Journal Club: Therapies for Multiple Sclerosis

Journal Club: Therapies for Multiple Sclerosis Sashank Prasad, MD Brigham and Women s Hospital Boston, MA Learning Objectives 1. Become familiar with recent risk estimates for progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) receiving natalizumab 2. Understand the efficacy and safety data concerning fingolimod, a recently approved oral medication for MS 3. Become familiar with several oral and infusion investigational agents for MS currently in phase 3 clinical trials CME Questions 1. What is the approximate risk of developing PML for an MS patient treated with natalizumab who has positive JC virus serology, has received prior immunosuppression, and has received natalizumab for greater than 2 years? a..1% b. 1% c. 10% d. 50% 2. What is the reported incidence of macular edema in patients receiving fingolimod 0.5mg (without a history of diabetes or uveitis)? a..04% b..4% c. 4% d. 40% 3. Dimethyl fumarate is related to a compound that is licensed in Europe to treat what condition? a. Rheumatoid arthritis b. Psoriasis c. Crohn s disease d. Myasthenia gravis Keywords 1. Multiple Sclerosis 2. Natalizumab 3. Fingolimod 4. Progressive Multifocal Leukoencephalopathy Introduction Recent progress makes it clear that we are in a new era regarding therapeutics for multiple sclerosis (MS). After a long history of treating MS symptomatically, the past two decades have brought a new armamentarium of diseasemodifying therapies that modulate the autoimmune response in a variety of ways. The clinician may now select from 8 medications approved for MS by the US Food and Drug Administration! Between 1993 and 2004, the main platform medications were injectable (either subcutaneous or intramuscular), but recently approved agents utilize intravenous and oral delivery routes [1, 2]. These factors can have a major impact on patient convenience and adherence. The clinical data regarding these developments are of great importance to the treating neurologist, who will be charged with balancing the risks and benefits of newly approved therapies in aiming to select appropriate choices for the patient. This syllabus will review clinical data regarding MS therapies that have been recently approved or are currently in phase 3 clinical trials. Recently approved agents Natalizumab Natalizumab (Tysabri, Biogen Idec and Elan) is a humanized monoclonal antibody that interrupts leukocyte trafficking by blocking the interaction between leukocyte α4 integrins and endothelial receptors. The efficacy of natalizumab was originally reported in two phase 3 clinical trials, AFFIRM and SENTINEL [3, 4]. In AFFIRM, 942 patients were randomized to receive natalizumab or placebo for 2 years. Compared to placebo, the group receiving natalizumab showed a 68% reduction in clinical relapse rate (p<0.001) and 42% reduction in risk of sustained disability in that time period (HR 0.58; 95% CI 0.43 0.77). Analysis of magnetic resonance imaging (MRI) scans obtained during the study demonstrated an 83% reduction in new or enlarging T2 lesions (p<0.001) and 92% reduction in gadolinium-enhancing lesions (p<0.001). In SENTINEL, 1171 patients were randomized to interferon β-1a intramuscular once a week with either natalizumab or placebo. Patients receiving natalizumab demonstrated a reduced relapse rate compared to those receiving placebo (34% vs. 75%, p<0.001) and were less likely to have sustained disability progression (23% vs. 29%; p=0.02). This study was terminated 1 month early, however, because 2 study patients in the natalizumab arm developed progressive multifocal leukoencephalopathy (PML). 2013 Annual Meeting Syllabus 71

Table 1. Risk of PML among patients with MS treated with natalizumab [adapted from [9]] Anti JC virus status Natalizumab exposure >24 mos Prior Immunosuppressant use Estimated risk of PML (95% CI) Negative +/- +/- <0.09 (0 0.48) Positive No No 0.56 (0.36 0.83) Positive No Yes 1.6 (0.91 2.6) Positive Yes No 4.6 (3.7 5.6) Positive Yes Yes 11.1 (8.3 14.5) Natalizumab was originally approved by the FDA in 2004, but then withdrawn from the market in 2005 because of the occurrence of PML in 3 patients treated with the drug. In 2006 it was brought back to market with a blackbox warning regarding the risk of PML. Post-marketing surveillance programs were initiated to address concerns regarding the incidence of PML in this population. These data have recently been analyzed to provide updated risk estimates for PML in patients with MS receiving natalizumab [5]. Among 99,571 patients treated with natalizumab (209,123 patient-years), 212 confirmed cases of PML were identified. Of these, 46 (22%) died; among the survivors with adequate follow-up data, 40% had severe disability. The over-all risk of PML was approximately 1/1000 patient-years, with a majority of cases occurring beyond 2 years of treatment. The authors of this study (all employees of Biogen Idec) evaluated the utility of an anti-jc virus antibody assay to predict the risk of PML in patients treated with natalizumab [5]. The studies used the STRATIFY JC virus assay, which was developed by Biogen Idec and licensed to Quest Diagnostics Focus Laboratory. Where it is allowable, Biogen Idec and Quest have made this assay available for free to MS patients. The 2-step antibody assay uses an ELISA screening test and, when necessary, a confirmatory supplemental inhibition assay; while retaining good specificity, this method has higher sensitivity than prior PCR-based tests for JC virus DNA, which are only effective when the virus is actively replicating and shedding [6]. Test characteristics of this JC virus antibody assay were recently evaluated in the STRATIFY-1 and TYGRIS surveillance studies for patients receiving natalizumab [7]. Based on comparison to urinary JC virus DNA PCR results, the JC virus antibody assay was found to have a false negative rate of approximately 2.7%. Overall JC virus seroprevalence was estimated to be 54%; the value correlated with age and female gender, but was independent of the duration of natalizumab therapy. In the recent investigation, stratified risk estimates for PML were calculated based upon 54 natalizumab-treated patients with PML who had undergone baseline JC virus antibody testing [5]. The analysis revealed that 100% of these patients had a positive JC virus antibody assay (compared to the estimated 54% seroprevalence in patients without PML) [7]. According to the authors calculations, negative JC virus status conferred an estimated risk of PML of <0.09% (95%CI 0 0.48). However, with combined positive JC virus status, prior immunosuppressant use, and greater than 24 months of natalizumab use, the estimated risk increases more than 100-fold to 11.1% (95%CI 8.3 14.5). Positive JC virus status associated with prior immunosuppressant use or greater than 24 months of natalizumab exposure (but not both) confers an intermediate risk of PML (between 0.56 and 4.6%). The FDA now recommends using JC virus antibody ELISA testing for all patients in whom treatment with natalizumab is being considered [8]. Periodic re-testing for JC virus antibodies will be an important way to detect new exposures (or falsenegative results), but the optimal frequency of re-testing remains to be determined. Fingolimod Fingolimod (Gilenya, Novartis) is an oral sphingosine-1 phosphate 1 receptor analogue that causes internalization and downregulation of S1P 1 leukocyte receptors, preventing the egress of leukocytes from lymph nodes [10]. In 2010, following reports from two large phase 3 clinical trials (FREEDOMS and TRANSFORMS), fingolimod became the first oral drug approved by the FDA for use in MS [11, 12]. In FREEDOMS, 1272 patients were randomized to receive oral fingolimod (at a dose of either 0.5mg or 1.25 daily) or oral placebo. Patients receiving the 0.5mg dose of fingolimod, compared to those receiving placebo, demonstrated a 54% reduction in relapse rate (0.18 vs 0.40, p<0.001) and 17.7% reduction in risk of disability progression (HR 0.70; 95%CI 0.52 0.96). In TRANSFORMS, 1292 patients were randomized to receive either intramuscular interferon β1a weekly or fingolimod 0.5mg daily. Patients receiving fingolimod demonstrated a 52% reduction in risk of relapse rate (0.16 vs 0.33; p<0.001), although this 1 year study did not demonstrate a significant reduction in disability scores. Reported side effects from these trials (including deaths related to infection) were greater with the 1.25mg dose, and only the 0.5mg dose has been approved for clinical use. 72 North American Neuro-Ophthalmology Society

The potential systemic side effects of treatment with fingolimod likely relate to consequences of S1P 1 inactivation in other tissues. Cardiac conduction defects including bradycardia and AV block occur in 1% of patients receiving 0.5mg fingolimod. Of note, post-martketing experience has identified syncope, transient asystole, and even unexplained death within 24hrs of the first dose. Recent changes to the full prescribing information, made in April 2012, now recommend monitoring patients for bradyarrhythmias for 6 hours following the first dose, including an electrocardiogram before and after the observation period. If abnormalities are present after 6 hours, continued observation or hospitalization for overnight telemetry should occur. Patients with pre-existing cardiac disease, including QTc prolongation, should undergo evaluation by a cardiologist, and upon receiving the first dose of fingolimod they should be monitored with overnight telemetry. The drug is contraindicated in patients with a history of myocardial infarction, unstable angina, second- or third-degree heart block, stroke, transient ischemic attack, or decompensated heart failure in the previous 6 months. Of particular relevance to neuro-ophthalmologists, some patients treated with fingolimod can develop macular edema (which may be either symptomatic or asymptomatic) [13]. At the 0.5mg dose of fingolimod in the TRANFORMS study, macular edema occurred in 2 patients (0.5%). It did not occur in any patients at that dosage in FREEDOMS. The package insert for fingolimod describes that the occurrence of macular edema is believed to be approximately 0.4%, but may increase to approximately 20% in the setting of diabetes or prior uveitis [14]. For this reason, a dilated ophthalmoscopic exam is recommended before and 3 months following the initiation of therapy. Symptomatic patients should be examined urgently; if macular edema is present, cessation of the drug should be strongly considered. NANOS and the AAO have recently released a joint consensus statement advising routine eye examination at the onset of therapy and following 3 4 months; macular OCT is suggested in patients with abnormalities on exam or unexplained decreased acuity [15]. Investigational agents in clinical trial Dimethyl fumarate Dimethyl fumarate, also known as BG-12 (Panaclar, Biogen Idec), is a fumaric acid ester that is believed to modulate the immune system by acting on oxidative pathways and stimulating anti-inflammatory cytokines. It is related to a drug that was licensed in Germany in 1995 (Fumaderm, Biogen Idec) to treat psoriasis. In the DEFINE trial, 1234 patients were randomized to receive placebo or 240mg dimethyl fumarate twice daily or three times daily [16]. Patients receiving the drug demonstrated a 49% reduction in relapses (p<0.0001) and 38% reduction in disability progression (p=0.012) over the 2 year study. In addition, there was an 85% reduction in new or enlarging T2 lesions (p=0.0001) and 73% reduction in gadolinium enhancing lesions (p=0.0001). Reported adverse effects included transaminitis, nausea, diarrhea, and flushing. Based upon these data, dimethyl fumarate has been fast-tracked for expedited FDA regulatory review. Laquinimod Laquinimod (Teva) is another orally administered drug; it is thought to have a number of immunomodulatory effects (including downregulation of MHC class II transcription factors and activation of anti-inflammatory cytokines). Conflicting results have arisen from the ALLEGRO and BRAVO trials. In the ALLEGRO study, 1106 patients were randomized to receive placebo or 0.6 mg laquinimod daily; patients receiving laquinimod demonstrated a 23% reduction in relapse rate (0.30 vs 0.39, p=0.002) and 29% reduction in disability progression (11.1% vs 15.7%; HR 0.64 95%CI 0.45 0.91) as well as a 37% reduction in new gadolinium enhancing lesions (p=0.012) [17]. In the BRAVO study, 1331 patients were randomized to laquinomod 0.6mg daily or intramuscular interferon β1a weekly. This study did not demonstrate a significant difference in relapse rate between groups, although the results may have been confounded by dissimilar levels of baseline disease activity judged by MRI [18]. Reported adverse side effects included transaminitis. Rates of herpes virus infection and cancers were similar in patients receiving drug and placebo. FDA approval of laquinimod is on hold until additional data are acquired. Teriflunomide Teriflunomide (Aubagio, Genzyme) is an oral drug that suppresses the immune system by inhibiting dihydroorotate dehydrogenase and suppressing synthesis of DNA pyrimidine bases. In the recent TEMSO trial, 1088 patients were randomized to receive either oral terflunomide (7mg or 14mg daily) or placebo. Patients receiving 14mg teriflunomide demonstrated a 31% reduction in annualized risk of relapse (0.37 vs 0.54, p<0.001) and 30% reduction in risk of disability progression (20.2% vs. 27.3%, p=0.03) [9]. Reported serious adverse effects included nasopharyngitis, diarrhea, transaminitis, and hair thinning. Related compounds are reported to have teratogenic side effects (pregnancy category 4) that may limit its use. Additional phase 3 trials of teriflunomide versus interferon or placebo are being conducted. In addition, TOPIC is a phase 3 trial assessing teriflunomide versus placebo in patients with a clinically isolated syndrome (CIS) [19]. Alemtuzumab Alemtuzumab (Campath, Genzyme) is a humanized monoclonal antibody that binds to CD52, a receptor found on both B and T lymphocytes. It is approved for treatment of B-cell chronic lymphocytic leukemia (B-CLL) and produces marked immunosuppression lasting up to 16 months. Two phase 3 trials are ongoing. In the CARE MS1 trial, 581 treatment-naïve patients were randomized to receive alemtuzumab or SQ IFN β1a; patients receiveing alemtuzumab demonstrated a 55% decrease in relapse rate but did not demonstrate a significant reduction in rate of disability progression [20]. Data have not yet been reported 2013 Annual Meeting Syllabus 73

from another phase 3 trial of alemtuzumab (CARE MS2), which is studying patients who have relapsed on platform therapy. An increased risk of infections and autoimmune conditions, including thyroid dysregulation and immune thrombocytopenic purpura (ITP), are reported to occur [21]. Daclizumab Daclizumab (Zenapax, Roche) is a monoclonal antibody that blocks IL-2 receptors on activated T cells. It has FDA approval for organ transplant patients. The phase 3 DECIDE trial is currently underway to evaluate its efficacy in MS (against IFN-β) [22]. Ocrelizumab Ocrelizumab (Roche and Biogen Idec) is the humanized version of the monoclonal antibody rituximab, which produces B cell depletion by targeting the CD20 cell surface epitope. Reported adverse side effects in phase 2 studies included one death from a systemic inflammatory response with brain edema [23]. The drug is currently being studied in the ORCHESTRA phase 3 trials for use in MS [24]. Conclusions We are in the midst of a revolution in MS therapeutics, with a number of promising newly approved and investigational disease-modifying agents. It is important for the treating neurologist to be aware of the clinical data regarding these therapies, in order to understand the balance between their clinical efficacy and toxicity. Most patients with newly diagnosed demyelinating disease will be best served by a platform immunomodulating therapy, including the interferons and glatiramer acetate; these agents have wellestablished safety profiles. However, for certain patients it may be reasonable to consider the newer agents reviewed in this syllabus. Relevant factors may include poor clinical or radiographic response to a platform therapy or an aggressive disease course at onset. For some patients with poor adherence to a platform therapy requiring frequent injections, a newer oral or infusion therapy may be a reasonable alternative, although the risks of this approach merit careful consideration. Continued detailed safety monitoring of these drugs is imperative to develop a more thorough understanding of their safety profiles, in support of balanced clinical decision making. Table 2. New and emerging therapies for MS Therapy Administration Reported side effects APPROVED INVESTIGATIONAL Natalizumab (Tysabri, Biogen Idec and Elan) Fingolimod (Gilenya, Novartis) Dimethyl fumarate (BG-12, Biogen) Laquinimod (Teva) Teriflunomide (Genzyme) Alemtuzumab (Campath, Genzyme) Daclizumab (Zenapax, Roche) Ocrelizumab (Roche and Biogen Idec) 300mg iv every 28days 0.5 mg po qd 120 240mg po tid 0.6mg po qd 7 14 mg po qd 12 24mg qd x5d iv once/year 2mg/kg SQ every other week 600 2000mg iv PML, headache, fatigue, UTIs, hypersensitivity reaction Macular edema, bradycardia, shingles, skin cancer Diarrhea, nausea, cramps, transaminitis Transaminitis Headache, diarrhea, nausea, back pain, transaminitis, nasopharyngitis, UTI ITP, thyroid dysfunction, headaches Rash, lymphadenopathy, transaminitis, diarrhea Systemic inflammatory response 74 North American Neuro-Ophthalmology Society

CME Answers 1. c 2. b 3. b References 1. Castro-Borrero, W., et al., Current and emerging therapies in multiple sclerosis: a systematic review. Ther Adv Neurol Disord. 5(4): p. 205 20. 2. Fox, E.J. and R.W. Rhoades, New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis. Current opinion in neurology, 2012. 25 Suppl: p. S11 9. 3. Polman, C.H., et al., A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. The New England journal of medicine, 2006. 354(9): p. 899 910. 4. Rudick, R.A., et al., Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. The New England journal of medicine, 2006. 354(9): p. 911 23. 5. Bloomgren, G., et al., Risk of natalizumab-associated progressive multifocal leukoencephalopathy. The New England journal of medicine, 2012. 366(20): p. 1870 80. 6. Rudick, R.A., et al., Assessment of JC virus DNA in blood and urine from natalizumab-treated patients. Annals of neurology, 2010. 68(3): p. 304 10. 7. Bozic, C., et al., Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Annals of neurology, 2011. 70(5): p. 742 50. 8. FDA. Tysabri (natalizumab): Drug safety communication new risk factor for Progressive Multifocal Leukoencephalopathy (PML). 2012 8/21/12]; Available from: http://www.fda.gov/safety/medwatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm288602.htm. 9. O Connor, P., et al., Randomized trial of oral teriflunomide for 2011. 365(14): p. 1293 303. 10. Mandala, S., et al., Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 2002. 296(5566): p. 346 9. 11. Kappos, L., et al., A placebo-controlled trial of oral fingolimod in 2010. 362(5): p. 387 401. 12. Cohen, J.A., et al., Oral fingolimod or intramuscular interferon for 2010. 362(5): p. 402 15. 13. Jain, N. and M.T. Bhatti, Fingolimod-associated macular edema: incidence, detection, and management. Neurology, 2012. 78(9): p. 672 80. 14. Novartis, Highlights of prescribing information: Gilenya (fingolimod) capsules, 2012. 15. Committee, O.N.-O., Oral MS drug may increase risk for macular edema: a report from the North American Neuro-Ophthalmology Society (NANOS) and the AAO, 2011. 16. Gold R, K.L., Bar-Or D, Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial., in 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).2011: Netherlands. 17. Comi, G., et al., Placebo-controlled trial of oral laquinimod for multiple sclerosis. The New England journal of medicine, 2012. 366(11): p. 1000 9. 18. Vollmer TL, S.P., Arnold DL., Benefit risk assessment of avonex and laquinomod (BRAVO) study group. A placebo controlled and active comparator phase 3 trial of oral laquinomod in relapsing-remitting multiple sclerosis patients., in 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS)2011. 19. Clinicaltrials.gov. Phase 3 study with teriflunomide versus placebo in patients with first clincial symptom of multiple sclerosis (TOPIC).. 2012 8/22/12]; Available from: http://clinicaltrials.gov/ct2/show/ NCT00622700. 20. Coles AJ, B.V., Arnold DL, Efficacy and safety results from CARE-MS 1: a phase 3 study comparing alemtuzumab and interferon-beta- 1a., in 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).2011: Amsterdam. 21. Cossburn, M., et al., Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology, 2011. 77(6): p. 573 9. 22. Clinicaltrials.gov. Efficacy and safety of daclizumab high yield process versus interferon B1a in patients with relapsing-remitting multiple sclerosis. 2012 8/22/12]; Available from: http://clinicaltrials.goc/ct2/ show/nct01064401. 23. Kappos, L., D. Li, and P. Calabresi, Ocrelizumab in relapsing-remitting multiple sclerosis: 49 week efficacy and safety results of a phase 2 randomized placebo controlled multicenter trial., in American Academy of Neurology (AAN) 63rd annual meeting2011: Honolulu, HI. 24. Clinicaltrials.gov. A study of ocrelizumab in comparison with interferon beta1a in patients with relapsing multiple sclerosis. 2012; Available from: http://clinicaltrials.gov/ct2/show/nct01412333. 2013 Annual Meeting Syllabus 75