Semin Neurol 2016; 36(02): 140-147
DOI: 10.1055/s-0036-1579695
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Parenteral Treatment of Multiple Sclerosis: The Advent of Monoclonal Antibodies

Barry A. Singer
1   The MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, Missouri
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
26. April 2016 (online)

Abstract

Improved disease control is critical for enhancing the lives of those living with multiple sclerosis. With specific immunologic targets, monoclonal antibody (mAb) treatments are highly effective options for relapsing forms of multiple sclerosis. The mechanism, efficacy, and current safety profiles are detailed for the two mAb therapies, natalizumab and alemtuzumab, with regulatory approval in multiple countries. Daclizumab, which targets the interleukin-2 receptor, and ocrelizumab, which depletes B cells, have convincing phase 3 clinical trial data and may very well provide new options in the near future. Trial results of other B-cell-directed therapies, ofatumumab and rituximab, are reviewed. Less-frequent dosing of glatiramer acetate and interferon β-1a highlight developments in the first generation of parenteral immunomodulatory therapy. Remyelination using mAbs has moved into clinical trials with the first agents, anti-LINGO-1, rHIgM22, and anti-SEMA 4D.

 
  • References

  • 1 Havari E, Turner MJ, Campos-Rivera J , et al. Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro. Immunology 2014; 141 (1) 123-131
  • 2 Freedman MS, Kaplan JM, Markovic-Plese S. Insights into the mechanisms of the therapeutic efficacy of alemtuzumab in multiple sclerosis. J Clin Cell Immunol 2013; 4 (4) 1000152
  • 3 European Medicines Agency website . Available at: http://www.ema.europa.eu/ema/ . Accessed May 24, 2015
  • 4 United States Food and Drug Administration website . Available at: http://www.fda.gov . Accessed May 24, 2015
  • 5 Fox EJ, Arnold DJ, Cohen JA. Durable efficacy of alemtuzumab on clinical outcomes over 5 years in CARE-MS II with most patients free from treatment for 5 years. Poster session presented at: 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 7–10, 2015; Barcelona, Spain
  • 6 Cohen JA, Coles AJ, Arnold DL , et al; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380 (9856) 1819-1828
  • 7 Coles AJ, Twyman CL, Arnold DL , et al; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380 (9856) 1829-1839
  • 8 Singer B, Fox EJ, Krieger S , et al. Durable efficacy of alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis who relapsed on a prior therapy. Poster presented at: 67th American Academy of Neurology Annual Meeting; April 18–25, 2015; Washington, DC
  • 9 Miller T, Habek M, Coles AJ , et al. Analysis of data from RRMS alemtuzumab-treated patients in the clinical program to evaluate incidence rates of malignancy. Poster presented at: 30th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 10–13, 2014; Boston, MA
  • 10 Hunter SF, Arnold DL, Coles AJ , et al. The efficacy of alemtuzumab is maintained in patients who develop thyroid adverse events. Poster presented at: 67th American Academy of Neurology Annual Meeting; April 18–25, 2015; Washington, DC
  • 11 Daniels GH, Vladic A, Brinar V , et al. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. J Clin Endocrinol Metab 2014; 99 (1) 80-89
  • 12 Wynn D, Arnold DL, Coles AJ , et al. Detection, incidence, and management of glomerulonephritis in the alemtuzumab clinical development program. Poster presented at: 29th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis; October 2–5, 2013; Copenhagen, Denmark
  • 13 Clatworthy MR, Wallin EF, Jayne DR. Anti-glomerular basement membrane disease after alemtuzumab. N Engl J Med 2008; 359 (7) 768-769
  • 14 Meyer D, Coles A, Oyuela P, Purvis A, Margolin DH. Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2013; 2 (1) 60-63
  • 15 Singer B, Giovannoni G, Hatung H-P, Margolin DH, Kasten L, Cohen JA. Improvements in quality of life are maintained in alemtuzumab-treated RRMS patients who develop autoimmune adverse events: CARE-MS 2. Poster presented at: Annual Meeting of the Consortium of Multiple Sclerosis Centers; May 29, 2015; Indianapolis, IN
  • 16 Mayer L, Casady L, Clayton G , et al. Management of infusion-associated reactions in alemtuzumab-treated relapsing-remitting multiple sclerosis patients. Poster presented at: 30th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 10–13, 2014; Boston, MA
  • 17 Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics 2013; 10 (1) 55-67
  • 18 Bielekova B, Richert N, Herman ML , et al. Intrathecal effects of daclizumab treatment of multiple sclerosis. Neurology 2011; 77 (21) 1877-1886
  • 19 Wynn D, Kaufman M, Montalban X , et al; CHOICE investigators. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 2010; 9 (4) 381-390
  • 20 Gold R, Giovannoni G, Selmaj K , et al; SELECT study investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013; 381 (9884) 2167-2175
  • 21 Kappos L, Wiendl H, Selmaj K , et al. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2015; 373 (15) 1418-1428
  • 22 Kircik L, Krueger J, Hougeir F , et al. Incidence, severity, duration and treatment of cutaneous adverse events in the DECIDE study of daclizumab HYP versus intramuscular interferon beta-1a in patients with relapsing-remitting multiple sclerosis. Poster session presented at: 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 7–10, 2015; Barcelona, Spain
  • 23 Polman CH, O'Connor PW, Havrdova E , et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354 (9) 899-910
  • 24 Rudick RA, Stuart WH, Calabresi PA , et al; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354 (9) 911-923
  • 25 Biogen. Medical information website. Available at: https://medinfo.biogenidec.com . Accessed November 15, 2015
  • 26 Kuesters G, Plavina T, Lee S , et al. Anti-JC virus (JCV) antibody index differentiates risk of progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients with no prior immunosuppressant use: an updated analysis. Poster presented at: 67th American Academy of Neurology Annual Meeting; April 18–15, 2015; Washington, DC
  • 27 Johnson KP, Nelson BJ. Multiple sclerosis: diagnostic usefulness of cerebrospinal fluid. Ann Neurol 1977; 2 (5) 425-431
  • 28 Baranzini SE, Jeong MC, Butunoi C, Murray RS, Bernard CCA, Oksenberg JR. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol 1999; 163 (9) 5133-5144
  • 29 Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004; 14 (2) 164-174
  • 30 Cross AH, Klein RS, Piccio L. Rituximab combination therapy in relapsing multiple sclerosis. Ther Adv Neurol Disord 2012; 5 (6) 311-319
  • 31 Barun B, Bar-Or A. Treatment of multiple sclerosis with anti-CD20 antibodies. Clin Immunol 2012; 142 (1) 31-37
  • 32 Zhang B. Ofatumumab. MAbs 2009; 1 (4) 326-331
  • 33 Kappos L, Li D, Calabresi PA , et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378 (9805) 1779-1787
  • 34 Hauser SL, Comi GC, Hartung HP , et al. Efficacy and safety of ocrelizumab in relapsing multiple sclerosis—results of the phase III double-blind, interferon beta-1a controlled OPERA I and II studies. Presented at: 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 9, 2015; Barcelona, Spain
  • 35 Montalban X, Hemmer B, Rammohan K , et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis—results of the phase III double-blind, placebo controlled ORATORIO Study. Presented at: 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 10, 2015; Barcelona, Spain
  • 36 Sorensen PS, Lisby S, Grove R , et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 2014; 82 (7) 573-581
  • 37 Bar-Or A, Grove R, Austin D , et al. The MIRROR study: a randomized double-blind, placebo-controlled, parallel-group, dose-ranging study to investigate the safety and MRI efficacy of subcutaneous ofatumumab in subjects with relapsing-remitting multiple sclerosis. Paper presented at: 66th American Academy of Neurology Annual Meeting; April 26–May 3, 2014; Philadelphia, PA
  • 38 Novartis website . Available at: http://novartis.com/news . Accessed November 15, 2015
  • 39 Hauser SL, Waubant E, Arnold DL , et al; HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358 (7) 676-688
  • 40 Hawker K, O'Connor P, Freedman MS , et al; OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66 (4) 460-471
  • 41 Tran JQ, Rana J, Barkhof F , et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm 2014; 1 (2) e18
  • 42 Cadavid D, Balcer L, Galetta S , et al. Evidence of remyelination with the ant-LINGO-1 monoclonal antibody BIIB033 after acute optic neuritis. Paper presented at: 67th American Academy of Neurology Meeting; April 18–25, 2015; Washington, DC
  • 43 ClinicalTrials.gov website Available at: https://clinicaltrials.gov . Accessed June 8, 2015
  • 44 Rodriguez M, Warrington AE, Pease LR. Invited article: human natural autoantibodies in the treatment of neurologic disease. Neurology 2009; 72 (14) 1269-1276
  • 45 Greenberg BM, Rodriquez M, Kantarci O , et al. Safety and tolerability of remyelinating therapeutic antibody rHIgM22 in patients with stable multiple sclerosis. Poster presented at: 67th American Academy of Neurology Annual Meeting; April 18–25, 2015; Washington, DC
  • 46 Jonason A, Klimatcheva E, Veeraraghavan J , et al. Development of an anti-SEMA4D monoclonal antibody for the treatment of multiple sclerosis. Poster presented at: 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 2–5, 2013; Copenhagen, Denmark
  • 47 Vaccinex.com website Available at: http://www.vaccinex.com/about-us-news-and-events.htm . Accessed June 7, 2015
  • 48 Calabresi PA, Kieseier BC, Arnold DL , et al; ADVANCE Study Investigators. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol 2014; 13 (7) 657-665
  • 49 Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R ; GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013; 73 (6) 705-713