Efficacy and Safety of Sarilumab Versus Adalimumab in a Phase 3, - PowerPoint PPT Presentation

Efficacy and Safety of Sarilumab Versus Adalimumab in a Phase 3, Randomized, Double-blind, Monotherapy Study in Patients With Active Rheumatoid Arthritis With Intolerance or Inadequate Response to Methotrexate Gerd R. Burmester, 1 Yong Lin, 2 Rahul Patel, 2 Janet van Adelsberg, 3 Erin K. Mangan, 3 Hubert van Hoogstraten, 2 Deborah Bauer, 2 Juan Ignacio Vargas, 4 Eun Bong Lee 5 1 Charité - University Hospital, Free University and Humboldt University of Berlin, Berlin, Germany; 2 Sanofi Genzyme, Bridgewater, NJ, USA; 3 Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 4 Quantum Research, Puerto Varas, Chile; 5 Seoul National University College of Medicine, Seoul, Republic of Korea MONARCH Clinical Trial Identifier: NCT02332590 American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC

Disclosures • Gerd R. Burmester has received research grants or consulting fees from AbbVie, Bristol-Myers Squibb, MedImmune, Merck, Pfizer, Roche, and UCB and has participated in speakers’ bureaus for AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and UCB • Eun Bong Lee has acted as a consultant to Pfizer • Juan Ignacio Vargas has received speaker fees from Roche, Bristol-Myers Squibb, and Pfizer and has participated in speakers’ bureaus for Bristol -Myers Squibb • Yong Lin, Rahul Patel, Hubert van Hoogstraten, and Deborah Bauer are employees of Sanofi Genzyme and may hold stock and/or stock options in the company • Janet van Adelsberg and Erin K. Mangan are employees of Regeneron Pharmaceuticals, Inc, and may hold stock and/or stock options in the company • This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc • Presentation development support was provided by Gretchen Chidester, PhD, MedThink SciCom, and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 2

Background • Sarilumab is a human mAb that blocks IL-6 from binding to both membrane- bound and soluble IL- 6Rα – Efficacy and safety of sarilumab plus conventional synthetic DMARDs (eg, methotrexate [MTX]) have previously been demonstrated 1,2 • 30% of patients with RA use biologics as monotherapy because of intolerance or contraindications to combination therapy 3 • In the phase 3 MONARCH trial, safety and efficacy of sarilumab monotherapy were compared with adalimumab monotherapy in adult patients with active RA who should not continue treatment with MTX due to intolerance or inadequate response 1. Genovese et al. Arthritis Rheumatol. 2015;67:1424-1437. 2. Fleischmann et al. Arthritis Rheumatol. In press. 3. Emery et al. Ann Rheum Dis. 2013;72:1897-1904. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 3

Key Inclusion and Exclusion Criteria Inclusion criteria • Diagnosis of RA for ≥3 months – Defined by ACR/EULAR criteria • Active disease – Defined as ≥6 out of 66 swollen joints and ≥8 out of 68 tender joints • hs- CRP ≥8 mg/L or ESR ≥28 mm/h • DAS28-ESR >5.1 – Assessed between screening and randomization • Per investigator judgment – Intolerant of OR – Considered inappropriate candidates for continued treatment with MTX OR – Inadequate responders if treated with an adequate MTX dose a Key exclusion criterion • Prior biologic disease-modifying antirheumatic drug (bDMARD) experience a Adequate MTX dose defined as 10-25 mg/wk, or 6-25 mg/wk for patients within the Asia-Pacific region. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 4

Study Design Double-blind, double-dummy, phase 3 superiority trial Adalimumab 40 mg q2w plus placebo q2w (n=185) Patients (N=369) • Active RA R • Sarilumab 200 mg q2w MTX intolerant a or plus placebo q2w (n=184) inadequate response b Primary endpoint Change from baseline in DAS28-ESR Randomization   Timeline (wk) 0 16 24  Dose escalation to weekly adalimumab or matching placebo permitted for patients with <20% response a Per investigator judgment. b If treated with an adequate MTX dose (10-25 mg/wk, or 6-25 mg/wk for patients within Asia- Pacific region) for ≥12 weeks. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 5

Primary and Secondary Efficacy Endpoints Hierarchy of efficacy endpoints a Additional endpoints (week 24) a • Prespecified • Primary endpoint – DAS28-ESR LDA (<3.2) – Change from baseline in DAS28-ESR – Change from baseline in each at week 24 individual ACR component • Secondary endpoints (week 24) – Change from baseline in DAS28-CRP – DAS28-ESR remission (<2.6) – DAS28-CRP remission (<2.6) – ACR20/50/70 response – DAS28-CRP LDA (<3.2) – Change from baseline in HAQ-DI – Change from baseline in CDAI – Change from baseline in SF-36 – CDAI remission (≤2.8) (physical and mental components) • Post hoc – Change from baseline in FACIT-F – CDAI LDA (<10) a All endpoints were also analyzed at week 12. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 6

Baseline Demographics Were Generally Balanced Adalimumab Sarilumab 40 mg q2w 200 mg q2w (n=185) (n=184) Age, mean, y 53.6 50.9 Sex, female, % 81.1 85.3 Race, white, % 88.6 92.9 Weight, mean, kg 71.8 72.3 Duration of RA, mean, y 6.6 8.1 Rheumatoid factor positive, % 64.8 66.9 ACPA positive, % 76.7 75.3 Reason for stopping MTX, % a Inadequate responder 55.7 52.7 Intolerant 43.8 47.3 Inappropriate for continued treatment 0.5 0 Concomitant oral corticosteroids, % 56.2 53.3 a Per investigator judgment, either intolerant of or considered inappropriate candidates for continued treatment with MTX, or inadequate responders if treated with an adequate MTX dose (10-25 mg/wk, or 6-25 mg/wk for patients within Asia- Pacific region) for ≥12 weeks. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 7

Baseline Disease Activity Was Well Balanced Adalimumab Sarilumab 40 mg q2w 200 mg q2w Mean (n=185) (n=184) DAS28-ESR a 6.8 6.8 DAS28-CRP a 6.0 6.0 Swollen joint count (66 assessed) a 17.5 18.6 Tender joint count (68 assessed)a 26.7 28.0 HAQ-DI score (0-3) a 1.6 1.6 SF-36 physical component score (0-100) b 31.5 30.8 SF-36 mental component score (0-100) b 36.9 36.4 FACIT-F (0-52) b 24.4 23.6 CDAI score a 42.4 43.6 ESR, mm/h a 47.5 46.5 CRP, mg/L a 24.1 17.4 a Higher scores represent more severe disease. b Lower scores represent more severe disease. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 8

Patient Disposition 369 patients randomized 185 patients assigned to adalimumab 184 patients assigned to sarilumab 40 mg q2w 200 mg q2w 28 (15.1%) patients discontinued 19 (10.3%) patients discontinued • 15 (8.1%) adverse events • 11 (6.0%) adverse events • 4 (2.2%) lack of efficacy • 2 (1.1%) lack of efficacy • 3 (1.6%) poor compliance • 1 (0.5%) poor compliance • 6 (3.2%) other • 5 (2.7%) other 8 (4.3%) patients had dose escalation 16 (8.6%) patients had dose escalation (placebo) (adalimumab) 156 patients completed 165 patients completed double-blind treatment double-blind treatment American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 9

Sarilumab Was Superior to Adalimumab in the Primary Endpoint Adalimumab Sarilumab 40 mg q2w 200 mg q2w DAS28-ESR at week 24 (n=185) (n=184) Change from baseline, mean (SD) -2.2 (1.4) -3.4 (1.4) LS mean (SE) -2.2 (0.11) -3.3 (0.1) LS mean difference (95% CI) -1.1 (-1.4, -0.8) P value vs adalimumab <0.0001 LS, least squares. After week 16, dose escalation to weekly administration of adalimumab or matching placebo was permitted for patients who did not achieve ≥20% improvement in tender and swollen joint counts. These patients were included in the primary analysis. The actual number of patients who received a dose-escalation kit on the basis of meeting protocol criteria was adalimumab, 6 (3.2%) and sarilumab (blinded so dose remained the same), 5 (2.7%). American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 10

Improvements With Sarilumab Were Observed as Early as Week 4 DAS28-CRP DAS28-ESR (week 24, primary endpoint) Week Week 0 4 8 12 16 20 24 0 12 24 LS mean change from baseline (SE) 0.0 0.0 -0.5 -0.5 -1.0 -1.0 -1.5 -1.5 † -2.0 -2.0 ‡ -2.5 -2.5 ‡ ‡ -3.0 -3.0 ‡ ‡ ‡ -3.5 -3.5 * -4.0 -4.0 * P <0.0001 vs adalimumab. † Nominal P <0.001 vs adalimumab. ‡ Nominal P <0.0001 vs adalimumab. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 11

More Patients Receiving Sarilumab vs Adalimumab Achieved LDA and Remission 50 50 CDAI DAS28-ESR § ‡ (week 24) (week 24) 45 45 42.9 41.8 40 40 35 35 Patients, % * 30 30 26.6 24.9 25 25 20 20 14.1 15 15 † 10 10 7.1 7.0 5 5 2.7 13 49 26 79 n 5 13 46 77 n 0 0 ≤2.8 ≤10 <2.6 <3.2 (remission) (LDA) (remission) (LDA) * P <0.0001 vs adalimumab. † Nominal P <0.05 vs adalimumab. ‡ Nominal P <0.01 vs adalimumab. § Nominal P <0.0001 vs adalimumab. American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC 12