-CdA), a prototype teratogen: induction of lumbar hernia in the rat and species comparison for the teratogenic responses. Teratology 2002;66(1):6-18
  • Gergely P, Nuesslein-Hildesheim B, Guerini D, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 2012;167(5):1035-47
  • Vachal P, Toth LM, Hale JJ, et al. Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor. Bioorg Med Chem Lett 2006;16(14):3684-7
  • Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 2013;12(8):756-67
  • Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND). Available from: https://clinicaltrials.gov/ct2/show/ NCT01665144
  • Kappos L, Bar-Or A, Cree B, et al. Siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis: Design of the phase 3 EXPAND trial. Mult Scler Relat Disord 2014;3(6):752
  • Komiya T, Sato K, Shioya H, et al. Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis. Clin Exp Immunol 2013;171(1):54-62
  • Vollmer T, Selmaj K, Bar-Or A, Zipp F. A double-blind, placebo-controlled, phase 2, 26-week DreaMS trial of a selective S1P receptor agonist ONO-4641 in patients with relapsing-remitting multiple sclerosis. Neurology 2012;79(11):e87-91
  • Bolli MH, Abele S, Binkert C, et al. 2-Imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem 2010;53:4198-211
  • Piali L, Froidevaux S, Hess P, et al. The selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation. J Pharmacol Exp Ther 2011;337:547-56
  • Olsson T, Boster A, Fernández Ó, et al. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry 2014;85(11):1198-208
  • Cohen J, Arnold DL, Comi G, et al. Phase 2 results of the RADIANCE trial: a randomized, double-blind, placebo-controlled trial of oral RPC1063 in relapsing multiple sclerosis. Multiple Sclerosis J 2014;20(S1):10.1177/1352458514547847
  • Dubreuil P, Letard S, Ciufolini M, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 2009;4(9):e7258
  • Silverman AJ, Sutherland AK, Wilhelm M, Silver R. Mast cells migrate from blood to brain. J Neurosci 2000;20:401-8
  • Vermersch P, Benrabah R, Schmidt N, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol 2012;12:36
  • Arun T, Tomassini V, Sbardella E, et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 2013;136(Pt 1):106-15
  • Grove RA, Shackelford S, Sopper S, et al. Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis. Eur J Neurol 2013;20(7):1032-42
  • MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial. Available from: https://clinicaltrials.gov/ct2/show/NCT01910259
  • Amiloride Clinical Trial In Optic Neuritis (ACTION). Available from: https://clinicaltrials.gov/ct2/show/NCT01802489
  • Miller DH, Weber T, Grove R, et al. Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2012;11(2):131-9
  • Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev 2013;6:CD008933
  • Massacesi L, Tramacere I, Amoroso S, et al. Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial. PLoS One 2014;9(11):e113371
  • Kappos L, Radue EW, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of multiple sclerosis disease-activity freedom: the effect of fingolimod. Abstract presented at: 2014 Joint ACTRIMS-ECTRIMS Meeting; 10-13 September 2014; Boston, Massachusetts; Abstract 1570. Free communication FC1.5
  • Cutter G, Fahrbach K, Huelin R, et al. Relative efficacy of teriflunomide 14 mg among the approved disease-modifying therapies in relapsing forms of multiple sclerosis: a mixed treatment comparison. 2013. Available from: https://cmscactrims.confex.com/cmscactrims/2013/webprogram/Paper1826.html [Last accessed 5 March 2014]
  • Hadjigeorgiou GM, Doxani C, Miligkos M, et al. A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis. J Clin Pharm Ther 2013;38:433-9
  • Nixon R, Bergvall N, Tomic D, et al. No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis. Adv Ther 2014;31(11):1134-54
  • Leone C, D’Amico E, Cilia S, et al. Cognitive impairment and ‘invisible symptoms’ are not associated with CCSVI in MS. BMC Neurol 2013;13:97
  • Stangel M, Penner IK, Kallmann BA, et al. Towards the implementation of ’no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord 2015;8(1):3-13
  • Scheel M, Finke C, Oberwahrenbrock T, et al. Retinal nerve fibre layer thickness correlates with brain white matter damage in multiple sclerosis: a combined optical coherence tomography and diffusion tensor imaging study. Mult Scler 2014;20(14):1904-7
  • Oberwahrenbrock T, Ringelstein M, Jentschke S, et al. Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult Scler 2013;19(14):1887-95
  • Bennett JL, de Seze J, Lana-Peixoto M, et al. Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography. Mult Scler 2015;21(6):678-88
  • Coyle PK. Multiple sclerosis and pregnancy prescriptions. Expert Opin Drug Saf 2014;13(12):1565-8
  • Hofmann A, Stellmann JP, Kasper J, et al. Long-term treatment risks in multiple sclerosis: risk knowledge and risk perception in a large cohort of mitoxantrone-treated patients. MultScler 2013;19(7):920-5
  • Heesen C, Kleiter I, Nguyen F, et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler 2010;16(12):1507-12
  • Borisow N, Döring A, Pfueller CF, et al. Expert recommendations to personalization of medical approaches in treatment of Multiple Sclerosis: an overview of family planning and pregnancy. EPMA J 2012;3(1):9

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.