Charité - University Hospital, Free University and Humboldt University of Berlin, Berlin, Germany; 2 Sanofi Genzyme, Bridgewater, NJ, USA; 3

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1 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: NCT

2 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 2

3 Background Sarilumab is a human mab that blocks IL-6 from binding to both membranebound 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: Fleischmann et al. Arthritis Rheumatol. In press. 3. Emery et al. Ann Rheum Dis. 2013;72:

4 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 mg/wk, or 6-25 mg/wk for patients within the Asia-Pacific region. 4

5 Study Design Double-blind, double-dummy, phase 3 superiority trial Patients (N=369) Active RA MTX intolerant a or inadequate response b R Adalimumab 40 mg q2w plus placebo q2w (n=185) Sarilumab 200 mg q2w plus placebo q2w (n=184) Primary endpoint Change from baseline Randomization in DAS28-ESR Timeline (wk) 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. 5

6 Primary and Secondary Efficacy Endpoints Hierarchy of efficacy endpoints a Primary endpoint Change from baseline in DAS28-ESR at week 24 Secondary endpoints (week 24) DAS28-ESR remission (<2.6) ACR20/50/70 response Change from baseline in HAQ-DI Change from baseline in SF-36 (physical and mental components) Change from baseline in FACIT-F Additional endpoints (week 24) a Prespecified DAS28-ESR LDA (<3.2) Change from baseline in each individual ACR component Change from baseline in DAS28-CRP DAS28-CRP remission (<2.6) DAS28-CRP LDA (<3.2) Change from baseline in CDAI CDAI remission ( 2.8) Post hoc CDAI LDA (<10) a All endpoints were also analyzed at week 12. 6

7 Baseline Demographics Were Generally Balanced Adalimumab 40 mg q2w (n=185) Sarilumab 200 mg q2w (n=184) Age, mean, y Sex, female, % Race, white, % Weight, mean, kg Duration of RA, mean, y Rheumatoid factor positive, % ACPA positive, % Reason for stopping MTX, % a Inadequate responder Intolerant Inappropriate for continued treatment Concomitant oral corticosteroids, % 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

8 Baseline Disease Activity Was Well Balanced Mean Adalimumab 40 mg q2w (n=185) Sarilumab 200 mg q2w (n=184) DAS28-ESR a DAS28-CRP a Swollen joint count (66 assessed) a Tender joint count (68 assessed)a HAQ-DI score (0-3) a SF-36 physical component score (0-100) b SF-36 mental component score (0-100) b FACIT-F (0-52) b CDAI score a ESR, mm/h a CRP, mg/l a a Higher scores represent more severe disease. b Lower scores represent more severe disease. 8

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

10 Sarilumab Was Superior to Adalimumab in the Primary Endpoint DAS28-ESR at week 24 Adalimumab 40 mg q2w (n=185) Sarilumab 200 mg q2w (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 < 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%). 10

11 LS mean change from baseline (SE) Improvements With Sarilumab Were Observed as Early as Week 4 DAS28-CRP DAS28-ESR (week 24, primary endpoint) 0.0 Week Week * *P< vs adalimumab. Nominal P<0.001 vs adalimumab. Nominal P< vs adalimumab. 11

12 Patients, % More Patients Receiving Sarilumab vs Adalimumab Achieved LDA and Remission DAS28-ESR (week 24) CDAI (week 24) * <2.6 (remission) n n <3.2 (LDA) (remission) 10 (LDA) *P< vs adalimumab. Nominal P<0.05 vs adalimumab. Nominal P<0.01 vs adalimumab. Nominal P< vs adalimumab. 12

13 Patients, % Significantly Greater Proportions of Sarilumab- vs Adalimumab- Treated Patients Achieved ACR Responses at Week * 71.7 ACR responses (week 24) ACR20 ACR50 ACR n * * *P<0.01 vs adalimumab. 13

14 Patients, % Significantly Greater Proportions of Sarilumab- vs Adalimumab- Treated Patients Achieved ACR20/50/ ACR20 a ACR50 a ACR70 a * 40 * 20 * Week *P<0.01 vs adalimumab. Nominal P<0.05 vs adalimumab. Nominal P<0.01 vs adalimumab. a Nonresponder imputation. Patients were considered nonresponders from the time they discontinued study medication. Secondary endpoint within hierarchy 14

15 LS mean change from baseline Sarilumab-Treated Patients Had Significantly Greater Improvements in HAQ-DI HAQ-DI (week 24) * -1.0 Adalimumab 40 mg q2w Sarilumab 200 mg q2w *P<0.01 vs adalimumab. 15

16 Patients Receiving Sarilumab vs Adalimumab Demonstrated Improvements in PROs LS mean change from baseline (SE), week 24 Adalimumab 40 mg q2w (n=185) Sarilumab 200 mg q2w (n=184) P value SF-36 (physical component score) 6.1 (0.6) 8.7 (0.6) SF-36 (mental component score) 6.8 (0.8) 7.9 (0.8) FACIT-F 8.4 (0.7) 10.2 (0.7)

17 Incidences of AEs, SAEs, and Rates of Discontinuation Were Similar Between Groups Patients, n (%) Adalimumab 40 mg q2w (n=184) a Sarilumab 200 mg q2w (n=184) Patients with any AE 117 (63.6) 118 (64.1) Patients with any SAE 12 (6.5) 9 (4.9) Patients with any AE that led to treatment discontinuation 13 (7.1) 11 (6.0) Deaths b 0 1 (0.5) a One patient was randomized but not treated in the adalimumab group and was not included in the safety population. b One patient in the sarilumab group died of acute cardiac failure secondary to aortic dissection and papillary muscle rupture on day

18 The Incidence of Infections Was Similar Between Groups Most common AEs, n (%) a Infections Bronchitis Nasopharyngitis Upper respiratory tract infection Adalimumab 40 mg q2w (n=184) b 51 (27.7) 7 (3.8) 14 (7.6) 7 (3.8) Sarilumab 200 mg q2w (n=184) 53 (28.8) 12 (6.5) 11 (6.0) 3 (1.6) Neutropenia 1 (0.5) 25 (13.6) Headache 12 (6.5) 7 (3.8) Rheumatoid arthritis 7 (3.8) 1 (0.5) Injection site erythema 6 (3.3) 14 (7.6) Alanine aminotransferase increased 7 (3.8) 7 (3.8) Accidental overdose c 11 (6.0) 6 (3.3) a Occurring in 3% of patients in either group. b One patient was randomized but not treated in the adalimumab group and was not included in the safety population. c Protocol defined as 2 doses within 11 calendar days or within 6 days for adalimumab-treated patients who switched to weekly dosing. 18

19 Two Patients in Each Group Experienced a Serious Infection n (%) Adalimumab 40 mg q2w (n=184) a Sarilumab 200 mg q2w (n=184) Patients with 1 serious infection 2 (1.1) 2 (1.1) Bursitis, infective 0 1 (0.5) Mastitis 0 1 (0.5) Arthritis, bacterial 1 (0.5) 0 Respiratory tract infection 1 (0.5) 0 a One patient was randomized but not treated in the adalimumab group and was not included in the safety population. 19

20 Laboratory Parameters n (%) Absolute neutrophil count Grade 3: 0.5 to <1.0 Giga/L Grade 4: <0.5 Giga/L Alanine aminotransferase >3 to 5 ULN >5 to 10 ULN >10 to 20 ULN LDL cholesterol 160 to <190 mg/dl 190 mg/dl Adalimumab 40 mg q2w (n=184) a 2 (1.1) 0 3 (1.6) 1 (0.5) 1 (0.5) 12 (6.7) 6 (3.3) Sarilumab 200 mg q2w (n=184) 16 (8.7) 3 (1.6) 5 (2.7) 1 (0.5) 0 21 (11.4) 8 (4.3) HDL cholesterol 60 mg/dl 119 (65.7) 132 (71.7) a One patient was randomized but not treated in the adalimumab group and was not included in the safety population. There was no evidence of an association between decreases in neutrophil counts and risk of infections or serious infections 20

21 Conclusions In patients with active RA who were either intolerant of, or inadequate responders to, MTX, sarilumab monotherapy demonstrated superiority to adalimumab monotherapy in Reduction of disease activity Improvement in signs and symptoms of RA Improvement in physical function The overall incidences of AEs and SAEs were similar between groups, as was the rate of infections and serious infections 21

22 Acknowledgments The authors would like to thank the patients and investigators whose participation and contributions made this study possible 22