Efficacy and Safety of Ponesimod Compared to Teriflunomide in Patients with Relapsing Multiple Sclerosis: Results of the Randomi

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Efficacy and Safety of Ponesimod Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis: Results of the Randomized, Active-Controlled, Double-Blind, Parallel-Group Phase 3 OPTIMUM Study

L. Kappos1, M. Burcklen2, M. S Freedman3, R. Fox4, E.K. Havrdová5, B. Hennessy2, R. Hohlfeld6, F. Lublin7, X. Montalban8,9, C. Pozzilli10, T. Scherz2, P. Linscheid2, M. Pirozek-Lawniczek2, H. Kracker2, T. Sprenger11,12

1Departments of Medicine, Neurologic Clinical Research and Biomedical Engineering, University Hospital Basel, Basel, 2Actelion Pharmaceuticals, Allschwil, Switzerland, 3University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4Cleveland Clinic, Cleveland, OH, United States, 5Department of Neurology and Center for Clinical Neuroscience, Medical Faculty, Charles University, Prague, Czech Republic, 6Institute of Clinical Neuroimmunology, Munich, Germany, 7Icahn School of Medicine at Mount Sinai, New York, NY, United States, 8Division of Neurology, Toronto, BC, Canada, 9Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Barcelona, Spain, 10S. Andrea MS Centre, Rome, Italy, 11University Hospital Basel, Basel, Switzerland, 12DKD HELIOS Klinik Wiesbaden, Wiesbaden, Germany

Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseb y%3D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. 1 FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE SGUSMA.MS.19.09.0584b 10/19 Ponesimod

Role of S1P/S1P1 in T-cell trafficking in ● Orally active, selective, second immune system1 generation, rapidly reversible modulator of the sphingosine-1- phosphate receptor 1 (S1P1) ● Causes dose-dependent sequestration of lymphocytes in lymphoid organs leading to decrease of blood lymphocyte count2,3 ● Highly selective for S1P1, with no relevant effect on other S1P receptors3,4

1. Pyne NJ et al. Molecules. 2017;22:pii:E344.doi:10.3390/molecules22030344. 2. Olsson T et al. Neurol Neurosurg Psychiatry. 2014;85:1198–1208. 3. D’Ambrosio D et al. Ther Adv Chronic Dis. 2016;7:18–33. 4. Chun J et al. Pharmacol Rev. 2010;62:579–87. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 2 Ponesimod: Key Features

● Ponesimod is eliminated within 1 week of stopping treatment1,2

● Short t1/2 and lack of active metabolites allows rapid reversibility ● No active metabolites and low potential for drug-drug interactions ● Effects on the immune system are quickly reversible

● Lymphocytes are not destroyed and innate immunity is preserved

● Can be important in certain clinical situations, e.g. infections, vaccinations, DMT sequencing1 ● Functional preservation of specific T-cell and B cell subsets during ponesimod therapy

● Allows continued immune surveillance despite reduced circulating lymphocyte levels3 ● Gradual up-titration of ponesimod mitigates first-dose effects4

DMT, disease-modifying therapy. 1. D’Ambrosio D et al. Ther Adv Chronic Dis 2016;7(1):18-33; 2. Lott et al. Eur J Pharmaceut Sci 2016;89:83-93; 3. Jurcevic S et al. Drug Des Devel Ther 2017;11:123-131; 4. Hoch M et al. EACPT 2015 Poster no. 341.00. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 3 OPTIMUM: Study Design

Multicenter, randomized, double-blind, parallel-group, active controlled, superiority study

Population • Patients with RMS aged 18 to 55 years • Active disease 24 months prior to screening • Ambulatory patients with an EDSS score of 0 to 5.5 Primary Endpoint • Annualized relapse rate (confirmed relapses) Secondary Endpoint • Change from baseline to Week 108 in fatigue-related symptoms as measured by the symptom domain of the FSIQ-RMS • Mean number of combined UAL per year (defined as new GD+ T1 lesions plus new or enlarging T2 lesions) • Time to 12- and 24-week confirmed disability accumulation

Accelerated Up-titration elimination procedure

Ponesimod 20 mg – 550 patients Ponesimod 20 mg Teriflunomide 14 mg – 550 patients Mock-up titration

Screening Treatment period Follow-up Long –term extension Max. 45 days 108 weeks transition AC-058B303 Up to 240 Weeks

EDSS=Expanded Disability Status Scale; FSIQ-RMS=fatigue symptoms and impacts questionnaire-relapsing MS; Gd+=gadolinium enhancing. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 4 OPTIMUM: Study Design

Overall testing strategy

α ARR Primary H1

Secondary 1/3 1/3 1/3

1 1 1 H2 H3 H4 H5

Fatigue CUALs 12-week 24-week CDA CDA

● Primary endpoint tested at two-sided alpha of 1% to show conclusive evidence of efficacy ● Overall testing strategy across primary and secondary endpoints at two-sided alpha of 5%, multiplicity adjustment as shown above

ARR, annualized relapse rate; CDA, confirmed disability accumulation; CUALs, cumulative number of combined unique active lesions. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 5 OPTIMUM: Demographics

Full Analysis Set Ponesimod 20 mg Teriflunomide 14 mg Mean (SD) unless otherwise noted N=567 N=566 Female, n (%) 363 (64.0%) 372 (65.7%) Age, years, 36.7 (8.74) 36.8 (8.74) Race, White, n (%) 551 (97.2%) 553 (97.7%) Geographical region, n (%) EU and UK 289 (51.0%) 284 (50.2%) Europe (non-EU) and Russia 233 (41.1%) 239 (42.2%) North America 32 (5.6%) 24 (4.2%) Rest of World 13 (2.3%) 19 (3.4%)

EU=Europe; UK=United Kingdom. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 6 OPTIMUM: Baseline Characteristics

Full Analysis Set Ponesimod 20 mg Teriflunomide 14 mg Mean (SD) unless otherwise noted N=567 N=566 Baseline EDSS (strata), >3.5 n (%) 94 (16.6%) 95 (16.8%) DMT w/in 2 years of randomization (strata), yes, n (%) 224 (39.5%) 223 (39.4%) Baseline EDSS score 2.57 (1.17) 2.56 (1.23) Time since first symptom at randomization, years 7.63 (6.78) 7.65 (6.78) No. relapses in last year prior to study entry 1.2 (0.61) 1.3 (0.65) Fatigue symptom scorea at baseline 31.9 (20.4) 32.8 (19.1) Presence of Gd+ T1 lesionsb at baseline, yes, n (%) 226 (39.9) 256 (45.4)

abased on FSIQ-RMS; bfrom the central reader. DMT=disease modifying therapy; EDSS=Expanded Disability Status Scale; EU=Europe; FSIQ-RMS=fatigue symptoms and impacts questionnaire=relapsing MS; Gd+=gadolinium enhancing; UK=United Kingdom. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 7 OPTIMUM: Patient Disposition Screened (N=1468)

Randomized (n=1133)

Ponesimod 20 mg (n=567) Teriflunomide 14 mg (n=566)

Treated (n=565) Treated (n=566)

Treatment discontinuation (n=94) Treatment discontinuation (n=93) • AE/tolerability-related (n=37) • AE/tolerability-related (n=14) • Other (n=26) • Other (n=30) • Prespecified d/c criteriaa (n=12) • Prespecified d/c criteria (n=16) • Efficacy-related (n=11) • Efficacy-related (n=24) • Unknown reason (n=6) • Unknown reason (n=4) • Lost to follow up (n=1) • Lost to follow up (n=3) • Death (n=2)

Treatment completed Treatment completed (n=471 [83.1%]) (n=473 [83.6%])

Overall, treatment discontinuations were similar with 16.6% on ponesimod and 16.4% on teriflunomide

aNo patient discontinued due to first dose cardiac effects. Discontinuation in ponesimod due to prespecified criteria: macular edema, pregnancy, lymphopenia, malignancy. AE=adverse event; d/c=discontinuation. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 8 Primary Efficacy Endpoint OPTIMUM: Annualized Relapse Rate (ARR)

Confirmed Relapses Up to End of Study (EOS, Full Analysis Set)

Rate Ratio vs teriflunomide 14 mg: 0.695 (99% CL: 0.536, 0.902) 0.4

% Difference: 30.5% 0.3 P=0.0003

0.2

Mean ARR ARR Mean (99% CL) 0.1 ARR=0.202 ARR=0.290

0 Ponesimod 20 mg Teriflunomide 14 mg (N=567) (N=566) ● Ponesimod significantly reduced ARR up to EOS by 30.5% compared to teriflunomide (P=0.0003)

CL=confidence limits, based on negative binomial regression adjusted by EDSS strata, DMT in 2 years prior to randomization strata, number of relapses in year prior to study entry; DMT=disease modifying therapy.Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 9 OPTIMUM: Primary Endpoint Supplementary Analysis

Rate Ratio and 99% Cl

Ponesimod 20mg vs. 0.5 0.75 1 1.25 1.75 Rate Teriflunomide 14 mg 99% Cl n(Pon) rate(Pon)n(Ter) rate(Ter) Ratio

Confirmed relapses up to EOS 0.695 (0.536,0.902) 567 0.202 566 0.290

Confirmed relapses up to EOT +7 0.689 (0.527,0.901) 567 0.206 566 0.299

Confirmed relapses per protocola 0.696 (0.530,0.913) 557 0.205 559 0.294

All relapses up to EOS 0.700 (0.546,0.897) 567 0.232 566 0.332

Confirmed relapses up to start of DMT 0.785 (0.527,0.892) 567 0.202 566 0.295

0.679 (0.525,0.879) 567 0.202 566 0.304 Confirmed relapses (imputedb) up to EOS Favors Ponesimod Favors Teriflunomide

0.5 0.75 1 1.25 1.75

● ARR endpoint results were robust in favor of ponesimod and consistent with the primary analysis in terms of effect size

ARR= Annualized Relapse Rate; Cl= Confidence interval (Wald); Based on negative binomial regression. aPer Protocol Set; bRelapses with missing EDSS are imputed as confirmed relapses; n (Pon) and n (Ter) = # of subjects in Ponesimod 20mg and Teriflunomide 14mg, respectively; Rate (Pon) and rate (Ter) = mean ARRs estimate in Ponesimod 20mg and Teriflunomide 14mg, respectively; Rate ratio = treatment effect, i.e. ARR of Ponesimod 20mg relative to that of teriflunomide 14mg.Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 10 Secondary Endpoint OPTIMUM: Fatigue-related Symptoms Symptom Domain of FSIQ-RMS: Change From Baseline to Week 108

6 5 Ponesimod 20 mg Teriflunomide 14 mg 4 3 2 1 0 -1 -2 -3 -4 -5 P=0.2512 P=0.2130 P=0.0056 P=0.0092 P =0.0019

Week 12 Week 24 Week 60 Week 84 Week 108 LS Mean Baseline Mean LS Change fromCL) (95% No. Subjects

Ponesimod 20 mg (N=567) 412 417 409 386 344 Teriflunomide 14 mg (N=566) 421 422 417 389 328

● Ponesimod is superior to teriflunomide on fatigue at Week 108 as measured by FSIQ-RMS weekly symptom score (mean difference: –3.57, P=0.0019)

FSIQ-RMS=fatigue symptoms and impacts questionnaire-relapsing MS; N=subjects in analysis set. P=value for Wald test on mean difference between treatment arms. A negative change from baseline indicates an improvement in fatigue symptoms. FSIQ-RMS is based on the Mixed effect Model Repeat Measures (MMRM) analysis with unstructured covariance, treatment, visit, treatment by visit interaction, baseline by visit interaction as fixed effects, baseline EDSS score, EDSS strata (≤3.5, >3.5), DMT in last 2 years prior randomization strata (Y/N) as covariates. Least square (LS) means and 95% CLs are displayed. Includes subjects with baseline and at least one post baseline assessment. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 11 Secondary Endpoint OPTIMUM: Combined Unique Active Lesions (New Gd+ T1 Lesions Plus New or Enlarging T1 Lesions)

CUALs: Sum of Lesions/Year on MRI Scans up to Week 108 (FAS)

4 % Difference: 56.0% P<0.0001 3

1 3.164 CUALs per Year (95% CL) Year perCUALs 1.405 0 Ponesimod 20 mg Teriflunomide 14 mg (N=539) (N=536) ● Ponesimod reduced the number of new inflammatory lesions on brain MRI by 56% compared to teriflunomide (P<0.0001) Missing data: 28 and 30 subjects in the ponesimod 20 mg and teriflunomide 14 mg arms, respectively, had a missing baseline and/or post-baseline MRI. CUAL- Combined Unique Active Lesions, defined as new Gd+ T1 lesions plus new or enlarging T2 lesions without double counting; CL=confidence limit (available α=0.0333). Based on negative binomial regression adjusted by EDSS strata, DMT strata, presence of T2 Gd+ lesion. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 12 Secondary Endpoint OPTIMUM: Confirmed Disability Accumulation

Time to 12-Week Confirmed Disability Time to 24-Week Confirmed Disability Accumulation (Full Analysis Set) Accumulation (Full Analysis Set)

Ponesimod 20mg Teriflunomide 14mg

20 Risk Reduction vs. teriflunomide 14mg 20 Risk Reduction vs. teriflunomide 14mg 17% (95% Cl: – 18%; 42%) 16% (95% Cl: – 24%; 43%) p=0.2939(*) p=0.3720(**) 15 15 13.2% Meier) % Meier) % 10.8% 10.5% - - 10 10 8.7% (Kaplan (Kaplan

5 Patients with event 5 Patients with event

0 0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Weeks from randomization Weeks from randomization Number at Risk Number at Risk Ponesimod 20mg 547 525 547 543 492 460 403 458 467 225 Ponesimod 20mg 567 534 529 506 437 426 425 464 452 328

Teriflunomide 14mg 566 548 528 523 493 485 467 460 429 290 Teriflunomide 14mg 566 549 530 507 495 438 475 468 406 297

Non-significant result. Formal testing procedure stopped. Stratified log-rank test p-value Exploratory, not formally tested. Stratified log-rank test p-value and stratified and stratified Cox regression risk reduction estimate displayed. Cox regression risk reduction estimates displayed. ● 12- and 24-week confirmed disability risk estimates were 17% and 16% lower for ponesimod compared to teriflunomide – not statistically significant Analyses stratified by EDSS strata and DMTs in 2 years prior to randomization strata. CL=confidence limit; Event=12/24 week confirmed disability accumulation up to end of study; Unstratified Kaplan-Meier estimate at Week 108. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 13 OPTIMUM: Safety and Tolerability Overview

Overview of Treatment Emergent AEs (TEAEs)

Safety Set Ponesimod 20 mg Teriflunomide 14 mg N=565 N=566 n % n %

TEAEs 502 88.8 499 88.2

SAEs 49 8.7 46 8.1

TEAEs leading to discontinuation 49 8.7 34 6.0

Fatal TEAEs 0 2* 0.4

● Overall, proportion of patients experiencing at least one TEAE or SAE was similar across treatment groups

aOne death due to coronary artery insufficiency and one death due to multiple sclerosis. SAE, serious adverse event; TEAE, treatment-emergent adverse events. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 14 OPTIMUM: TEAEs Leading to Premature Discontinuation Safety Set by SOC termsa Ponesimod 20 mg Teriflunomide 14 mg N=565 N=566 n % n %

Patient with ≥1 TEAE leading to discontinuation 49 8.7 34 6.0 Investigations 12 2.1 10 1.8 Respiratory, thoracic and mediastinal disorders 7 1.2 0 Eye disorders 5 0.9 0 Gastrointestinal disorders 4 0.7 4 0.7 Blood and lymphatic system disorders 3 0.5 2 0.4 General disorders and administration site conditions 3 0.5 2 0.4 Hepatobiliary disorders 3 0.5 2 0.4 Pregnancy, puerperium and perinatal conditions 3 0.5 3 0.5 Vascular disorders 3 0.5 0 Nervous system disorders 2 0.4 4 0.7 Social circumstances 2 0.4 1 0.2 Cardiac disorders 1 0.2 2 0.4 Skin and subcutaneous tissue disorders 1 0.2 2 0.4

On Day 1, only 1 patient discontinued (dyspnea with ponesimod 2 mg); there were no cardiac-related AEs leading to discontinuation on Day 1. aonly SOCs with at least 2 events in at least one treatment arm are displayed. TEAE, treatment-emergent adverse events. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 15 OPTIMUM: Summary of TEAEs of Special Interest

Safety Set Ponesimod 20 mg Teriflunomide 14 mg N=565 N=566 n % n %

Hepatobiliary disorders / liver test abnormality to EOT + 1 day 128 22.7 69 12.2

With at least one serious event 2 0.4 4 0.7

Hypertension 57 10.1 51 9.0 Pulmonary events 45 8.0 15 2.7 Effect of HR and rhythm + hypotension on Day 1 12 2.1 2 0.4

Herpetic infection 27 4.8 27 4.8

Infection 9 1.6 5 0.9 Seizure 8 1.4 1 0.2

Macular edema 6 1.1 1 0.2

Skin malignancy 5a 0.9 1b 0.2 Non-skin malignancy 1 0.2 1 0.2

● Most common AEs of special interest were in the category of hepatobiliary disorders/liver enzyme abnormality, followed by category hypertension and pulmonary events

Unless otherwise stated AEs are summarized up to EOT + 15 days. MeDRA version 21.0. a2 basal cell carcinomas, 2 excision of pre-existing benign lesions (nevus) and 1 malignant melanoma. b1 basal cell carcinoma. AE, adverse events; EOT, end of treatment; HR, heart rate. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 16 OPTIMUM: Summary of Liver Test Abnormalities (Up to End of Treatment + 1 Day)

Elevation Ponesimod 20 mg Teriflunomide 14 mg n/N, % N=565 N=566 ALT≥ 3 x ULN 97/560 17.3% 47/564 8.3% ALT≥ 5 x ULN 26/560 4.6% 14/564 2.5% ALT≥ 8 x ULN 4/560 0.7% 12/564 2.1% ALT≥ 10 x ULN 3/560 0.5% 10/564 1.8% ALT≥ 20 x ULN 0/560 — 2/564 0.4% TBIL ≥ 2 x ULN 8/560 1.4% 2/564 0.4% ALT or AST ≥ 3 x ULN + TBIL ≥ 2 x ULN 1a/560 0.2 0/564 —

● Most ALT increases ≥3 x ULN were single transient asymptomatic episode that resolved on treatment or after protocol mandated discontinuation

● Rate of ALT increase ≥8 x ULN was lower in the ponesimod group versus teriflunomide

aPatient with pre-existing ALT elevation (>5X ULN) and resolved after discontinuation. ALT ULN: 44 U/L (male) and 33 U/L (female). AST ULN 39 U/L (male) and 34 U/L (female). Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 17 OPTIMUM: Treatment-emergent AE of Special Interest: Effect on Heart Rate and Rhythm on Day 1a

Safety Set Ponesimod 20 mg Teriflunomide 14 mg n, % N=565 N=566 Incidence 12 (2.1%) 2 (0.4%) Bradycardia 4 (0.7%) — Atrioventricular block first degree 3 (0.5%) — Intraventricular conduction delay 2 (0.4%) — Bundle branch block left 1 (0.2%) — Bundle branch block right 1 (0.2%) — Sinus arrhythmia 1 (0.2%) — Sinus bradycardia 1 (0.2%) — ECG QT prolonged — 1 (0.2%) Presyncope — 1 (0.2%)

● Events were neither serious or led to permanent treatment discontinuation

aIncludes hypotension; patients received ponesimod 2 mg on Day 1; MedDRA version 21.0. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 18 OPTIMUM: Conclusions

● OPTIMUM is the first controlled study with oral ponesimod demonstrating superior efficacy over an approved oral DMT ● Robust statistically significant effects shown on ARR (primary) and key secondary outcomes: fatigue and inflammatory lesions on MRI ● First study to implement a validated disease-specific fatigue measure (PRO) as a prespecified endpoint which showed statistically significant fatigue reduction over an active comparator ● Effect on time to 12/24-week CDA was not found to be significantly different for ponesimod as compared with teriflunomide ● Ponesimod is a selective S1P receptor modulator with rapidly reversable PK profile and low DDI potential ● Safety results consistent with previous observations in phase II and with other S1P functional antagonists ARR, annualized relapse rate; CDA, confirmed disability accumulation; DDI, drug-drug interactions; DMT, disease-modifying therapy; MRI, magnetic resonance imaging; PK, pharmacokinetic; PO, patient-reported outcomes. Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 19 OPTIMUM: Acknowledgements

● Investigators and all study site staff

● Patients and their families, caregivers and supporters

Kappos L et al. ECTRIMS 2019;279416;93. Available at: https://onlinelibrary.ectrims- congress.eu/ectrims/2019/stockholm/279416/ludwig.kappos.efficacy.and.safety.of.ponesimod.compared.to.teriflunomide.in.html?f=listing%3D0%2Abrowseby%3 D8%2Asortby%3D1%2Asearch%3Doptimum. Accessed Oct 7, 2019. FOR SANOFI GENZYME PAYOR ADVISORY BOARD USE ONLY – DO NOT COPY OR DISTRIBUTE 20 SGUSMA.MS.19.09.0584b 10/19