Efficacy and Safety of Existing and Emerging Monoclonal Antibody Therapies for Multiple Sclerosis

European Neurological Review, 2016;11(2):96–100 DOI: https://doi.org/10.17925/ENR.2016.11.02.96

Abstract:

The introduction of monoclonal antibodies for multiple sclerosis (MS) has provided a molecular targeted approach to modify the course of disease. A major advantage of monoclonal antibodies in the treatment of MS is that they are designed to be specific to their target and have very few off-target effects. Monoclonal antibodies have distinct structural characteristics and different targets, and their various mechanisms of action include cross-linking, blocking interactions, induction of signal transduction via receptor binding, complement-dependent cytotoxicity, and antibody-dependent cell-mediated cytotoxicity. Monoclonal antibodies should not therefore be considered a single class of treatments. Natalizumab and alemtuzumab are highly efficacious treatments approved for treating MS, though they tend to be reserved for patients with more active disease. Other monoclonal antibodies in advanced development include ocrelizumab, ofatumumab, daclizumab and opicinumab (anti-LINGO-1). Screening and monitoring is required to enable the optimal utilisation of all monoclonal antibodies and the benefit–risk profile of each monoclonal antibody needs to be fully considered before use. At present, patients have variable access to effective MS treatments, and this issue is likely to become even more important to address as new therapies become available.
Keywords: Monoclonal antibodies, multiple sclerosis (MS), alemtuzumab, daclizumab, natalizumab, ocrelizumab, ofatumumab, opicinumab
Disclosure: Gavin Giovannoni has received compensation for serving as a consultant or speaker for, or has received research support from: AbbVie, Bayer Schering Healthcare, Biogen Idec, Canbex, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GlaxoSmithKline, Ironwood Pharmaceuticals, Merck- Serono, Novartis, Roche, Sanofi-Aventis, Synthon BV, Teva Pharmaceutical Industries, UCB and Vertex Pharmaceuticals.
Acknowledgments: Medical writing assistance was provided by Catherine Amey at Touch Medical Media, funded by Roche.
Received: May 31, 2016 Accepted August 05, 2016
Correspondence: Gavin Giovannoni, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, 4 Newark Street, London E1 2AT, UK; Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, UK. E: g.giovannoni@qmul.ac.uk
Support: The publication of this article was supported by an independent, educational grant provided by Roche. Roche had no influence on the development or content of the article except in reviewing the accuracy of the medical data presented.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

The options available for treating multiple sclerosis (MS) have increased substantially over the last two decades. Initial first-line disease-modifying therapies (DMTs), included intramuscular (IM) interferon (IFN) β-1a (Avonex®, Biogen, Cambridge, Massachusetts, US), subcutaneous (SC) IFN β-1a (Rebif®, EMD Serono, Rockland, Massachusetts, US), SC IFN β-1b (Betaferon®, Bayer, Leverkusen, Germany; Extavia®, Novartis, Basel, Switzerland [2007]) and SC glatiramer acetate [GA] (Copaxone®, Teva Neuroscience, Petah Tikva, Israel). Mitoxantrone and later natalizumab, both high efficacy treatments, were generally used second-line.1–7 Although moderately efficacious, patient adherence to IFNs and GA was and remains an important challenge despite innovations in the formulation and delivery of these DMTs.8,9 Further, some patients with MS develop neutralising antibodies (NAbs) when treated with IFN-β, which abrogates the therapeutic efficacy.10 Poor adherence to these DMTs has been shown to result in a reduction in efficacy and in worse patient outcomes.11

It is common practice in some countries for physicians to prescribe several first-line therapies such as IFN β-1a or GA before switching to monoclonal antibodies.12 However, there is growing evidence that, in addition to the early initiation of treatment after diagnosis,13 early treatment optimisation after insufficient response to initial treatment is important to achieve a favourable outcome.14 Recently, a new strategy has emerged, ‘treating to target,’ where the aim is to achieve no evidence of disease activity (NEDA). This composite measure is defined as no relapse activity, no Expanded Disability Status Scale (EDSS) disability progression, and no new magnetic resonance imaging (MRI) lesions (T1 Gd+ and/or active T2 lesions).15–17 Confirming NEDA necessitates regular monitoring of relapses, disability and for subclinical activity on MRI.18 There is a report from a study of 152 patients indicating that the monoclonal antibody, natalizumab, is associated with a higher proportion of patients achieving NEDA status compared with those reported previously for injectable treatments.19

Monoclonal antibodies are used therapeutically in a variety of medical disciplines including oncology, rheumatology, gastroenterology, dermatology and prevention of transplant rejection. Three monoclonal antibody treatments are currently approved for treating MS, (natalizumab,20–24 alemtuzumab25–30 and daclizumab31). These are high efficacy treatments but tend to be reserved for more active patients, in particular in patients with rapidly-evolving severe MS (Table 1). Other humanised monoclonal antibodies are currently in advanced development (Phase II and III) mainly in the treatment of patients with relapsing-remitting MS (RRMS). These include ocrelizumab,32,33 ofatumumab (both anti-CD20)34,35 and opicinumab (anti-LINGO-1).36

References:
1. Derwenskus J, Lublin FD, Future treatment approaches to multiple sclerosis, Handb Clin Neurol, 2014;122:563–77.
2. Kim W, Zandona ME, Kim SH, Kim HJ, Oral disease-modifying therapies for multiple sclerosis, J Clin Neurol, 2015;11:9–19.
3. Loleit V, Biberacher V, Hemmer B, Current and future therapies targeting the immune system in multiple sclerosis, Curr Pharm Biotechnol, 2014;15:276–96.
4. Ransohoff RM, Hafler DA, Lucchinetti CF, Multiple sclerosis-a quiet revolution, Nat Rev Neurol, 2015;11:134–42.
5. Sedal L, Wilson IB, McDonald EA, Current management of relapsing-remitting multiple sclerosis, Intern Med J, 2014;44:950–7.
6. Sorensen PS, New management algorithms in multiple sclerosis, Curr Opin Neurol, 2014;27:246–59.
7. Weinstock-Guttman B, An update on new and emerging therapies for relapsing-remitting multiple sclerosis, Am J Manag Care, 2013;19(17 Suppl):s343–54.
8. Bruce JM, Lynch SG, Multiple sclerosis: MS treatment adherence--how to keep patients on medication?, Nat Rev Neurol, 2011;7:421–2.
9. Wong J, Gomes T, Mamdani M, et al., Adherence to multiple sclerosis disease-modifying therapies in Ontario is low, Can J Neurol Sci, 2011;38:429–33.
10. Manceau P, Latarche C, Pittion S, et al., Neutralizing antibodies and fatigue as predictors of low response to interferon-beta treatment in patients with multiple sclerosis, BMC Neurol, 2014;14:215.
11. Patti F, Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence, Patient Prefer Adherence, 2010;4:1–9.
12. Rio J, Comabella M, Montalban X, Multiple sclerosis: current treatment algorithms, Curr Opin Neurol, 2011;24:230–7.
13. Tintore M, Early MS treatment, Int MS J, 2007;14:5–10.
14. Ziemssen T, De Stefano N, Pia Sormani M, et al., Optimizing therapy early in multiple sclerosis: An evidence-based view, Mult Scler Relat Disord, 2015;4:460–9.
15. Havrdova E, Galetta S, Hutchinson M, et al., Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study, Lancet Neurol, 2009;8:254–60.
16. Giovannoni G, Cook S, Rammohan K, et al., Sustained diseaseactivity- 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;10:329–37.
17. Kieseier BC, Stuve O, A critical appraisal of treatment decisions in multiple sclerosis--old versus new, Nat Rev Neurol, 2011;7:255–62.
18. Ziemssen T, Derfuss T, de Stefano N, et al., Optimizing treatment success in multiple sclerosis, J Neurol, 2016;263:1053–65.
19. Prosperini L, Fanelli F, Pozzilli C, Long-term assessment of No Evidence of Disease Activity with natalizumab in relapsing multiple sclerosis, J Neurol Sci, 2016;364:145–7.
20. Chataway J, Miller DH, Natalizumab therapy for multiple sclerosis, Neurotherapeutics, 2013;10:19–28.
21. Hoepner R, Faissner S, Salmen A, et al., Efficacy and side effects of natalizumab therapy in patients with multiple sclerosis, J Cent Nerv Syst Dis, 2014;6:41–9.
22. Iaffaldano P, Lucchese G, Trojano M, Treating multiple sclerosis with natalizumab, Expert Rev Neurother, 2011;11:1683–92.
23. McCormack PL, Natalizumab: a review of its use in the management of relapsing-remitting multiple sclerosis, Drugs, 2013;73:1463–81.
24. Pucci E, Giuliani G, Solari A, et al., Natalizumab for relapsing remitting multiple sclerosis, Cochrane Database Syst Rev, 2011:CD007621.
25. Coles AJ, Alemtuzumab therapy for multiple sclerosis, Neurotherapeutics, 2013;10:29–33.
26. Coles AJ, Alemtuzumab treatment of multiple sclerosis, Semin Neurol, 2013;33:66–73.
27. Hartung HP, Aktas O, Boyko AN, Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis, Mult Scler, 2015;21:22–34.
28. Havrdova E, Horakova D, Kovarova I, Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use, Ther Adv Neurol Disord, 2015;8:31–45.
29. Jones DE, Goldman MD, Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety, Expert Rev Clin Immunol, 2014;10:1281–91.
30. Ruck T, Bittner S, Wiendl H, Meuth SG, Alemtuzumab in Multiple Sclerosis: Mechanism of Action and Beyond, Int J Mol Sci, 2015;16:16414–39.
31. Kappos L, Wiendl H, Selmaj K, et al., Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis, N Engl J Med, 2015;373:1418–28.
32. Chaudhuri A, Ocrelizumab in multiple sclerosis: risks and benefits, Lancet, 2012;379:1196–7; author reply 7.
33. Kappos L, Li D, Calabresi PA, et al., Ocrelizumab in relapsingremitting multiple sclerosis: a phase 2, randomised, placebocontrolled, multicentre trial, Lancet, 2011;378:1779–87.
34. Sorensen PS, Lisby S, Grove R, et al., Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study, Neurology, 2014;82:573–81.
35. Zhang B, Ofatumumab, mAbs, 2009;1:326–31.
36. Cadavid D, Balcer LJ, Galetta SL, et al., Axonal Protective Role of LINGO-1 Blockade in the Visual System: Results From a Study in Rats and Designof of a Phase 2 Clinical Trial for BIIB033, an Anti-LINGO-1 Monoclonal Antibody, in Subjects With a First Episode of Acute Optic Neuritis, Presented at: 66th Annual Meeting of the American Academy of Neurology, 26 April-3 May, Philadelphia, PA, USA, 2014.
37. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E, Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review, PLoS One, 2013;8:e66308.
38. Araki M, Matsuoka T, Miyamoto K, et al., Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study, Neurology, 2014;82:1302–6.
39. Lauenstein AS, Stettner M, Kieseier BC, Lensch E, Treating neuromyelitis optica with the interleukin-6 receptor antagonist tocilizumab, BMJ Case Rep, 2014;2014.
40. Paul F, Hope for a rare disease: eculizumab in neuromyelitis optica, Lancet Neurol, 2013;12:529–31.
41. Pittock SJ, Lennon VA, McKeon A, et al., Eculizumab in AQP4- IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study, Lancet Neurol, 2013;12:554–62.
42. Gensicke H, Leppert D, Yaldizli O, et al., Monoclonal antibodies and recombinant immunoglobulins for the treatment of multiple sclerosis, CNS Drugs, 2012;26:11–37.
43. Cross AH, Naismith RT, Established and novel diseasemodifying treatments in multiple sclerosis, J Intern Med, 2014;275:350–63.
44. Kieseier BC, Wiendl H, Hartung HP, Stuve O, The future of multiple sclerosis therapy, Pharmacological Research, 2009;60:207–11.
45. D’Amico E, Caserta C, Patti F, Monoclonal antibody therapy in multiple sclerosis: critical appraisal and new perspectives, Expert Rev Neurother, 2015;15:251–68.
46. Knier B, Hemmer B, Korn T, Novel monoclonal antibodies for therapy of multiple sclerosis, Expert Opin Biol Ther, 2014;14:503–13.
47. Kornek B, An update on the use of natalizumab in the treatment of multiple sclerosis: appropriate patient selection and special considerations, Patient Prefer Adherence, 2015;9:675–84.
48. Fontoura P, Monoclonal antibody therapy in multiple sclerosis: Paradigm shifts and emerging challenges, mAbs, 2010;2:670–81.
49. Kobelt G, Berg J, Lindgren P, et al., Costs and quality of life of patients with multiple sclerosis in Europe, J Neurol Neurosurg Psychiatry, 2006;77:918–26.
50. Miller DH, Khan OA, Sheremata WA, et al., A controlled trial of natalizumab for relapsing multiple sclerosis, N Eng J Med, 2003;348:15–23.
51. Polman CH, O’Connor PW, Havrdova E, et al., A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis, N Eng J Med, 2006;354:899–910.
52. Miller DH, Soon D, Fernando KT, et al., MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS, Neurology, 2007;68:1390–401.
53. Hutchinson M, Kappos L, Calabresi PA, et al., The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL, J Neurol, 2009;256:405–15.
54. Butzkueven H, Kappos L, Pellegrini F, et al., Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results, J Neurol Neurosurg Psychiatry, 2014;85:1190–7.
55. Coles AJ, Compston DA, Selmaj KW, et al., Alemtuzumab vs. interferon beta-1a in early multiple sclerosis, N Eng J Med, 2008;359:1786–801.
56. Coles AJ, Fox E, Vladic A, et al., Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial, Neurology, 2012;78:1069–78.
57. Cohen JA, Coles AJ, Arnold DL, et al., Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial, Lancet, 2012;380:1819–28.
58. Coles AJ, Twyman CL, Arnold DL, et al., Alemtuzumab for patients with relapsing multiple sclerosis after diseasemodifying therapy: a randomised controlled phase 3 trial, Lancet, 2012;380:1829–39.
59. European Medicines Agency, LEMTRADA Summary of Product Characteristics, 2013. Available from: www.ema.europa.eu/ docs/en_GB/document_library/EPAR_-_Product_Information/ human/003718/WC500150521.pdf (accessed date 15 August 2016)
60. Gold R, Giovannoni G, Selmaj K, et al., Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial, Lancet, 2013;381:2167–75.
61. Phillips G, Guo S, Bender R, et al., Assessing the impact of multiple sclerosis disease activity and daclizumab HYP treatment on patient-reported outcomes: Results from the SELECT trial, Mult Scler Relat Disord, 2016;6:66–72.
62. Havrdova E, Giovannoni G, Stefoski D, et al., Disease-activityfree status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study, Mult Scler, 2014;20:464–70.
63. Giovannoni G, Gold R, Selmaj K, et al., Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial, Lancet Neurol, 2014;13:472–81.
64. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP) Summary of Opinion. Zinbryta, 2016. Available from: http://www.ema.europa.eu/ema/index. jsp?curl=pages/medicines/human/medicines/003862/smops/ Positive/human_smop_000970.jsp&mid=WC0b01ac058001d127 (accessed date: 15 August 2016)
65. Hauser SL, Comi GC, Hartung HP, et al., on behalf of the OPERA I and II clinical investigators, Efficacy and safety of ocrelizumab in relapsing multiple sclerosis - results of the interferonbeta- 1a-controlled, double-blind, Phase III OPERA I and II studies, Presented at: Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Barcelona, Spain, 9 October 2015.
66. Montalban X, Hemmer B, Rammohan K, et al., on behalf of the ORATORIO Clinical Investigators. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis - results of the placebo-controlled, double-blind, Phase III ORATORIO study, Presented at: Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Barcelona, Spain, 10 October 2015.
67. Carim-Todd L, Escarceller M, Estivill X, Sumoy L, LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with enriched expression in limbic system and neocortex, Eur J Neurosci, 2003;18:3167–82.
68. Mi S, Lee X, Shao Z, et al., LINGO-1 is a component of the Nogo- 66 receptor/p75 signaling complex, Nat Neurosci, 2004;7:221–8.
69. Lee X, Yang Z, Shao Z, et al., NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination, J Neurosci, 2007;27:220–5.
70. Mi S, Miller RH, Lee X, et al., LINGO-1 negatively regulates myelination by oligodendrocytes, Nat Neurosci, 2005;8:745–51.
71. Hersh CM, Cohen JA, Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis, Immunotherapy, 2014;6:249–59.
72. Lycke J, Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes, Ther Adv Neurol Disord, 2015;8:274–93.
Keywords: Monoclonal antibodies, multiple sclerosis (MS), alemtuzumab, daclizumab, natalizumab, ocrelizumab, ofatumumab, opicinumab