1932

Abstract

Since 2004, five drugs with new mechanisms of action have been approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis (MS). The expanded armamentarium of treatment options offers new opportunities for improved disease control and increased tolerability of medications, and also presents new safety concerns and monitoring requirements with which physicians must familiarize themselves. We review each of the newly approved agents—natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and alemtuzumab—with regard to their mechanism of action, clinical trial data, safety and tolerability concerns, and monitoring requirements. We also review available data for promising agents that are currently in late-phase clinical trials, including daclizumab, ocrelizumab, and ofatumumab.

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/content/journals/10.1146/annurev-med-052814-023415
2016-01-14
2024-06-24
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Literature Cited

  1. Polman CH, O'Connor PW, Havrdova E. 1.  et al. 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354:899–910 [Google Scholar]
  2. Rudick RA, Stuart WH, Calabresi PA. 2.  et al. 2006. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N. Engl. J. Med. 354:911–23 [Google Scholar]
  3. Kleinschmidt-DeMasters BK, Tyler KL. 3.  2005. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N. Engl. J. Med. 353:369–74 [Google Scholar]
  4. Van Assche G, Van Ranst M, Sciot R. 4.  et al. 2005. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N. Engl. J. Med. 353:362–68 [Google Scholar]
  5. Fox RJ, Rudick RA. 5.  2012. Risk stratification and patient counseling for natalizumab in multiple sclerosis. Neurology 78:436–37 [Google Scholar]
  6. Bloomgren G, Richman S, Hotermans C. 6.  et al. 2012. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N. Engl. J. Med. 366:1870–80 [Google Scholar]
  7. Sorensen PS, Bertolotto A, Edan G. 7.  et al. 2012. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult. Scler. 18:143–52 [Google Scholar]
  8. Gorelik L, Lerner M, Bixler S. 8.  et al. 2010. Anti-JC virus antibodies: implications for PML risk stratification. Ann. Neurol. 68:295–303 [Google Scholar]
  9. Tubridy N, Behan PO, Capildeo R. 9.  et al. 1999. The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.. Neurology 53:466–72 [Google Scholar]
  10. Gueguen A, Roux P, Deschamps R. 10.  et al. 2014. Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 85:1038–40 [Google Scholar]
  11. O'Connor PW, Goodman A, Kappos L. 11.  et al. 2011. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76:1858–65 [Google Scholar]
  12. Sorensen PS, Koch-Henriksen N, Petersen T. 12.  et al. 2014. Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients. Neurology 261:1170–77 [Google Scholar]
  13. O'Connor P, Goodman A, Kappos L. 13.  et al. 2014. Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. Neurology 83:78–86 [Google Scholar]
  14. 14. Novartis 2010. Gilenya™ (fingolimod) highlights of prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008lbl.pdf
  15. Brinkmann V, Davis MD, Heise CE. 15.  et al. 2002. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277:21453–57 [Google Scholar]
  16. Groves A, Kihara Y, Chun J. 16.  2013. Fingolimod: Direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J. Neurol. Sci. 328:9–18 [Google Scholar]
  17. Kappos L, Radue EW, O'Connor P. 17.  et al. 2010. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362:387–401 [Google Scholar]
  18. Kappos L, O'Connor P, Radue EW. 18.  et al. 2015. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology 84:1582–91 [Google Scholar]
  19. Cohen JA, Barkhof F, Comi G. 19.  et al. 2010. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362:402–15 [Google Scholar]
  20. Aguiar C, Batista S, Pacheco R. 20.  2014. Cardiovascular effects of fingolimod: relevance, detection and approach. Rev. Port. Cardiol. 34:279–85 [Google Scholar]
  21. Espinosa PS, Berger JR. 21.  2011. Delayed fingolimod-associated asystole. Mult. Scler. 17:1387–89 [Google Scholar]
  22. Lindsey JW, Haden-Pinneri K, Memon NB, Buja LM. 22.  2012. Sudden unexpected death on fingolimod. Mult. Scler. 18:1507–8 [Google Scholar]
  23. Kappos L, Antel J, Comi G. 23.  et al. 2006. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med. 355:1124–40 [Google Scholar]
  24. Calabresi PA, Radue EW, Goodin D. 24.  et al. 2014. 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 13:545–56 [Google Scholar]
  25. 25. Novartis 2015. Gilenya safety update. http://www.novartis.com/newsroom/product-related-info-center/gilenya-safety-update.shtml
  26. Warnke C, Meyer zu Horste G, Hartung HP. 26.  et al. 2009. Review of teriflunomide and its potential in the treatment of multiple sclerosis. Neuropsychiatr. Dis. Treat. 5:333–40 [Google Scholar]
  27. Gold R, Wolinsky JS. 27.  2010. Pathophysiology of multiple sclerosis and the place of teriflunomide. Acta. Neurol. Scand. 124:75–84 [Google Scholar]
  28. O'Connor P, Wolinsky JS, Confavreux C. 28.  et al. 2011. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N. Engl. J. Med. 365:1293–303 [Google Scholar]
  29. Confavreux C, O'Connor P, Comi G. 29.  et al. 2014. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 13:247–56 [Google Scholar]
  30. Miller AE, Wolinsky JS, Kappos L. 30.  et al. 2014. 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 13:977–86 [Google Scholar]
  31. Vermersch P, Czlonkowska A, Grimaldi LM. 31.  et al. 2014. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult. Scler. 20:705–16 [Google Scholar]
  32. 32. Genzyme 2012. Aubagio® (teriflunomide) highlights of prescribing information. Cambridge, MA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202992s000lbl.pdf
  33. Papadopoulou A, Kappos L, Sprenger T. 33.  2015. Safety of teriflunomide for the management of relapsing-remitting multiple sclerosis. Expert Opin. Drug Saf. 14:749–59 [Google Scholar]
  34. Gold R, Kappos L, Arnold DL. 34.  et al. 2012. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 367:1098–107 [Google Scholar]
  35. Fox RJ, Miller DH, Phillips JT. 35.  et al. 2012. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N. Engl. J. Med. 367:1087–97 [Google Scholar]
  36. Rosenkranz T, Novas M, Terborg C. 36.  2015. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N. Engl. J. Med. 372:1476–78 [Google Scholar]
  37. Nieuwkamp DJ, Murk JL, van Oosten BW. 37.  et al. 2015. PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N. Engl. J. Med. 372:1474–76 [Google Scholar]
  38. 38. Genzyme 2014. Lemtrada™ (alemtuzumab) highlights of prescribing information. Cambridge, MA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103948s5139lbl.pdf
  39. Coles AJ, Twyman CL, Arnold DL. 39.  et al. 2012. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380:1829–39 [Google Scholar]
  40. Cohen JA, Coles AJ, Arnold DL. 40.  et al. 2012. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380:1819–28 [Google Scholar]
  41. Pace AA, Zajicek JP. 41.  2009. Melanoma following treatment with alemtuzumab for multiple sclerosis. Eur. J. Neurol. 16:e70–e71 [Google Scholar]
  42. Bielekova B, Catalfamo M, Reichert-Scrivner S. 42.  et al. 2006. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. PNAS 103:5941–46 [Google Scholar]
  43. Wynn D, Kaufman M, Montalban X. 43.  et al. 2010. Daclizumab in active relapsing multiple sclerosis (CHOICE Study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 9:381–90 [Google Scholar]
  44. Gold R, Giovannoni G, Selmaj K. 44.  et al. 2013. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 381:2167–75 [Google Scholar]
  45. Pfender N, Martin R. 45.  2014. Daclizumab (anti-CD25) in multiple sclerosis. Exp. Neurol. 262:Pt. A44–51 [Google Scholar]
  46. Giovannoni G, Gold R, Selmaj K. 46.  et al. 2014. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol 13:472–81 [Google Scholar]
  47. Kappos LSK, Arnold DL, Havrdova E. 47.  et al. 2014. Primary results of DECIDE: a randomized, double-blind, double-dummy, active controlled trial of daxlizumab HYP versus interferon beta-1a in RRMS patients Presented at Joint Meet. Am. Comm. Treatment and Research in Multiple Sclerosis and Eur. Comm. Treatment and Research in Multiple Sclerosis (ACTRIMS-ECTRIMS), Boston, Sep. [Google Scholar]
  48. Hauser SL, Waubant E, Arnold DL. 48.  et al. 2008. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358:676–88 [Google Scholar]
  49. Hawker K, O'Connor P, Freedman MS. 49.  et al. 2009. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 66:460–71 [Google Scholar]
  50. Clifford DB, Ances B, Costello C. 50.  et al. 2011. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch. Neurol. 68:1156–64 [Google Scholar]
  51. Tuccori M, Focosi D, Blandizzi C. 51.  et al. 2010. Inclusion of rituximab in treatment protocols for non-Hodgkin's lymphomas and risk for progressive multifocal leukoencephalopathy. Oncologist 15:1214–19 [Google Scholar]
  52. Kappos L, Li D, Calabresi PA. 52.  et al. 2011. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378:1779–87 [Google Scholar]
  53. Sorensen PS, Lisby S, Grove R. 53.  et al. 2014. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 82:573–81 [Google Scholar]
/content/journals/10.1146/annurev-med-052814-023415
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