Fred D. Lublin, M.D. Corinne Goldsmith Dickinson Center for Multiple Sclerosis Icahn School of Medicine at Mount Sinai New York, NY, USA

Research Support: Acorda, Biogen Idec, Genzyme, National Institute of Health, National Multiple Sclerosis Society, Novartis, Sanofi, Teva, Transparency Life Sciences, Celgene Consultant: Actelion, Acorda, Bayer, Biogen Idec, EMD Serono, Forward-Pharma, Genentech, Genzyme, Johnson & Johnson, MedImmune, Novartis, Receptos, Revalesio, Roche, Sanofi-aventis, Questcor, Teva, to-BBB technologies, XenoPort, Abbvie, Toyama, Akros Other:Genzyme Shareholder:Cognition Pharmaceuticals Discussion of Off-Label, Investigational, or Experimental Drug Use: Disclosed

 We are making headway  Door is open to solving the problem of progressive MS  But….. The challenges

 Successful studies  ORATORIO  Biotin: 1 for 2  Simvastatin  Decent pipeline  Siponimod  Mastinib  Ibudilast  Idebenone  GZ  Progressive MS Alliance

 What to target  Inflammation  Degeneration  Who to target  Age, sex, duration of disease, activity (prior and during)  Best end-point  confirmed vs. sustained  Event rates  Duration of study

 What have we learned from prior studies?  PROMISE  OLYMPUS  INFORMS  ORATORIO  ASCEND  TRANSFORM  How should we measure outcome?  Composite scoring  EDSS  Other, ? cognition  Phase II – proof of concept studies – volume?

2013 MS disease modifiers phenotypes Progressive disease (PP, SP) Active* and with progression † Active but without progression Not active but with progression Not active and without progression (stable disease) *Activity = clinical relapses and/or MRI (Gd-enhancing MRI lesions; new/enlarging T2 lesions) † Progression measured by clinical evaluation at least annually Gd, gadolinium; MRI, magnetic resonance imaging

8 Primary Progressive - INFORMS Lublin et al. Lancet (in press) Inclusion criteria: Diagnosis of PPMS (McDonald 2005) ≥1 year of disease progression plus two of three criteria: positive brain MRI; positive spinal cord MRI; or positive CSF Age 25–65 years EDSS 3.5–6.0 pyramidal FS≥2, 25TWT <30 sec Disease duration 2 – 10 years ≥0.5 EDSS increase in prior 2 years Primary outcome: fingolimod vs placebo on delaying time to 3-mo CDP on novel composite endpoint of meeting any of 3 criteria Increase from baseline EDSS (if baseline score ≤5.0, or by 0.5 point if baseline score ≥5.5 ≥20% increase of from baseline 25-Foot-Timed-Walk Increase of ≥20% increase from baseline 9-Hole Peg Test

9 Primary Progressive - INFORMS Lublin et al. Lancet (in press) Main secondary outcome: fingolimod vs placebo on delaying time to 3-mo CDP on conventional endpoint of meeting increase from baseline EDSS (if baseline score ≤5.0, or by 0.5 point if baseline score ≥5.5)

10 Primary Progressive - INFORMS Lublin et al. Lancet (in press) Main secondary outcome: fingolimod vs placebo on percent brain volume change (PBVC) from baseline measured by SIENA

Primary Objective (Part 1): To investigate whether treatment with natalizumab slows the accumulation of disability not related to relapses in participants with SPMS. Primary endpoint Percentage of patients with CDP (confirmed at a second visit ≥6 months later and at week 96 using one or more of the assessments) – Primary composite endpoint was not met EDSS score: increased ≥ 1 point if baseline EDSS ≤5.5, or ≥0.5 point if baseline EDSS ≥6.0 T25FW: ≥20% increase from baseline in the time taken for the 25-foot walk 9HPT: ≥20% increase from baseline in the time taken for the 9HPT (increase must be confirmed in the same hand) – Significant improvement in 9HPT (only) demonstrated with natalizumab vs placebo Secondary endpoints (2-year endpoints) Percentage of participants with a T25-FW response (improvement from the best pre-dose T25-FW in at least 75% of the scheduled on-treatment visits Change in the 12-Item MS Walking Scale (MSWS-12) Change in manual ability score based on the ABILHAND Questionnaire Change in in the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical) score) Change from week 24 in whole brain volume Percentage of participants with confirmed worsening in individual EDSS Physical Functional System scores (≥ 1 point increase if baseline EDSS ≤ 5.5 or ≥ 0.5 point increase if baseline EDSS > 5.5). US Medical Affairs / Genentech Confidential — Do not copy, distribute or use without prior written consent A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With SPMS (ASCEND in SPMS) (NCT )

12 Primary Progressive - Oratorio Montalban et al. ECTRIMS (and in preparation) Primary outcome: ocrelizumab vs placebo on delaying time to 12-week CDP on conventional endpoint of meeting increase from baseline EDSS (if baseline score ≤5.0, or by 0.5 point if baseline score ≥5.5) Inclusion criteria: Diagnosis of PPMS (variant McDonald 2005) ≥1 year of disease progression plus two of three criteria: positive brain MRI; positive spinal cord MRI; AND positive CSF Age 18–55 years EDSS 3.0–6.5

MS-SPI: Study Design ■ Randomized, multicenter, double-blind, placebo-controlled study to evaluate the efficacy of oral biotin 300 mg/day in patients with SPMS or PPMS over 1 year ■ Key eligibility criteria Age 18–75 years PPMS or SPMS Evidence of disease progression in the preceding 2 years EDSS 4.5–7.0 Tourbah, et al. AAN 2015 Washington, DC.

MS-SPI: Endpoints ■ Primary endpoint: Proportion of patients who improved at month 9 and confirmed at month12, defined as decreased EDSS (by at least 1 point for EDSS ≤5.5 and.5 point for EDSS ≥6) or improved TW25 of ≥20% ■ Secondary endpoints: MS Walking Scale Clinical Global Impressions Scale (CGI) Proportion of patients with stable or worsened EDSS SF-36 Fatigue Impact Scale 9HPT Tourbah, et al. AAN 2015 Washington, DC.

MS-SPI: Baseline Characteristics All (N=154) Demographics Male, n (%)218 (49.7) Mean age, years51.4 Clinical Characteristics Primary progressive MS, %41% Mean disease duration, years16.6 EDSS score, mean Tourbah, et al. AAN 2015 Washington, DC.

MS-SPI: Efficacy ■ 13% of patients receiving MD1003 met the primary endpoint vs 0% in placebo arm; p= ■ Patients receiving MD1003 had -0.3 mean change in EDSS at 1 year vs 0.13 for placebo; p<0.014 ■ 4% of patients receiving MD1003 progressed at 1 year vs 13.6% for placebo; p< ■ No difference in TW25 ■ The proportion of responders was higher in patients with Baseline EDSS score of 4.5–5 vs 6–7; (21.4% vs 9.3%) No concomitant fampridine administration vs concomitant fampridine administration (20.7% vs 2.2%) and SPMS, compared to PPMS (14.8% vs 9.5%). Tourbah, et al. AAN 2015 Washington, DC; Tourbah et al. ECTRIMS 2015 Barcelona, Spain.

 Study underway but high dose arm (1.5 mg/day) dropped for safety

 We are making progress with progressive disease  We learn from each study  I wish I had more breaking news to report  We are developing a clearer understanding of how to more effectively approach progression