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

American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC

Efficacy and Safety of Sarilumab Versus Adalimumab in a Phase 3, Randomized, Double-blind, Monotherapy Study in Patients With Active Rheumatoid Arthritis With Intolerance

• r 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 Lee5

1Charité - University Hospital, Free University and Humboldt University of Berlin,

Berlin, Germany; 2Sanofi Genzyme, Bridgewater, NJ, USA;

3Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 4Quantum Research,

Puerto Varas, Chile; 5Seoul National University College of Medicine, Seoul, Republic of Korea

MONARCH Clinical Trial Identifier: NCT02332590

2 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

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Background

• 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.

• 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 demonstrated1,2

• 30% of patients with RA use biologics as monotherapy because of intolerance
• r contraindications to combination therapy3
• 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

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Key Inclusion and Exclusion Criteria

aAdequate MTX dose defined as 10-25 mg/wk, or 6-25 mg/wk for patients within the Asia-Pacific region.

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 dosea

Key exclusion criterion

• Prior biologic disease-modifying antirheumatic drug (bDMARD) experience

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Study Design

aPer investigator judgment. bIf treated with an adequate MTX dose (10-25 mg/wk, or 6-25 mg/wk for patients within Asia-Pacific region) for ≥12 weeks.

Patients (N=369)

• Active RA
• MTX intoleranta or

inadequate responseb Sarilumab 200 mg q2w plus placebo q2w (n=184) Adalimumab 40 mg q2w plus placebo q2w (n=185) Primary endpoint Change from baseline in DAS28-ESR Timeline (wk) Randomization  16 24

R

 Dose escalation to weekly adalimumab or matching placebo permitted for patients with <20% response



Double-blind, double-dummy, phase 3 superiority trial

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Primary and Secondary Efficacy Endpoints

• 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

• 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)

Hierarchy of efficacy endpointsa Additional endpoints (week 24)a

aAll endpoints were also analyzed at week 12.

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Adalimumab 40 mg q2w (n=185) Sarilumab 200 mg q2w (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 Intolerant Inappropriate for continued treatment 55.7 43.8 0.5 52.7 47.3 Concomitant oral corticosteroids, % 56.2 53.3

aPer 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.

Baseline Demographics Were Generally Balanced

8 American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC

Baseline Disease Activity Was Well Balanced

Mean Adalimumab 40 mg q2w (n=185) Sarilumab 200 mg q2w (n=184) DAS28-ESRa 6.8 6.8 DAS28-CRPa 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 scorea 42.4 43.6 ESR, mm/ha 47.5 46.5 CRP, mg/La 24.1 17.4

aHigher scores represent more severe disease. bLower scores represent more severe disease.

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Patient Disposition

369 patients randomized 185 patients assigned to adalimumab 40 mg q2w 184 patients assigned to sarilumab 200 mg q2w 156 patients completed double-blind treatment 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

165 patients completed double-blind treatment 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

16 (8.6%) patients had dose escalation (adalimumab) 8 (4.3%) patients had dose escalation (placebo)

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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 <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%).

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• 4.0
• 3.5
• 3.0
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0 4 8 12 16 20 24

DAS28-ESR

(week 24, primary endpoint)

Improvements With Sarilumab Were Observed as Early as Week 4

*P<0.0001 vs adalimumab.

†Nominal P<0.001 vs adalimumab. ‡Nominal P<0.0001 vs adalimumab.

LS mean change from baseline (SE)

• 4.0
• 3.5
• 3.0
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0 12 24

*

‡

Week

DAS28-CRP

Week

† ‡ ‡ ‡ ‡ ‡

12 American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC

7.0 14.1 26.6 42.9 5 10 15 20 25 30 35 40 45 50 <2.6 (remission) <3.2 (LDA)

More Patients Receiving Sarilumab vs Adalimumab Achieved LDA and Remission

2.7 24.9 7.1 41.8 5 10 15 20 25 30 35 40 45 50 ≤2.8 (remission) ≤10 (LDA)

DAS28-ESR (week 24) CDAI (week 24)

Patients, %

† ‡ 13 49 26 79 n 5 13 46 77 n §

*

*P<0.0001 vs adalimumab.

†Nominal P<0.05 vs adalimumab. ‡Nominal P<0.01 vs adalimumab. §Nominal P<0.0001 vs adalimumab.

13 American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC

Significantly Greater Proportions of Sarilumab- vs Adalimumab- Treated Patients Achieved ACR Responses at Week 24

*P<0.01 vs adalimumab.

58.4 29.7 11.9 71.7 45.7 23.4 10 20 30 40 50 60 70 80 90 100 ACR20 ACR50 ACR70 Patients, %

ACR responses (week 24)

108 132 n 55 84 22 43

* * *

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Significantly Greater Proportions of Sarilumab- vs Adalimumab- Treated Patients Achieved ACR20/50/70

20 40 60 80 100 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

Week

ACR20a ACR50a ACR70a

Patients, %

*

† ‡ ‡ ‡ †

*

‡ ‡ ‡

*

†

Secondary endpoint within hierarchy

*P<0.01 vs adalimumab.

†Nominal P<0.05 vs adalimumab. ‡Nominal P<0.01 vs adalimumab. aNonresponder imputation. Patients were considered nonresponders from the time they discontinued study medication.

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Sarilumab-Treated Patients Had Significantly Greater Improvements in HAQ-DI

• 0.43
• 0.61
• 1.0
• 0.5

0.0 Adalimumab 40 mg q2w Sarilumab 200 mg q2w

*

LS mean change from baseline

HAQ-DI (week 24)

*P<0.01 vs adalimumab.

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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) 0.0006 SF-36 (mental component score) 6.8 (0.8) 7.9 (0.8) 0.3319 FACIT-F 8.4 (0.7) 10.2 (0.7) 0.0689

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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) Deathsb 1 (0.5)

aOne patient was randomized but not treated in the adalimumab group and was not included in the safety population. bOne patient in the sarilumab group died of acute cardiac failure secondary to aortic dissection and papillary muscle rupture

• n day 36.

18 American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC

The Incidence of Infections Was Similar Between Groups

Most common AEs, n (%)a Adalimumab 40 mg q2w (n=184)b Sarilumab 200 mg q2w (n=184) Infections Bronchitis Nasopharyngitis Upper respiratory tract infection 51 (27.7) 7 (3.8) 14 (7.6) 7 (3.8) 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 overdosec 11 (6.0) 6 (3.3)

aOccurring in ≥3% of patients in either group. bOne patient was randomized but not treated in the adalimumab group and was not included in the safety population. cProtocol defined as ≥2 doses within 11 calendar days or within 6 days for adalimumab-treated patients who switched to

weekly dosing.

19 American College of Rheumatology Annual Meeting; November 11-16, 2016; Washington, DC

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 1 (0.5) Mastitis 1 (0.5) Arthritis, bacterial 1 (0.5) Respiratory tract infection 1 (0.5)

aOne patient was randomized but not treated in the adalimumab group and was not included in the safety population.

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Laboratory Parameters

• There was no evidence of an association between decreases in neutrophil counts and risk of

infections or serious infections

n (%) Adalimumab 40 mg q2w (n=184)a Sarilumab 200 mg q2w (n=184) Absolute neutrophil count Grade 3: ≥0.5 to <1.0 Giga/L Grade 4: <0.5 Giga/L 2 (1.1) 16 (8.7) 3 (1.6) Alanine aminotransferase >3 to 5 × ULN >5 to 10 × ULN >10 to 20 × ULN 3 (1.6) 1 (0.5) 1 (0.5) 5 (2.7) 1 (0.5) LDL cholesterol 160 to <190 mg/dL ≥190 mg/dL 12 (6.7) 6 (3.3) 21 (11.4) 8 (4.3) HDL cholesterol ≥60 mg/dL 119 (65.7) 132 (71.7)

aOne patient was randomized but not treated in the adalimumab group and was not included in the safety population.

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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

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Acknowledgments

• The authors would like to thank the patients and investigators whose

participation and contributions made this study possible