- Email: [email protected]
Immunological treatment of multiple sclerosis
Author’s Accepted Manuscript Immunological treatment of Multiple Sclerosis Martin Diebold, Tobias Derfuss
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0037-1963(16)30028-2 http://dx.doi.org/10.1053/j.seminhematol.2016.04.016 YSHEM50872
To appear in: Seminars in Hematology Cite this article as: Martin Diebold and Tobias Derfuss, Immunological treatment of Multiple Sclerosis, Seminars in Hematology, http://dx.doi.org/10.1053/j.seminhematol.2016.04.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Immunological treatment of Multiple Sclerosis Martin Diebold, Tobias Derfuss Departments of Neurology and Biomedicine, University Hospital Basel, Switzerland
corresponding author: Prof. Dr. T. Derfuss Departments of Neurology and Biomedicine University Hospital Basel Petersgraben 4 4031 Basel Switzerland tel: 0041 61 3286726 e-mail: [email protected]
Disclosures: T. Derfuss is on scientific advisory boards for Biogen, Novartis Pharma, Genzyme, Merck Serono, Bayer Schering, Octapharma, GeNeuro, Roche, received travel funding and speaker honoraria from Bayer Schering, Biogen, Merck Serono, Novartis Pharma, Roche, Genzyme, is on the editorial board of Plos One, is a member of steering committees by Mitsubishi Pharma, Novartis Pharma, and GeNeuro, is on the executive board of ECTRIMS, received research support from Novartis Pharma, Merck Serono, Biogen, Swiss National Foundation, European Union, Swiss MS Society. M. Diebold declares no conflict of interest.
Abstract Treatment of Multiple Sclerosis (MS) has been a challenge since its first description by Charcot. The advent of immunomodulatory drugs in the mid 90ies brought the first big change in the treatment of MS patients. During the last 10 years there has been an ongoing tremendous evolution of novel treatment options for relapsing-remitting MS. These options include monoclonal antibodies, which inhibit migration of lymphocytes (natalizumab), deplete lymphocytes (alemtuzumab), or block the cytokine receptor IL-2 (daclizumab), teriflunomide that inhibits proliferation of activated lymphocytes, fingolimod that modulates the sphingosine-receptor system, and dimethylfumarate that combines features of immunomodulatory and immunosuppressive drugs. The topic of this review is to discuss currently available treatments and provide an outlook into the near future.
Keywords multiple sclerosis, clinically isolated syndrome, immunomodulation
Multiple Sclerosis is an autoimmune disease of the central nervous system that leads to the destruction of myelin and neurons1. The disease is clinically characterized by a phase of relapses and remissions that often transitions into a phase of chronic and slow progression of disability2. This progressive stage of the disease is thought to be the consequence of ongoing inflammatory damage to neurons and axons3. In the beginning the neurodegenerative damage can be partly repaired or compensated. As inflammation and neurodegeneration continue there is an exhaustion of the compensatory mechanisms and irreversible neuronal damage accumulates. The current concept of the treatment of MS is to prevent damage of the CNS from early on. Patients are therefore treated already after the first attack, a disease stage called the clinically isolated syndrome (CIS)4,5. Currently available treatments only target the inflammatory component of MS. So far, no treatments are available to directly prevent neurodegeneration or to enhance the repair of myelin or neurons. The main challenge of MS treatment today is to decide which treatment is chosen for which patient. MS is a very heterogeneous disease and the individual prognosis is hard to predict. Biomarkers for the prediction of prognosis as well as biomarkers for treatment response are available on a population level but still need to be validated on the individual patient level6. Patients are often started on a baseline therapy that has a moderate efficacy but shows a favourable safety profile. Clinical disease activity exemplified by relapses and disability progression are taken as an indication of an unsatisfactory treatment response7. In addition to these clinical parameters the MRI of the brain and spinal cord can be used to detect disease activity that is not clinically apparent 8. The combination of clinical assessments and MRI of the CNS increases the predictive value and MRI has therefore become a valuable tool for treatment monitoring in clinical practice. With more effective treatments becoming available the treatment goal is to achieve a state of „no evidence of disease activity“(NEDA)9. NEDA is defined as (1) no relapses, (2) no 2
disability progression, and (3) no new T2 hyperintense and/or T1 gadolinium (GD) enhancing lesions in brain MRI (NEDA-3)10. During the last 25 years there has been a tremendous progress in the therapeutic arena of MS. During the mid-90’ies the first immunomodulatory drugs have shown a benefit in trials with relapsing-remitting MS (RR-MS) patients. Various interferon beta formulations have therefore been registered for RR-MS (Betaferon, Rebif, Avonex). Subsequently, the novel immunomodulator glatirameracetate (Copaxone) was introduced as another treatment for RR-MS. In clinical trials these drugs reached a relapse rate reduction of around 30 %11-14. In addition they had an impact on the inflammatory activity in MRI: a reduction in new T2 and in Gd enhancing T1 lesions. During the last 20 years these immunmodulatory drugs have accumulated a solid and extensive safety record. This is especially important since young patients are often treated for many years with these drugs. A disadvantage of these treatments is that they have to be injected in frequencies of up to daily. The side effects of local injection site reactions and flu-like symptoms in the case of the interferons have contributed to a suboptimal tolerability profile which often leads to a reduced adherence. To improve this tolerability issue a long-acting interferon formulation has been developed. This pegylated form of interferon (Plegridy) needs only one subcutaneous injection in two weeks. In a one year, Placebo controlled trial it showed a similar efficacy as the previous registered immunmodulators (ADVANCE study)15. With the establishment of immunomodulatory treatments different questions arose: (1) Which patients should be treated? (2) From what stage of the disease on should treatment be started? (3) Does the efficacy seen during a two year clinical trial translate into a reduction of disability progression in the long-term? So far, only one of these questions has been answered conclusively by different clinical trials. Immunomodulation with interferons or copaxone has a benefit already in patients with CIS16-19. This means that treatment should be initiated upon first clinical signs of disease. Unfortunately, we do not have an answer to the question which patients will benefit most from an immunomodulatory treatment. By now, no genetic polymorphism or gene expression profile has been identified that would help selecting patients for a certain treatment 6. Also a definite answer to the question of the long-term effect of these treatments on disability progression is lacking. Different patient cohorts have been studied to find out if interferon treatment is associated with reduced secondary progression. However, these studies yielded conflicting results 20,21. The lack of a proper untreated control group that is comparable to the treated group is probably the reason for this continuing uncertainty. Experimental research on the factors that are responsible for migration of immune cells into the CNS finally led to the registration of natalizumab, a monoclonal antibody that blocks a4 integrin22. This integrin has been shown in animal models to be critical for migration of lymphocytes across the blood brain barrier. The pivotal trials with this antibody showed a clear reduction of relapses and disability progression23,24. Also MRI parameters of brain inflammation responded dramatically to this treatment. Natalizumab was therefore considered as a major breakthrough in the treatment of RRMS. Unexpectedly, already during the clinical trial phase a severe side effect of natalizumab treatment emerged: progressive multifocal leucencephalopathy (PML) caused by the JC virus. Meanwhile we know that natalizumab is the immunosuppressive drug that is most commonly associated with PML. A number of risk factors have been 3
identified to contribute to an increased risk for PML during natalizumab treatment: duration of natalizumab treatment over 2 years; previous immunosuppressive treatment; a positive JCV-antibody status25. The risk of PML led to a more restricted label of the drug. It has been registered only for highly active patients as a first line therapy and for patients that show breakthrough disease despite an ongoing immunomodulatory baseline therapy. The next step in the development was the approval of Fingolimod (Gilenya), the first oral therapy in MS26. Fingolimod is a first in class compound that targets the sphingosin receptor system. It acts as an agonist that binds to the receptor and finally leads to an internalization and degradation of the receptor. Its efficacy is thought to be linked to S1P receptor 1 binding that is expressed on lymphocytes. Lymphocytes need this receptor for an efficient egress from lymphnodes. Treatment with fingolimod leads to a reduction of lymphocytes in the blood that is attributed to a redistribution of lymphocytes to secondary lymphoid organs. Unlike classical immunosuppressive agents fingolimod does not destroy lymphocytes and the redistribution is reversible after stopping of fingolimod. It also does not affect all lymphocytes in the same way but mainly targets naive and central memory T cells and largely spares effector memory T cells that can still be found in the blood27. Despite a considerable decrease in blood circulating T cells the overall rate of infections was not significantly increased. However, there seems to be a slight increase of herpesviral infections in fingolimod treated patients28,29. In pivotal trials fingolimod showed an around 50 % reduction in relapse rates compared to Placebo and also compared to the active comparator Avonex (FREEDOMS and TRANSFORMS trials)30-32. Since fingolimod can cross the blood brain barrier and its receptors are also expressed on CNS residents cells (e.g. neurons, oligodendrocytes, and astrocytes) it was speculated that it could also have a neuroprotective effect (reduced astrogliosis and enhanced remyelination33,34) in addition to its immunomodulatory effect35. (INFORMS study). A well designed randomized, Placebo-controlled phase III trial, however, failed to show an effect of fingolimod on disability progression inprimary progressive MS (INFORMS study, https://www.novartis.com/news/mediareleases/novartis-provides-update-fingolimod-phase-iii-trial-primary-progressive-msppms). Together with one negative trial of natalizumab-treatment in secondary progressive MS (ASCEND study) this stresses the difficulties we have in treating patients with progressive forms of MS. Teriflunomide was the next oral agent that was introduced as treatment for RR-MS36. It is a follow-up compound of leflunomide that is registered for rheumatoid arthritis. Teriflunomide is the active metabolite of leflunomide and inhibits the activity of the dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidine in activated lymphocytes. In two large phase III trials the compound showed a significant reduction of relapse rates of more than 30 % and a reduction in the proportion of patients who developed a confirmed disability progression (TOWER and TEMSO trials)37,38. In a further trial teriflunomide proofed to be effective also in patients with CIS (TOPIC trial)39. The up to now last oral compound that has been registered for RR-MS is dimethylfumarate (DMF, Tecfidera)40. DMF was originally used to treat patients with psoriasis. The clinical observation that psoriasis patients that had concomitant MS also seemed to benefit from DMF treatment led to the clinical development program of the drug in MS. The mode of action of DMF is still under investigation and mechanisms proposed comprise an activation of the NRF2 anti-oxidative stress response, inhibition 4
of NF kappa B activation, a shift in the cytokine profile from pro- to anti-inflammatory, and the induction of apoptosis in lymphocytes. Two large controlled trials were performed in patients with RR-MS (DEFINE and CONFIRM trials)41,42. Both trials showed a reduction of the annualized relapse rate in DMF treated patients compared to Placebo by around 50 %. One trial included in addition an open label comparison to Copaxone treatment which was associated with a relapse rate reduction of around 30 % compared to the Placebo arm. The last compound that was registered in the treatment arena of MS is alemtuzumab (Lemtrada)43. Alemtuzumab is a monoclonal antibody against the surface molecule CD52. It leads to a rapid and long-lasting depletion of lymphocytes. It is thought that the treatment of alemtuzumab leads to a reset of the immune response with a change of the T cell receptor repertoire and phenotype of T cells re-occuring after depletion. Two phase III trials have been performed in RR-MS (CARE-MS I and II)44,45. Alemtuzumab was tested against Rebif in both trials and could show a significant reduction in relapses rates compared to the active comparator. MS CARE II also showed a significant reduction of disability progression in alemtuzumab treated patients compared to Rebif treated patients. Despite these promising efficacy results there is some concern regarding the safety profile of the drug. The two most relevant side effects are an increased rate of infections, mainly in the first months after an infusion cycle, and the occurence of secondary autoimmunity, especially thyroid autoimmune disease and rarely other B cell mediated autoimmune disorders like thrombocytopenia and glomerulonephritis. In clinical practice these side effects limit the use of alemtuzumab to MS patients with highly active disease and patients that failed on other immunmodulatory drugs. Despite this plethora of available therapies clinical research to develop novel treatments for MS is ongoing. Two drugs that showed promising results in phase III trials, but are not registered so far, are ocrelizumab and daclizumab. Daclizumab is a monoclonal antibody against CD25, the high-affinity IL2 receptor alpha chain46,47. The other drug is ocrelizumab, a B cell depleting antibody directed against CD20. Especially the recently announced results of the three phase III trials of ocrelizumab raised a lot of interest (OPERA I and II, ORATORIO), because the drug seemed not only to work in RR-MS but also showed a reduction of disability progression in PP-MS (http://www.roche.com/media/store/releases/med-cor-2015-06-30.htm). This makes ocrelizumab the first compound that showed positive results in a well-controlled phase III trial for PP-MS. With all these new drugs the treatment landscape of MS is rapidly changing. The main tasks for the future will be to develop tools to stratify patients for the right treatment and to define a rationale for sequencing these therapies. Despite promising results it is also clear that none of these treatments are a cure of MS. Many patients will still deteriorate despite immunomodulatory treatment. It is therefore mandatory to continue research with the goal to develop true neuroprotective and regenerating therapies that tackle the neurodegenerative part of MS that is the main driver of disability in the progressive stages of the disease. Literature : 1. Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221-31. 2. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278-86. 5
3. Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol 2007;6:903-12. 4. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol 2012;11:157-69. 5. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4:281-8. 6. Comabella M, Montalban X. Body fluid biomarkers in multiple sclerosis. Lancet Neurol 2014;13:113-26. 7. Rio J, Nos C, Tintore M, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol 2006;59:344-52. 8. Sormani MP, Rio J, Tintore M, et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler 2013;19:605-12. 9. 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. 10. Stangel M, Penner IK, Kallmann BA, Lukas C, Kieseier BC. Towards the implementation of 'no evidence of disease activity' in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord 2015;8:3-13. 11. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology 1993;43:655-61. 12. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285-94. 13. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998;352:1498-504. 14. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45:1268-76. 15. Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol 2014;13:657-65. 16. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370:389-97. 17. Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012;11:33-41. 18. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009;374:1503-11.
6
19. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898-904. 20. Trojano M, Pellegrini F, Paolicelli D, et al. Real-life impact of early interferon beta therapy in relapsing multiple sclerosis. Ann Neurol 2009;66:513-20. 21. Shirani A, Zhao Y, Karim ME, et al. Interferon beta and long-term disability in multiple sclerosis. JAMA Neurol 2013;70:651-2. 22. Derfuss T, Kuhle J, Lindberg R, Kappos L. Natalizumab therapy for multiple sclerosis. Semin Neurol 2013;33:26-36. 23. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-23. 24. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910. 25. McGuigan C, Craner M, Guadagno J, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry 2015. 26. Mehling M, Kappos L, Derfuss T. Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. Curr Neurol Neurosci Rep 2011;11:4927. 27. Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008;71:1261-7. 28. Arvin AM, Wolinsky JS, Kappos L, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol 2015;72:31-9. 29. Ricklin ME, Lorscheider J, Waschbisch A, et al. T-cell response against varicellazoster virus in fingolimod-treated MS patients. Neurology 2013;81:174-81. 30. 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;362:387-401. 31. 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;13:545-56. 32. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-15. 33. Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 2011;108:751-6. 34. Miron VE, Ludwin SK, Darlington PJ, et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol 2010;176:2682-94. 35. Miron VE, Schubart A, Antel JP. Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 2008;274:13-7. 36. Papadopoulou A, Kappos L, Sprenger T. Teriflunomide for oral therapy in multiple sclerosis. Expert Rev Clin Pharmacol 2012;5:617-28. 37. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303. 38. 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;13:247-56.
7
39. 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;13:977-86. 40. Salmen A, Gold R. Mode of action and clinical studies with fumarates in multiple sclerosis. Exp Neurol 2014;262 Pt A:52-6. 41. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107. 42. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97. 43. 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. 44. 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. 45. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829-39. 46. 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. 47. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsingremitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013;381:2167-75.
8
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0037-1963(16)30028-2 http://dx.doi.org/10.1053/j.seminhematol.2016.04.016 YSHEM50872
To appear in: Seminars in Hematology Cite this article as: Martin Diebold and Tobias Derfuss, Immunological treatment of Multiple Sclerosis, Seminars in Hematology, http://dx.doi.org/10.1053/j.seminhematol.2016.04.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Immunological treatment of Multiple Sclerosis Martin Diebold, Tobias Derfuss Departments of Neurology and Biomedicine, University Hospital Basel, Switzerland
corresponding author: Prof. Dr. T. Derfuss Departments of Neurology and Biomedicine University Hospital Basel Petersgraben 4 4031 Basel Switzerland tel: 0041 61 3286726 e-mail: [email protected]
Disclosures: T. Derfuss is on scientific advisory boards for Biogen, Novartis Pharma, Genzyme, Merck Serono, Bayer Schering, Octapharma, GeNeuro, Roche, received travel funding and speaker honoraria from Bayer Schering, Biogen, Merck Serono, Novartis Pharma, Roche, Genzyme, is on the editorial board of Plos One, is a member of steering committees by Mitsubishi Pharma, Novartis Pharma, and GeNeuro, is on the executive board of ECTRIMS, received research support from Novartis Pharma, Merck Serono, Biogen, Swiss National Foundation, European Union, Swiss MS Society. M. Diebold declares no conflict of interest.
Abstract Treatment of Multiple Sclerosis (MS) has been a challenge since its first description by Charcot. The advent of immunomodulatory drugs in the mid 90ies brought the first big change in the treatment of MS patients. During the last 10 years there has been an ongoing tremendous evolution of novel treatment options for relapsing-remitting MS. These options include monoclonal antibodies, which inhibit migration of lymphocytes (natalizumab), deplete lymphocytes (alemtuzumab), or block the cytokine receptor IL-2 (daclizumab), teriflunomide that inhibits proliferation of activated lymphocytes, fingolimod that modulates the sphingosine-receptor system, and dimethylfumarate that combines features of immunomodulatory and immunosuppressive drugs. The topic of this review is to discuss currently available treatments and provide an outlook into the near future.
Keywords multiple sclerosis, clinically isolated syndrome, immunomodulation
Multiple Sclerosis is an autoimmune disease of the central nervous system that leads to the destruction of myelin and neurons1. The disease is clinically characterized by a phase of relapses and remissions that often transitions into a phase of chronic and slow progression of disability2. This progressive stage of the disease is thought to be the consequence of ongoing inflammatory damage to neurons and axons3. In the beginning the neurodegenerative damage can be partly repaired or compensated. As inflammation and neurodegeneration continue there is an exhaustion of the compensatory mechanisms and irreversible neuronal damage accumulates. The current concept of the treatment of MS is to prevent damage of the CNS from early on. Patients are therefore treated already after the first attack, a disease stage called the clinically isolated syndrome (CIS)4,5. Currently available treatments only target the inflammatory component of MS. So far, no treatments are available to directly prevent neurodegeneration or to enhance the repair of myelin or neurons. The main challenge of MS treatment today is to decide which treatment is chosen for which patient. MS is a very heterogeneous disease and the individual prognosis is hard to predict. Biomarkers for the prediction of prognosis as well as biomarkers for treatment response are available on a population level but still need to be validated on the individual patient level6. Patients are often started on a baseline therapy that has a moderate efficacy but shows a favourable safety profile. Clinical disease activity exemplified by relapses and disability progression are taken as an indication of an unsatisfactory treatment response7. In addition to these clinical parameters the MRI of the brain and spinal cord can be used to detect disease activity that is not clinically apparent 8. The combination of clinical assessments and MRI of the CNS increases the predictive value and MRI has therefore become a valuable tool for treatment monitoring in clinical practice. With more effective treatments becoming available the treatment goal is to achieve a state of „no evidence of disease activity“(NEDA)9. NEDA is defined as (1) no relapses, (2) no 2
disability progression, and (3) no new T2 hyperintense and/or T1 gadolinium (GD) enhancing lesions in brain MRI (NEDA-3)10. During the last 25 years there has been a tremendous progress in the therapeutic arena of MS. During the mid-90’ies the first immunomodulatory drugs have shown a benefit in trials with relapsing-remitting MS (RR-MS) patients. Various interferon beta formulations have therefore been registered for RR-MS (Betaferon, Rebif, Avonex). Subsequently, the novel immunomodulator glatirameracetate (Copaxone) was introduced as another treatment for RR-MS. In clinical trials these drugs reached a relapse rate reduction of around 30 %11-14. In addition they had an impact on the inflammatory activity in MRI: a reduction in new T2 and in Gd enhancing T1 lesions. During the last 20 years these immunmodulatory drugs have accumulated a solid and extensive safety record. This is especially important since young patients are often treated for many years with these drugs. A disadvantage of these treatments is that they have to be injected in frequencies of up to daily. The side effects of local injection site reactions and flu-like symptoms in the case of the interferons have contributed to a suboptimal tolerability profile which often leads to a reduced adherence. To improve this tolerability issue a long-acting interferon formulation has been developed. This pegylated form of interferon (Plegridy) needs only one subcutaneous injection in two weeks. In a one year, Placebo controlled trial it showed a similar efficacy as the previous registered immunmodulators (ADVANCE study)15. With the establishment of immunomodulatory treatments different questions arose: (1) Which patients should be treated? (2) From what stage of the disease on should treatment be started? (3) Does the efficacy seen during a two year clinical trial translate into a reduction of disability progression in the long-term? So far, only one of these questions has been answered conclusively by different clinical trials. Immunomodulation with interferons or copaxone has a benefit already in patients with CIS16-19. This means that treatment should be initiated upon first clinical signs of disease. Unfortunately, we do not have an answer to the question which patients will benefit most from an immunomodulatory treatment. By now, no genetic polymorphism or gene expression profile has been identified that would help selecting patients for a certain treatment 6. Also a definite answer to the question of the long-term effect of these treatments on disability progression is lacking. Different patient cohorts have been studied to find out if interferon treatment is associated with reduced secondary progression. However, these studies yielded conflicting results 20,21. The lack of a proper untreated control group that is comparable to the treated group is probably the reason for this continuing uncertainty. Experimental research on the factors that are responsible for migration of immune cells into the CNS finally led to the registration of natalizumab, a monoclonal antibody that blocks a4 integrin22. This integrin has been shown in animal models to be critical for migration of lymphocytes across the blood brain barrier. The pivotal trials with this antibody showed a clear reduction of relapses and disability progression23,24. Also MRI parameters of brain inflammation responded dramatically to this treatment. Natalizumab was therefore considered as a major breakthrough in the treatment of RRMS. Unexpectedly, already during the clinical trial phase a severe side effect of natalizumab treatment emerged: progressive multifocal leucencephalopathy (PML) caused by the JC virus. Meanwhile we know that natalizumab is the immunosuppressive drug that is most commonly associated with PML. A number of risk factors have been 3
identified to contribute to an increased risk for PML during natalizumab treatment: duration of natalizumab treatment over 2 years; previous immunosuppressive treatment; a positive JCV-antibody status25. The risk of PML led to a more restricted label of the drug. It has been registered only for highly active patients as a first line therapy and for patients that show breakthrough disease despite an ongoing immunomodulatory baseline therapy. The next step in the development was the approval of Fingolimod (Gilenya), the first oral therapy in MS26. Fingolimod is a first in class compound that targets the sphingosin receptor system. It acts as an agonist that binds to the receptor and finally leads to an internalization and degradation of the receptor. Its efficacy is thought to be linked to S1P receptor 1 binding that is expressed on lymphocytes. Lymphocytes need this receptor for an efficient egress from lymphnodes. Treatment with fingolimod leads to a reduction of lymphocytes in the blood that is attributed to a redistribution of lymphocytes to secondary lymphoid organs. Unlike classical immunosuppressive agents fingolimod does not destroy lymphocytes and the redistribution is reversible after stopping of fingolimod. It also does not affect all lymphocytes in the same way but mainly targets naive and central memory T cells and largely spares effector memory T cells that can still be found in the blood27. Despite a considerable decrease in blood circulating T cells the overall rate of infections was not significantly increased. However, there seems to be a slight increase of herpesviral infections in fingolimod treated patients28,29. In pivotal trials fingolimod showed an around 50 % reduction in relapse rates compared to Placebo and also compared to the active comparator Avonex (FREEDOMS and TRANSFORMS trials)30-32. Since fingolimod can cross the blood brain barrier and its receptors are also expressed on CNS residents cells (e.g. neurons, oligodendrocytes, and astrocytes) it was speculated that it could also have a neuroprotective effect (reduced astrogliosis and enhanced remyelination33,34) in addition to its immunomodulatory effect35. (INFORMS study). A well designed randomized, Placebo-controlled phase III trial, however, failed to show an effect of fingolimod on disability progression inprimary progressive MS (INFORMS study, https://www.novartis.com/news/mediareleases/novartis-provides-update-fingolimod-phase-iii-trial-primary-progressive-msppms). Together with one negative trial of natalizumab-treatment in secondary progressive MS (ASCEND study) this stresses the difficulties we have in treating patients with progressive forms of MS. Teriflunomide was the next oral agent that was introduced as treatment for RR-MS36. It is a follow-up compound of leflunomide that is registered for rheumatoid arthritis. Teriflunomide is the active metabolite of leflunomide and inhibits the activity of the dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidine in activated lymphocytes. In two large phase III trials the compound showed a significant reduction of relapse rates of more than 30 % and a reduction in the proportion of patients who developed a confirmed disability progression (TOWER and TEMSO trials)37,38. In a further trial teriflunomide proofed to be effective also in patients with CIS (TOPIC trial)39. The up to now last oral compound that has been registered for RR-MS is dimethylfumarate (DMF, Tecfidera)40. DMF was originally used to treat patients with psoriasis. The clinical observation that psoriasis patients that had concomitant MS also seemed to benefit from DMF treatment led to the clinical development program of the drug in MS. The mode of action of DMF is still under investigation and mechanisms proposed comprise an activation of the NRF2 anti-oxidative stress response, inhibition 4
of NF kappa B activation, a shift in the cytokine profile from pro- to anti-inflammatory, and the induction of apoptosis in lymphocytes. Two large controlled trials were performed in patients with RR-MS (DEFINE and CONFIRM trials)41,42. Both trials showed a reduction of the annualized relapse rate in DMF treated patients compared to Placebo by around 50 %. One trial included in addition an open label comparison to Copaxone treatment which was associated with a relapse rate reduction of around 30 % compared to the Placebo arm. The last compound that was registered in the treatment arena of MS is alemtuzumab (Lemtrada)43. Alemtuzumab is a monoclonal antibody against the surface molecule CD52. It leads to a rapid and long-lasting depletion of lymphocytes. It is thought that the treatment of alemtuzumab leads to a reset of the immune response with a change of the T cell receptor repertoire and phenotype of T cells re-occuring after depletion. Two phase III trials have been performed in RR-MS (CARE-MS I and II)44,45. Alemtuzumab was tested against Rebif in both trials and could show a significant reduction in relapses rates compared to the active comparator. MS CARE II also showed a significant reduction of disability progression in alemtuzumab treated patients compared to Rebif treated patients. Despite these promising efficacy results there is some concern regarding the safety profile of the drug. The two most relevant side effects are an increased rate of infections, mainly in the first months after an infusion cycle, and the occurence of secondary autoimmunity, especially thyroid autoimmune disease and rarely other B cell mediated autoimmune disorders like thrombocytopenia and glomerulonephritis. In clinical practice these side effects limit the use of alemtuzumab to MS patients with highly active disease and patients that failed on other immunmodulatory drugs. Despite this plethora of available therapies clinical research to develop novel treatments for MS is ongoing. Two drugs that showed promising results in phase III trials, but are not registered so far, are ocrelizumab and daclizumab. Daclizumab is a monoclonal antibody against CD25, the high-affinity IL2 receptor alpha chain46,47. The other drug is ocrelizumab, a B cell depleting antibody directed against CD20. Especially the recently announced results of the three phase III trials of ocrelizumab raised a lot of interest (OPERA I and II, ORATORIO), because the drug seemed not only to work in RR-MS but also showed a reduction of disability progression in PP-MS (http://www.roche.com/media/store/releases/med-cor-2015-06-30.htm). This makes ocrelizumab the first compound that showed positive results in a well-controlled phase III trial for PP-MS. With all these new drugs the treatment landscape of MS is rapidly changing. The main tasks for the future will be to develop tools to stratify patients for the right treatment and to define a rationale for sequencing these therapies. Despite promising results it is also clear that none of these treatments are a cure of MS. Many patients will still deteriorate despite immunomodulatory treatment. It is therefore mandatory to continue research with the goal to develop true neuroprotective and regenerating therapies that tackle the neurodegenerative part of MS that is the main driver of disability in the progressive stages of the disease. Literature : 1. Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221-31. 2. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278-86. 5
3. Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol 2007;6:903-12. 4. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol 2012;11:157-69. 5. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4:281-8. 6. Comabella M, Montalban X. Body fluid biomarkers in multiple sclerosis. Lancet Neurol 2014;13:113-26. 7. Rio J, Nos C, Tintore M, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol 2006;59:344-52. 8. Sormani MP, Rio J, Tintore M, et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler 2013;19:605-12. 9. 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. 10. Stangel M, Penner IK, Kallmann BA, Lukas C, Kieseier BC. Towards the implementation of 'no evidence of disease activity' in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord 2015;8:3-13. 11. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology 1993;43:655-61. 12. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285-94. 13. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998;352:1498-504. 14. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45:1268-76. 15. Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol 2014;13:657-65. 16. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370:389-97. 17. Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012;11:33-41. 18. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009;374:1503-11.
6
19. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898-904. 20. Trojano M, Pellegrini F, Paolicelli D, et al. Real-life impact of early interferon beta therapy in relapsing multiple sclerosis. Ann Neurol 2009;66:513-20. 21. Shirani A, Zhao Y, Karim ME, et al. Interferon beta and long-term disability in multiple sclerosis. JAMA Neurol 2013;70:651-2. 22. Derfuss T, Kuhle J, Lindberg R, Kappos L. Natalizumab therapy for multiple sclerosis. Semin Neurol 2013;33:26-36. 23. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-23. 24. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910. 25. McGuigan C, Craner M, Guadagno J, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry 2015. 26. Mehling M, Kappos L, Derfuss T. Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. Curr Neurol Neurosci Rep 2011;11:4927. 27. Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008;71:1261-7. 28. Arvin AM, Wolinsky JS, Kappos L, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol 2015;72:31-9. 29. Ricklin ME, Lorscheider J, Waschbisch A, et al. T-cell response against varicellazoster virus in fingolimod-treated MS patients. Neurology 2013;81:174-81. 30. 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;362:387-401. 31. 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;13:545-56. 32. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-15. 33. Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 2011;108:751-6. 34. Miron VE, Ludwin SK, Darlington PJ, et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol 2010;176:2682-94. 35. Miron VE, Schubart A, Antel JP. Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 2008;274:13-7. 36. Papadopoulou A, Kappos L, Sprenger T. Teriflunomide for oral therapy in multiple sclerosis. Expert Rev Clin Pharmacol 2012;5:617-28. 37. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303. 38. 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;13:247-56.
7
39. 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;13:977-86. 40. Salmen A, Gold R. Mode of action and clinical studies with fumarates in multiple sclerosis. Exp Neurol 2014;262 Pt A:52-6. 41. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107. 42. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97. 43. 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. 44. 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. 45. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829-39. 46. 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. 47. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsingremitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013;381:2167-75.
8