Table 1.

Published clinical studies of sirukumab

Author	Design	Population	Duration (weeks)	Treatment arms	Main findings
Xu et al67	Phase I, double-blind, placebo-controlled, ascending single-dose study	45 healthy subjects (7♀)	20	SRK (0.3, 1, 3, 6, or 10 mg/kg) single IV dose, or placebo	SRK showed linear pharmacokinetics, without sex differences. Median terminal half-life: 18.5–29.6 days. Population estimates: clearance 0.364 L/d; central volume of distribution 3.28 L; inter-compatimental clearance: 0.588 L/d; peripheral volume distribution 4.97 L. No subjects tested positive for anti-SRK antibodies.
Zhuang et al68	Phase I, randomized, placebo-controlled, ascending single-dose study	49 healthy ♂subjects (25 Japanese, 24 Caucasian)	15	SRK (25, 50, or 100 mg) single SC dose, or placebo	SRK showed linear pharmacokinetics, without racial differences. Mean half-life: 15–18 days. Population estimates: clearance 0.54 L/d; volume of distribution 12.2 L. No subjects tested positive for anti-SRK antibodies.
Zhuang et al69	Phase I, open-label, multicenter, single-dose study	12 RA patients (7♀)	54	SRK 300 mg single SC dose	SRK reversed IL-6-mediated suppression of CYP activity in RA patients: after SRK administration, area under the plasma concentration-time curve for midazolam (CYP3A substrate), omeprazole (CYP2C19), and S-warfarin (CYP2C9) was reduced by 30%–35%, 37%–45%, and 18%–19%, respectively. The effect of SRK on CYP substrates was sustained for 6 weeks.
Smolen et al70	Phase II, two-part (Part A: proof-of-concept; Part B: dose-finding), randomized, double-blind, placebo-controlled study	Part A: 36 RA patients (25♀) Part B: 151 RA patients (128♀)	Part A: 22 Part B: 24	Part A: SRK 100 mg q2w SC, or placebo through week 10 with crossover treatment during weeks 12–22 Part B: SRK (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) SC through week 24, or placebo through week 10 with crossover to SRK 100 mg q2w(weeks 12–24)	The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w vs 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 vs placebo in both Part A (2.1 vs 0.6, P<0.001) and Part B (2.2 vs 1.1; P<0.001). Two patients tested positive for anti-SRK antibodies.
Szepietowski et al82	Phase I, two-part, double-blind, placebo-controlled, multiple IV, dose ascending study	Part A: 33 CLE patients (21♀) Part B: 15 SLE patients (13♀)	22	Part A: SRK (1, 4, or 10 mg/kg) four IV infusions q2w, or placebo Part B: SRK 10 mg/kg four IV infusions q2w, or placebo	SRK showed linear pharmacokinetics, with similar systemic exposure between CLE and SLE patients. Mean half-life was also comparable between CLE (16–23 days) and SLE patients (18 days). No patients tested positive for anti-SRK antibodies. CRP and serum amyloid A were suppressed from week 1 to week 14.
Rovin et al83	Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel group, proof-of-concept study	25 patients with active lupus nephritis (21♀) despite immuno-suppression	40	SRK 10 mg/kg q4w IV, or placebo through week 24	At week 24, the median percent change in proteinuria from baseline in SRK-treated patients was 0.0% (95% CI: -61.8, 39.6), while the placebo (n=4) patients showed a median percent increase in proteinuria of 43.3% at week 24. Nevertheless, a subset of 5 SRK-treated patients had ≥50% improvement in proteinuria through week 28. In the SRK group 47.6% of patients had ≥1 serious adverse event, mainly infections, vs 0 patients in the placebo group. Five patients discontinued the study early due to adverse events.

Abbreviations: SRK, sirukumab; CRP, C-reactive protein; RA, rheumatoid arthritis; IV, intravenously; SC, subcutaneously; CYP, cytochrome P450; DAS28-CRP, disease activity score in 28 joints using CRP; CLE, cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; q2w, every 2 weeks; q4w, every 4 weeks; CI, confidence interval.