Spotlight on sirukumab for the treatment of rheumatoid arthritis: the evidence to date

Figures & data

Figure 1 The IL-6 receptor signaling system.

Abbreviations: IL-6, interleukin-6; mIL-6R, transmembrane interleukin-6 receptor; sIL-6R, soluble interleukin-6 receptor; gp130, 130 kD signal-transducing chain; JAK, Janus kinase; SHP-2, Src Homology domain-containing protein thyrosin Phospatase-2; STATs, signal transducer and activator of transcription proteins; Grb2, growth factor receptor bound protein 2; Ras/ERK/MAPK, rat sarcoma protein/extracellular signal-regulated kinase/mitogen- activated protein kinase; PI3K, phosphoinositol-3 kinase; Akt, protein kinase B.

Figure 2 The role of IL-6 in the pathogenesis of joint damage and extra-articular manifestations in rheumatoid arthritis.

Abbreviations: IL-6, interleukin-6; IL-6R, interleukin-6 receptor; VEGF, vascular endothelial growth factor; MMPs, matrix metalloproteinases; RANK, receptor activator of nuclear factor-kB; RANKL, receptor activator of nuclear factor-kB ligand; CVD, cardiovascular disease.

Table 1 Published clinical studies of sirukumab

Author	Design	Population	Duration (weeks)	Treatment arms	Main findings
Xu et al^Citation67	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 al^Citation68	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 al^Citation69	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 al^Citation70	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 al^Citation82	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 al^Citation83	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.

Table 2 AEs in Phase I/II trials of SRK

Author	Treatment arms	Any AEs (at least 1)	Serious AEs	Death	Serious infection	Neoplasm	Injection site reactions
Xu et al^Citation67	SRK (0.3, 1, 3, 6, 10 mg/kg) IV single dose	56%	0	0	0	0	0
	Placebo	73%	0	0	0	0	0
Zhuang et al^Citation68	SRK (25, 50, or 100 mg) SC single dose	61%	0	0	0	NA	25%
	Placebo	46%	0	0	0	NA	21%
Zhuang et al^Citation69	SRK 300 mg SC single dose	100%	0	0	0	NA	67%
Smolen et al^Citation70	Part A
	SRK 100 mg SC q2w	71%	6%	0	6%	0	35%
	Placebo	63%	0	0	0	0	10%
	Part B
	SRK (25, 50, 100 mg) SC q2w or q4w	86%	13%	1%	5%	1%	16%
	Placebo	67%	9%	0	3%	0	3%
Szepietowski et al^Citation82	Part A
	SRK (1, 4, 10 mg/kg) IV q2w	91%	13%	4%	0	4%	NA
	Placebo	63%	0	0	0	0	NA
	Part B
	SRK 10 mg/kg IV q2w	90%	20%	0	10%	0	NA
	Placebo	80%	20%	0	0	0	NA
Rovin et al^Citation83	SRK 10 mg/kg IV q4w	100%	48%	0	38%	0	NA
	Placebo	100%	0	0	0	0	NA

Abbreviations: AEs, adverse events; SRK, sirukumab; IV, intravenously; SC, subcutaneously; q2w, every 2 weeks; q4w, every 4 weeks; NA, datum not available.

Table 3 Ongoing clinical trials of SRK

Name/number	Design	Population prior treatment	Treatment arms	Primary endpoint	Study status	Estimated completion date
SIRROUND-D^Citation71	Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group study	1,670 RA patients with active disease despite DMARD therapy	Group 1: SRK 100 mg SC q2w through week 52, or SRK 50 mg SC q4w through week 104, or placebo Group 2: SRK 100 mg SC q2w through week 104 Group 3: SRK 50 mg SC q4w through week 104, or placebo	Proportion of patients with ACR20 response, and change from baseline in vdH score	Active, nonrecruiting	January 2017
SIRROUND-H^Citation72	Phase III, multicenter, randomized, double-blind, parallel group study	559 RA patients with active disease	Group 1: adalimumab 40 mg q2w through week 52 Group 2: SRK 100 mg q2w through week 52 Group 3: SRK 50 ng q4w through week 52	Change from baseline in DAS28-ESR, and percentage of ACR50 response	Active, nonrecruiting	August 2016
SIRROUND-T^Citation73	Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group study	878 RA patients with active disease despite anti-TNF-α therapy	Group 1: SRK 100 mg SC q2w through week 23, or SRK 50 mg SC q4w through week 52, or placebo Group 2: SRK 100 mg SC q2w through week 52 Group 3: SRK 50 mg SC q4w through week 52, or placebo	Proportion of patients with ACR20 response	Completed	January 2016
SIRROUND-M^Citation74	Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group study	121 RA patients with active disease unresponsive to methotrexate or sulfasalazine	Group 1: SRK 100 mg SC q2w through week 52 Group 2: SRK 50 mg SC q4w through week 52, or placebo	Proportion of patients with AEs	Completed	March 2015
SIRROUND-LTE^Citation75	Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group study	RA patients completing SIRROUND-D and SIRROUND-T studies	Group 1: SRK 100 mg SC q2w through week 156 (SIRROUND-D participants) and 208 (SIRROUND-T participants) Group 2: SRK 50 mg SC q4w through week 156 (SIRROUND-D participants) and 208 (SIRROUND-T participants)	Proportion of patients with cardiovascular serious AEs, malignancies, serious infections, or gastrointestinal perforations	Enrolling by invitation	April 2020
SIRRESTA^Citation85	Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group study	Estimated enrollment of 204 GCA patients under prednisone treatment	SRK 100 mg q2w SC, or SRK 50 mg q4w SC through week 52 (Part A, double-blind treatment phase) and week 104 (Part B, long-term extension phase), or placebo	Proportion of patients in sustained remission at week 52	Active, recruiting	May 2020
NCT02473289^Citation88	Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel study	Estimated enrollment of 192 patients with major depressive disorder under treatment with a monoaminergic antidepressant	Group 1: SRK 50 mg SC on day 1, 28, and 56 Group 2: placebo	Change from baseline in HDRS17 at week 12	Active, recruiting	October 2017

Abbreviations: RA, rheumatoid arthritis; SRK, sirukumab; SC, subcutaneously; q2w, every 2 weeks; q4w, every 4 weeks; ACR, American College of Rheumatology; DAS28-ESR, disease activity score in 28 joints using erythrocyte sedimentation rate; vdH, van der Heijde score; AEs, adverse events; TNF-α, tumor necrosis factor-α; HDRS17, Hamilton Depression Rating Scale; GCA, giant-cell arteritis.

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