Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study

Abstract

Objectives: Interleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study (ClinicalTrials.gov identifier NCT01604343) evaluated the efficacy and safety of sirukumab in patients with active RA refractory to disease-modifying antirheumatic drugs.

Methods: Patients were randomised 1:1:1 to treatment with sirukumab 100 mg every 2 weeks, 50 mg every 4 weeks or placebo every 2 weeks subcutaneously. Results through week 52 are reported.

Results: Of 1670 randomised patients, significantly more patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with sirukumab 100 mg every 2 weeks (53.5%) or 50 mg every 4 weeks (54.8%) versus placebo (26.4%; both p<0.001). Mean (SD) change from baseline in modified Sharp/van der Heijde score at week 52 (coprimary endpoint) was significantly lower with sirukumab (100 mg every 2 weeks: 0.46 (3.26); 50 mg every 4 weeks: 0.50 (2.96)) versus placebo (3.69 (9.25); both p<0.001). All major secondary endpoints (week 24 Health Assessment Questionnaire-Disability Index change from baseline, ACR50 response, 28-joint Disease Activity Score based on C reactive protein and major clinical response (ACR70 for six continuous months by week 52)) were met. The most common adverse events with sirukumab were elevated liver enzymes, upper respiratory tract infection, injection site erythema and nasopharyngitis.

Conclusions: Sirukumab 100 mg every 2 weeks and 50 mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile.

Trial registration number: NCT01604343; Results.

Keywords: DMARDs (biologic); DMARDs (synthetic); cytokines; rheumatoid arthritis; treatment.

Conflict of interest statement

Competing interests: TT: grant/research support from Astellas Pharma, Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd. and SymBio Pharmaceuticals Ltd; consultant for AstraZeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol-Myers K.K. and Nipponkayaku Co. Ltd.; speakers bureau for AbbVie GK, Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Astellas Pharma, Daiichi Sankyo Co., Ltd., Celtrion and Nipponkayaku Co. Ltd. CT: grant/research support from Celgene, Novartis and Pfizer; advisory board and consultant for AbbVie, Amgen, Celgene, Hospira, Lilly, Novartis and Pfizer; steering committee for Janssen/Centocor/Johnson & Johnson. GK: grant/research support from Pfizer; consultant for Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Pfizer, Regeneron, Roche and Sanofi; speakers bureau for Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Pfizer, Regeneron, Roche and Sanofi. SS, WX, KF and BH: employees and shareholders of Janssen Research & Development, LLC. RR and PPT: employees and shareholders of GlaxoSmithKline.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Patient disposition through week 52. EE, early escape; LE, late escape; q2w, every 2 weeks; q4w, every 4 weeks. aIncludes placebo patients who escaped (EE/LE) to sirukumab 50 mg q4w or 100 mg q2w.

Figure 2

(A) Proportions of patients with an ACR20 response at week 16a and ACR20 response over time.b,c,d (B) Change from baseline in SHS results at weeks 24 and 52.e (C) Proportions of patients with no radiographic progression from baseline to week 52.e EE, early escape; JSN, joint space narrowing; LE, late escape; NR, non-responder; q2w, every 2 weeks; q4w, every 4 weeks; SHS, Sharp/van der Heijde score; TF, treatment failure. aBased on imputed values by missing data (NR)/TF(NR). bBased on imputed values by missing data (NR)/TF(NR)/EE(NR)/LE(NR). cp<0.001 for both doses of sirukumab versus placebo across all timepoints based on Cochran-Mantel-Haenszel test. dNot significant for sirukumab 50 mg q4w versus sirukumab 100 mg q2w across all timepoints based on Cochran-Mantel-Haenszel test. eBased on imputed values by EE rules and then missing data rules. fp<0.001 versus placebo based on Cochran-Mantel-Haenszel test. gp<0.001 versus placebo based on van der Waerden analysis of variance.