Oral Therapies in MS Management: Where We Are and What Is on the Horizon

Transcription

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2 Oral Therapy for MS Management: State of the Union Bruce Cree, MD, PhD, MAS Associate Professor of Clinical Neurology Clinical Research Director University of California San Francisco San Francisco, CA

3 Existing and Emerging MS Therapies Ozanimod Ofatumumab Ocrelizumab Ampyra (4-amino pyradine) Daclizumab Betaseron (IFNβ-1b) Tysabri (natalizumab) Nuedexta (Dextromehtorphan Quinidine) Siponimod Avonex (IFNβ-1a) Copaxone (glatiramer acetate) Novantrone (mitoxantrone) Rebif (IFNβ-1a) Extavia (IFNβ-1b) Laquinimod Cladribine Lemtrada (alemtuzumab) Gilenya Aubagio (Fingolimod) (Teriflunomide) Tecfidera (Dimethyl Fumarate) (BG-12) Approval date Estimated launch date Approved therapies Phase III completed In Phase III *In March 2011, the FDA did not approve cladribine and requested Merck KGaA provide an improved understanding of its safety risks and overall benefit-risk profile. Oral Therapies Overview In theory, orally bioavailable therapies will be better tolerated than parenterally administered medications. In practice, adherence to treatment is dependent on more than route of administration. Frequency of treatment, common adverse events, as well as, more rare but serious adverse events influence adherence. A recent non-industry sponsored, single-center study using a patient reported outcome found that adherence for never missing a dose was highest for an infusible medication, followed by injectables, and then by oral therapies. 93.3% vs 70.8% vs 55%, P<.005, N=209 Dione C, CMSC 2015, Abstract DX19. Fingolimod: Efficacy Indicated for relapsing MS, single once-daily capsule Proven efficacy 1 54% relative reduction in relapses 30% reduction in hazard ratio for disability (3 month sustained change) Superior to interferon β-1a IM (TRANSFORMS Study) 2 Robust effects on lesion evolution and brain volume loss Annualized Relapse Rate % With 3-Month Confirmed EDSS Progression Fingolimod 0.5 mg vs placebo HR=0.70 P=.02 in time to disability progression Fingolimod 1.25 mg vs placebo HR=0.68 P=.02 in time to disability progression Placebo (24%) Fingolimod 0.5 mg (18%)* Fingolimod 1.25 mg (17%) *P=.03 vs placebo P=.01 vs placebo Days on Study 1. Kappos K, et al. N Engl J Med. 2010;362: Reprinted with permission. 2. Cohen J, et al. N Engl J Med. 2010;362:

4 Therapeutic Satisfaction: EPOC Study Primary Results Change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Scores in Subjects Switching to Fingolimod Versus Staying on Injectables LSM changes (± standard error) in TSQM Global Satisfaction scores from baseline to 6 months were significantly superior following a switch to fingolimod compared with remaining on GA (17.08 ± 1.56 vs 0.81 ± 2.89, respectively), IM IFN beta-1a (17.57 ± 1.51 vs 2.10 ± 3.22, respectively), SC IFN beta-1a (24.70 ± 1.62 vs 2.29 ± 2.96, respectively) or IFN beta-1b (22.34 ± 1.85 vs 4.45 ± 3.29, respectively); all P<.001. IFN, interferon; GA, glatiramer acetate Calkwood J, et al. BMC Neurology. 2014;14:220. Fingolimod: Mechanism of Action Activation Proliferation and differentiation Afferent lymphatic vessel Activated T cells S1P Lymphatic sinus Sinus-lining endothelium Naïve T cell S1P 1 receptor Efferent lymphatic vessel Lymph node S1P 1 downregulation Sinus-lining endothelial cell barrier enhancement S1P=sphingosine-1 phosphate. Fingolimod Reduced T cell egress Horga A, et al. Expert Rev Neurother. 2008;8: Fingolimod Suppression of Peripheral Lymphocytes Fingolimod diminishes peripheral lymphocyte counts by ~75% 1,2 1. Mehling M, et al. Neurology. 2008;71: Kappos K, et al. N Engl J Med. 2010;362:

5 S1P Receptor Is Located in Multiple Organ Systems Airways hyperactivity (S1P1 3) Bronchial smooth muscle Angiogenesis (S1P 1) Vasodilation (S1P1, 3) Barrier decrease (S1P2 3) Barrier enhancement (S1P1) Retina S1P Vascular endothelium Heart-rate reduction and regulation (S1P1, 3) Swelling (S1P2) Vasoconstriction, blood pressure increase (S1P1 3) Vascular smooth muscle Atrial myocytes Vascular formation during embryogenesis Brinkmann V. Pharmacol Ther. 2007;115: Current Strategies for Mitigating the Potential Risks Associated With Fingolimod Potential AE or Risk Mitigation Strategy Observe all patients for 6 h after initial dose for signs and symptoms of bradycardia, ECG pre- and post- first dose Bradycardia/AV block If patients go off medication for prolonged time period, they must be observed when restarting therapy Macular edema Ophthalmologic exam at baseline and 3 to 4 months after treatment initiation Patients should be vaccinated for varicella zoster virus (VZV) Risk of VZV reactivation, especially with corticosteroids Infection PML and crypotoccal infection risks Avoid live attenuated vaccines for at least 2 months after stopping therapy FEV 1 and DLCO Spirometric evaluation when indicated LFT elevations Monitor regularly, as needed Pregnancy risk category C Counsel patients about fetal risks Use effective contraception on treatment and for at least 2 months after stopping therapy AV: atrioventricular; DLCO: diffusion capacity of the lung for carbon monoxide; FEV1: forced expiratory volume over 1 second. Gilenya (fingolimod) 0.5 mg capsules. PostmarketDrugSafetyInformationforPatientsandProviders/UCM pdf. Accessed September 30, Fingolimod as an Immune Suppressant Opportunistic infection risk 1 Three reported PML cases with >100,000 MS patients treated 1 Also 1 neuromyelitis optica spectrum disorder patient with prior immune suppressant exposure Several cases of cryptococcal infections including disseminated cryptococcus and cryptococcal meningitis 2 One case of Kaposi sarcoma 3 One case of primary CNS lymphoma 1 Risk of primary herpes virus infections and reactivation 1 How risk of all these potential complications should be communicated to patients remains to be determined Overall risk of serious IS complications might be ~1:10,000, not accounting for duration of exposure Huang D. Neurology. 2015;85: Tully T, et al. Neurology. 2015;84:

6 Teriflunomide Indicated for relapsing MS 1 Antimetabolite, inhibits dihydro-orotate dehydrogenase thereby inhibiting de novo DNA synthesis in proliferating lymphocytes Proven efficacy 2 32% relative reduction in relapses (14 mg) 30% reduction in hazard ratio for disability Single once-daily pill Generally, well-tolerated, but with boxed warnings No known PML risk O Connor P, et al. N Engl J Med. 2011;365: Evaluating Treatment Satisfaction: TSQM in the TENERE Phase 3 trial of Teriflunomide vs IFNβ-1a P<.0001 P<.0001 N= P=.02 P= NS Effectiveness Side effects Convenience Global satisfaction Teri 7 mg Teri 14 mg IFN-b Vermersch P, et al. Mult Scler. 2014;20: Teriflunomide: Targeting Activated Lymphocyte Proliferation Teriflunomide selectively and reversibly inhibits mitochondrial dihydro-orotate dehydrogenase (DHODH), impairing the proliferation of activated lymphocytes while sparing resting and slowly dividing cells* 1,2 Pyrimidine salvage pathway is not affected by teriflunomide 1 Stimulated lymphocyte De Xnovo pyrimidine synthesis pathway: DHODH PYRIMIDINE DEMAND Resting and slowly dividing lymphocytes SALVAGE PATHWAY * The exact mechanism by which teriflunomide exerts its therapeutic effect in MS is not fully understood 1. Gold R, et al. Acta Neurol Scand. 2011;124: Warnke C, et al. Neuropsychiatr Dis Treat. 2009;5: Inhibition of actively proliferating lymphocytes Homeostatic proliferation preserved

7 Mean Lymphocyte and Neutrophil Counts in the Pivotal Clinical Trials Lymphocytes, mean SE (giga/l) Mean Lymphocyte Counts* Mean Neutrophil Counts* 2.5 Teriflunomide 14 mg Teriflunomide7 mg Placebo Week No. of patients 14 mg mg Placebo Decreases observed with teriflunomide occurred during the first 6 weeks (neutrophils) or 12 weeks (lymphocytes) of treatment; mean counts remained within normal range and stable thereafter *For weeks 26 and 28, only data from the Phase 2 study were available. Normal range for general population: /L. Normal range for general population: /L. Neutrophils, mean SE (giga/l) LLN LLN 2.5 Teriflunomide 14 mg Teriflunomide 7 mg Placebo Week No. of patients 14 mg mg Placebo Comi G, et al. ACTRIMS-ECTRIMS P060. Teriflunomide Risk Stratification Parent compound leflunomide is associated with severe and fatal liver injury in rheumatoid arthritis patients Similar risk to MS patients is assumed Based on animal studies, teriflunomide could cause fetal death and malformations Additional risks include tuberculosis reactivation, nephropathy, peripheral neuropathy, alopecia, hypertension Pretreatment: screen for tuberculosis, infection, pregnancy, renal failure, peripheral neuropathy, interstitial pulmonary disease, hypertension; assess WBC, renal function, and LFTs During treatment: Blood pressure monitoring; serum transaminase determinations; renal function Women of childbearing age should not be started on therapy until pregnancy is excluded and confirmation of reliable contraception (Category X) Pregnancies Reported in Teriflunomide Clinical Trial Database Pregnancies in patients exposed to teriflunomide, in unblinded data: 83 pregnancies in women 22 pregnancies in partners of men Pregnancy outcomes No structural defects in newborns No functional deficits in newborns Median birth weight: 3300 grams (7.2 pounds) Rate of miscarriage: 17% Similar to previous reports for GA and IFN Elimination procedure Discontinue treatment Undergo elimination procedure Cholestyramine or activated charcoal until plasma drug levels <0.02 mcg/ml Male patients are advised the same Kieseier B, et al. Neurol Ther. 2014;3:

8 Dimethyl Fumarate Indicated for relapsing MS 1 Mechanism unclear, may induce anti-oxidative genes through Keap1 inhibition that allows Nrf2 to translocate to nucleus and induce antioxidative response Proven efficacy 2 53% relative reduction in relapses 38% reduction in hazard ratio for disability (3 month sustained change in EDSS) Twice daily capsule Generally well tolerated Risk of PML in setting of chronic lymphopenia and hypothetical risk of RCC based on dimethyl fumarate used for psoriasis Gold R, et al. N Engl J Med. 2012;367: Sheremata W, et al. Expert Opin Drug Saf. 2015;14(1): DMF and its Metabolite, MMF, Inhibit the Inhibitor MMF Keap1 MMF Keap1 CYTOPLASM NUCLEUS Gene Transcription GSTA2 NQO1 HO-1 Adapted from Brück W, et al. JAMA Neurol. 2013;70: Dimethyl Fumarate Nrf2 is reported to have antiproliferative and immunomodulatory activity. 1-3 DMF 56% and multiple ethyl fumarates promotes development of anti-inflammatory type II DC. 4 DMF may also exert effects through other pathways. For example, flushing induced by DMF has been attributed to activation of the nicotinic acid receptor, HCA 2. 5 The protective effect of DMF is mediated, in part, by HCA Williams MA, et al. J Immunol. 2008;181(7): Rockwell CE, et al. J Immunol. 2012;188(4): Lehmann JC, et al. J Invest Dermatol. 2007;127(4): Ghoreschi K, et al. J Exp Med. 2011;208(11): Tang H, et al. Biochem Biophys Res Commun. 2009;378(3): Chen H, et al. J Clin Invest. 2014;124(5):

9 PML in a Patient Without Severe Lymphocytopenia Receiving Dimethyl Fumarate Nieuwkamp DJ, et al. N Engl J Med. 2015;372(15): Reprinted with permission. CD8 Lymphocytes Are Disproportionately Suppressed With DMF Treatment Lymphocyte counts go down over time with each of the subsets, whether you look at CD3, CD19, CD56 NK cells, or CD4 or CD8 cells The level of CD8 lymphopenia is relatively low The CD4/CD8 ratio is reversed over time Spencer CM, et al. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e76. Risk Mitigation With DMF GI symptoms and flushing are common May cause lymphopenia: recent complete blood cell count (<6 months) before starting treatment and every 6 months thereafter or as clinically indicated Liver function tests at baseline Administration with food may decrease flushing Co-treatment with aspirin can reduce flushing Withholding treatment should be considered in patients with severe infections Check JCV serology? 1 case of PML reported in MS patients treated with DMF, several other cases associated with DMF in psoriasis patients Will checking lymphocyte subsets help mitigate risk of potential opportunistic infections?

10 Is Tiered Treatment Still Applicable? Oral therapies have changed the way relapsing MS is managed Oral treatment options are likely to be better tolerated compared to autoinjectable medications Some oral DMTs may be more effective than injectable therapies in reducing relapses Fingolimod was compared to interferon β-1a IM and showed superior efficacy 1 Dimethyl fumarate was compared to glatiramer acetate and showed apparent superior efficacy (post-hoc analysis) 2 Oral therapies may be associated with greater therapeutic satisfaction Whether adherence is improved remains to be established Each oral therapy has a unique risk/benefit ratio Is therapeutic satisfaction (and potentially greater efficacy) worth the added risk? 1. Cohen JA, et al. N Engl J Med. 2010;362: Fox RJ, et al. N Engl J Med. 2012;367: Emerging Oral Agents for MS Management Amit Bar-Or, MD, FRCPC Professor, Neuroimmunology Montreal Neurological Institute McGill University Montreal, Quebec, Canada

11 Objectives Clinical review of oral agents in late-stage development for MS therapy: Ponesimod Phase 2; OPTIMUM Ozanimod (RPC1063) RADIANCE/SUNBEAM Siponimod/BAF312 BOLD; EXPAND (MT-1303 MOMENTUM) Laquinimod CONCERTO, ARPEGGIO Objectives Clinical review of oral agents in late-stage development for MS therapy: Ponesimod Phase 2; OPTIMUM Ozanimod (RPC1063) RADIANCE/SUNBEAM Siponimod/BAF312 BOLD; EXPAND (MT-1303 MOMENTUM) Laquinimod CONCERTO, ARPEGGIO Ponesimod Profile suitable for once-daily oral dosing Selective S1P1 receptor modulator Lymphocyte reduction is rapid, dose-dependent, reversible Penetrates into brain and spinal cord Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11):

12 Phase 2 Dose-finding Study in MS Randomization Placebo (N=121) 10 mg o.d. ponesimod (N=108) 20 mg o.d. ponesimod (N=116) Baseline 40 mg o.d. ponesimod (N=119) Screening Treatment 24 weeks Core Follow-up Extension Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11): Primary Endpoint: Cumulative Number of New T1 Gd+ Lesions (Week 12 to Week 24) Per-protocol population 8 Cumulative new T 1 Gd+ lesions from week 12 to week 24 (Mean ± SE) Placebo (N=110) 43% reduction * Ponesimod 10 mg (N=88) 83% reduction *** Ponesimod 20 mg (N=98) *P<.05, ***P<.0001 vs placebo 77% reduction *** Ponesimod 40 mg (N=93) Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11): Reprinted with permission. Maximum Effect on Lymphocytes With 20 mg Mean change from baseline in lymphocyte count (%) All-treated set Ponesimod 40 mg Ponesimod 20 mg Ponesimod 10 mg Placebo Day 8 Day 13 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Olsson T, et al. J Neurol Neurosurg Psychiatry. 2014;85(11): Reprinted with permission.

13 Ongoing Phase 2 Extension Study in MS 1,2 End of Treatment Randomization Randomization 10 mg ponesimod Placebo 20 mg ponesimod 40 mg ponesimod 10 mg ponesimod 20 mg ponesimod 40 mg ponesimod 10 mg ponesimod 20 mg ponesimod 10 mg ponesimod 20 mg ponesimod Treatment Treatment Period 1 24 weeks Up to 96 weeks Core Extension 1. Freedman M, et al. AAN 2013 (P01.156). 2. Pozzilli C, et al. ECTRIMS 2013 (P995). Treatment Period 2 Up to 432 weeks Followup Ponesimod Phase 3 Study Ongoing OPTIMUM: Oral Ponesimod versus Teriflunomide in RMS A multicenter, randomized, double-blind, parallel-group, active-controlled, superiority study 200 centers in North America, Latin America, Eastern and Western Europe, Pacific 1100 patients randomized 1:1 ratio to either ponesimod 20 mg or teriflunomide 14 mg New dose up-titration scheme implemented Enrollment ongoing ClinicalTrials.gov Identifier: NCT Objectives Clinical review of oral agents in late-stage development for MS therapy: Ponesimod Phase 2; OPTIMUM Ozanimod (RPC1063) RADIANCE/SUNBEAM Siponimod/BAF312 BOLD; EXPAND (MT-1303 MOMENTUM) Laquinimod CONCERTO, ARPEGGIO

14 RADIANCE Phase 2/3 Trial Overview Blinded Safety-Extension 1 mg RPC1063 Phase mg RPC mg RPC mg RPC1063 Interim analysis of Phase 2 (Nov 2013) gated initiation of Phase 3 (Dec 2013) Phase 3 IFN -1a 30 g IM (N=400) Cohen J, et al. Program and abstracts of the 2014 Joint ACTRIMS/ECTRIMS Meeting; September 10-13, 2014; Boston, Massachusetts. Abstract LB1.1. Used with permission. Patient Disposition Randomized (N=258) Placebo (N=88) RPC mg (N=87) RPC mg (N=83) Discontinued 3 (3.4%) Adverse event 0 Lost to follow-up 1 (1.1%) Protocol violation 0 Consent withdrawn 2 (2.3%) Discontinued 2 (2.3%) Adverse event 0 Lost to follow-up 0 Protocol violation 1 (1.1%) Consent withdrawn 1 (1.1%) Discontinued 1 (1.2%) Adverse event 0 Lost to follow-up 0 Protocol violation 0 Consent withdrawn 1 (1.1%) Completed 85 (96.6%) Completed 85 (97.7%) Completed 82 (98.8%) Very high rate of study compliance and completion (252 of 258) Favorable tolerability with 249 of 252 completers entering the extension Cohen J, et al. Program and abstracts of the 2014 Joint ACTRIMS/ECTRIMS Meeting; September 10-13, 2014; Boston, Massachusetts. Abstract LB1.1. Used with permission. Effects of Ozanimod on GdE Lesions Primary Endpoint: Total Cumulative Number of GdE Lesions (Weeks 12 to 24) Secondary Endpoint: Number of GdE Lesions at Week 24 GdE: Gadolinium-enhancing Cohen J, et al. Program and abstracts of the 2014 Joint ACTRIMS/ECTRIMS Meeting; September 10-13, 2014; Boston, Massachusetts. Abstract LB1.1. Used with permission.

15 Safety: Ozanimod Adverse Safety Events (AEs) of Special Interest Likely due to S1P pharmacology (eg, fingolimod) No notable cardiac, pulmonary, ophthalmologic, infectious, or malignancy TEAEs 3 TEAEs of elevated liver enzymes ( 3x ULN) without clinical signs issues All were isolated ALT elevations, without AST or Bilirubin elevations None 5x ULN Transient elevations despite continued treatment Thorough QT Study: Therapeutic dose-titration and supratherapeutic dosing (N=62); Placebo (N=62) No effect on QTc or other CV parameters Cohen J, et al. Program and abstracts of the 2014 Joint ACTRIMS/ECTRIMS Meeting; September 10-13, 2014; Boston, Massachusetts. Abstract LB1.1. Adverse Events of Special Interest (AESI) AEs reported in fingolimod s label, most related to S1P pharmacology S1P 1R : Bradycardia (symptomatic or HR<35 bpm), first dose AV block S1P 3R : Hypertension, cardiac conduction abnormalities (QT prolongation, long-term AV conduction delays) S1P 1R : Hepatic: confirmed ALT or AST 3x ULN S1P 3R : Pulmonary function: decline in FEV 1 or FVC <50% predicted S1P 1R : Ophthalmologic: new onset or significantly worse macular edema (not explained by an alternative cause) Immunomodulation: Malignancy and infection: serious & opportunistic infections Fingolimod prescribing information. Objectives Clinical review of oral agents in late-stage development for MS therapy: Ponesimod Phase 2; OPTIMUM Ozanimod (RPC1063) RADIANCE/SUNBEAM Siponimod/BAF312 BOLD; EXPAND (MT-1303 MOMENTUM) Laquinimod CONCERTO, ARPEGGIO

16 Siponimod (BAF312): S1P1 and S1P5 Selective Modulator 1-4 Selective S1P receptor modulator Novel chemotype, highly lipophilic Peripheral and potentially CNS effects Safety and efficacy of Siponimod in RRMS patients was investigated in BOLD* study BOLD primary endpoint Met; Siponimod reduced CUAL at 3 months compared to placebo BBB, blood-brain barrier; CNS, central nervous system; EC50, half maximal effective concentration; Emax, maximum effect; MS, multiple sclerosis; S1P, sphingosine 1-phosphate; SD, standard deviation 1. Jackson SJ, et al. J Neuroinflammation. 2011;8: Gergely P, et al. Br J Pharmacol. 2012;167: Seabrook TJ, et al. Mult Scler. 2010;16:S301. Abstract P Brinkmann V. Br J Pharmacol. 2009;158:1173. BOLD: ARR Over 6 Months (Cohorts 1 and 2) a 0.8 ARR** (95% CI) % 66% 48% * 0.0 ( ) ( ) ( ) ( ) ( ) ( ) Placebo (n=45) Siponimod 0.25 mg (n=51) Siponimod 0.5 mg (n=43) Siponimod 1.25 mg (n=42) Siponimod 2 mg (n=49) Siponimod 10 mg (n=50) a Main secondary outcome; Interim extension analyses of all doses mg and 1.25 mg are post-hoc analysis. 1,2 *P<.05. **0.25 mg and 1.25 mg are post-hoc analysis. ARR, annualized relapse rate; CI, confidence interval. 1. Selmaj K, et al. Mult Scler J. 2011;17:S510. Abstract P Stuve O, et al. Neurology. 2012;78:S EXPAND: Ongoing Event-driven Phase 3 Trial Investigating Safety and Efficacy of Siponimod in SPMS 1-3 Randomized, double-blind, placebo-controlled, multicentre, event-driven Phase 3 study Screening and baseline phase Double-blind treatment phase (with a variable duration) Siponimod 2 mg/day (N ~1020) Planned extension phase Month Randomization (2:1) 6-day dose titration a,b Matching placebo (N ~510) MRI EDSS/T25W Study end Event-driven study design: Study will be stopped when the required number of patients with 3-month confirmed disability progression is observed (374 events are required) a Regimen: 0.25 mg on day 1, 0.25 mg on day 2, 0.5 mg on day 3, 0.75 mg on day 4, 1.25 mg on day 5, and 2 mg on day 6 1. Clinical Trials.gov. Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND). Available at 2. Novartis Pharma AG, data on file. Use with permission. 3. Kappos L, et al. P presented at AAN 2013.

17 EXPAND MS History and Baseline Disease Characteristics Disease Duration (1 st Sx) N Mean ± SD Disease Duration (Dx) N Mean ± SD Time since SPMS Dx (yrs) N Mean ± SD Total patient population N= ± ± ± 3.5 Kappos L, et al. P presented at AAN EXPAND MS History and Baseline Disease Characteristics Distribution of baseline EDSS scores Baseline EDSS score (N=1649) Kappos L, et al. P presented at AAN Objectives Clinical review of oral agents in late-stage development for MS therapy: Ponesimod Phase 2; OPTIMUM Ozanimod (RPC1063) RADIANCE/SUNBEAM Siponimod/BAF312 BOLD; EXPAND (MT-1303 MOMENTUM) Laquinimod CONCERTO, ARPEGGIO

18 Results of MOMENTUM, a randomized, doubleblind, placebo-controlled, Phase 2 trial with MT-1303, a novel selective sphingosine 1-phosphate receptor 1 (S1P1) modulator, in relapsing-remitting MS Ludwig Kappos, Douglas Arnold, Amit Bar-Or, John Camm, Tobias Derfuss, Bernd Kieseier, Till Sprenger, Kristin Greenough, Pingping Ni, Tomohiko Harada and the MOMENTUM Investigators kappos-pa@usb.ch Late Breaking News Presentation, Saturday, October 10, 2015 Objectives Clinical review of oral agents in late-stage development for MS therapy: Ponesimod Phase 2; OPTIMUM Ozanimod (RPC1063) RADIANCE/SUNBEAM Siponimod/BAF312 BOLD; EXPAND (MT-1303 MOMENTUM) Laquinimod CONCERTO, ARPEGGIO Laquinimod: Results From RRMS That Provide a Rationale for PPMS Study 1,2 proportion of patients experiencing 3-month CDP Placebo 25% Laquinimod 0.6 mg 22.1% 27% 20% 18.9% 15% 10% 7.6% 39% 5% 4.8% 0 Relapse-free (n=1220) Relapsing (n=770) CDP: confirmed disability progression 1. Comi G, et al. AAN 2014: P Sorman MP, et al. Neurology ;75(4): Reprinted with permission.

19 CONCERTO Design A multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study followed by an active treatment period, to evaluate the efficacy, safety, and tolerability of 2 doses of oral administration of laquinimod (0.6 or 1.2 mg/day) in subjects with relapsing remitting multiple sclerosis (RRMS). Vollmer T, et al. ECTRIMS 2013:P1054. Used with permission. Primary endpoint: 3 months confirmed disability progression Secondary endpoints: BA and time to first relapse Exploratory endpoints: Include cognitive (Symbol Digital Modalities Test), MRI, and quality of life measures ARPEGGIO Design 1:1:1 Randomization LAQ 1.5 mg/day Screening LAQ 0.6 mg/day Placebo daily 4 Week Every 12 weeks = MRI Brain and C-spine Completion visit = EDSS, T25FW, 9HPT, SDMT, MSWS = LCVA = OCT, BICAMS Part A (Core) Part B (Data Analysis) Giovannoni G, et al. AAN 2015:P Used with permission. Objectives Clinical review of oral agents in late-stage development for MS therapy: Ponesimod Phase 2; OPTIMUM Ozanimod (RPC1063) RADIANCE/SUNBEAM Siponimod/BAF312 BOLD; EXPAND (MT-1303 MOMENTUM) Laquinimod CONCERTO, ARPEGGIO

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