Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy

Abstract

Objectives: The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy.

Methods: In Part A (proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12-22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12-24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts.

Results: The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm).

Conclusions: Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors.

Trial registration number: NCT00718718.

Keywords: Cytokines; DMARDs (biologic); Methotrexate; Rheumatoid Arthritis; Treatment.

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Figures

Figure 1

Patient disposition in (A) Part A and (B) Part B. Adverse events (AEs) leading to study agent discontinuation before week 12 were worsening of rheumatoid arthritis (placebo), cellulitis staphylococcal and pneumonia (sirukumab) in Part A; and included bacterial arthritis (placebo and sirukumab), fibrosarcoma (sirukumab), and serum sickness (sirukumab) in Part B.

Figure 2

Proportions of patients with American College of Rheumatology 50 (ACR50) response (A, C) and mean changes from baseline in DAS28-C-reactive protein (CRP) (B, D), clinical disease activity index (CDAI) score (E, G), and simplified disease activity index (SDAI) score (F, H) in Parts A and B. Data from one of the study sites that participated in Part A were excluded from all efficacy analyses due to questionable data integrity. At week 12 in Part A, patients randomised to placebo crossed over to sirukumab 100 mg every 2 weeks, and patients randomised to sirukumab crossed over to placebo through week 22. At week 12 in Part B, patients randomised to placebo crossed over to sirukumab 100 mg every 2 weeks through week 24.

Figure 3

Mean (SD) serum sirukumab concentration versus time after multiple subcutaneous administrations of sirukumab in (A) Part A and (B) Part B and mean per cent change from baseline in serum concentrations of C-reactive protein (CRP) in (C) Part A and (D) Part B. Data from one of the study sites that participated in Part A were excluded from all pharmacokinetics and pharmacodynamics analyses due to questionable data integrity. Serum sirukumab concentrations were plotted starting on day 2 (Part A) and day 5 (Part B).