Sirukumab for Rheumatoid Arthritis: the Phase III SIRROUND-D Study

Shawn Yee, Mercer University College of Pharmacy

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. Disease-modifying antirheumatic drug (DMARD) therapy, such as methotrexate (MTX) is commonly used for the treatment of RA. However, for patients unresponsive or refractory to this therapy, a newer treatment with monoclonal antibodies (mAb) is being further studied. [1]

One of the proposed underlying mechanisms of RA includes the activity of interleukin-6 (IL-6) in the joints, where higher levels of IL-6 is associated with joint damage and inflammation. [1,2] Therefore, inhibiting the activity of IL-6 with drug therapy is thought to improve RA symptoms and overall disease progression. [1] Previous studies analyzing the effect IL-6 receptor antagonism with monoclonal antibodies such as tocilizumab and sarilumab found success with improving RA outcomes, and showed reduction in RA symptoms, improved physical function and reduced the rate of RA progression. [3,4,5,6]

In a previous phase II trial, sirukumab (selective IL-6 cytokine human mAb), showed efficacy in patients refractory to MTX therapy. [7] The phase III trial is summarized below. [1]

Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study
Design Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III trial; N= 1,670
Objective Evaluate the efficacy and safety of sirukumab in rheumatoid arthritis (RA) patients who are refractory to disease-modifying antirheumatic drugs (DMARDs)
Study Groups
  • Sirukumab 100 mg subcutaneous injection every two weeks (n= 557)
  • Sirukumab 50 mg subcutaneous injection every four weeks (n= 557)
  • Placebo subcutaneous injection every two weeks (n= 556)
Methods Patients from 18 countries were randomized in a 1:1:1 ratio into each treatment group. There was screening period for up to six weeks, a treatment period for 104 weeks, and safety follow-up for 16 weeks. The Sharp/van der Heijde score (SHS) was used to analyze radiographic data of joints to determine degree of damage, with higher scores indicating narrowing of joint space. The health assessment questionnaire disability index (HAQ-DI) scoring was calculated from patient answers to the questionnaire, and scores ranged from zero (no disability) to three (complete disability). Disease Activity Score 28 joints C-reactive protein (DAS28-CRP) calculator was used to evaluate RA disease severity. The disease improvement data was monitored with the American College of Rheumatology (ACR) response criteria, with ACR20 indicating 20% improvement.
Inclusion Criteria:

  • Age ≥ 18 years
  • Active RA (moderate to severe) that is refractory to ≥ one agent of DMARD therapy including methotrexate (MTX) or sulfasalazine
  • Need ≥ 6/68 tender joints and ≥ 6/66 swollen joints
  • C reactive protein (CRP) ≥ 8.0 mg/L
  • One of the following three criteria prior to treatment:
    • (1) anticitrullinated peptide antibody-positive (anti-CCP positive)
    • (2) rheumatoid factor (RF) positive
    • (3) documented history of radiographic evidence of erosive RA in the hands and/or feet
  • If using non-biological DMARDs, must have been on a stable dose for ≥ four weeks prior to receiving sirukumab
  • If not currently using DMARDs, must not have received DMARDs for ≥ four weeks prior to receiving sirukumab

Exclusion Criteria:

  • Received biologicals within the past three months (six weeks for etanercept or yisaipu and four weeks for anakinra)
  • Patients with a history of serious infection or current serious infection (including tuberculosis)
Duration July 2012 to September 2015
Primary Outcome Measure
  • Sirukumab 100 mg every two weeks versus placebo: ACR20 response or change from baseline in week 16 and week 52
  • Sirukumab 50 mg every four weeks versus placebo: ACR20 response or change from baseline in week 16 and week 52
Baseline Characteristics
Values are represented as mean (standard deviation) unless stated otherwise
Characteristic Placebo (n= 556) Sirukumab 50 mg every four weeks (n= 557) Sirukumab 100 mg every two weeks (n= 557) Total (n= 1,670)
Female, n (%) 436 (78.4) 447 (80.3) 452 (81.1) 1,335 (79.9)
Age, years 52.9 (11.9) 52.9 (11.8) 53.0 (11.3) 52.9 (11.7)
Race, n (%)
White 403 (72.5) 397 (71.3) 408 (73.2) 1,208 (72.3)
Black or African-American 16 (2.9) 15 (2.7) 10 (1.8) 41 (2.5)
Region, n (%)
Eastern Europe 271 (48.7) 263 (47.2) 273 (49.0) 807 (48.3)
North America 85 (15.3) 96 (17.2) 91 (16.3) 272 (16.3)
Disease duration, years 8.3 (7.0) 8.7 (7.5) 8.8 (7.6) 8.6 (7.4)
CRP, mg/L 25 (34) 24 (26) 24 (26) 24 (29)
RF positive, n (%) 444 (79.9) 433 (77.7) 468 (84.0) 1,345 (80.5)
Anti-CCP positive, n (%) 467 (84.0) 476 (85.5) 484 (86.9) 1,427 (85.4)
SHS 41.9 (46.7) 41.8 (45.4) 42.5 (49.3) 42.1 (47.1)
HAQ-DI score 1.6 (0.7) 1.5 (0.6) 1.5 (0.7) 1.5 (0.6)
DAS28-CRP 5.9 (0.9) 5.9 (0.9) 5.8 (0.9) 5.9 (0.9)
Prior medication use
1 DMARD 183 (32.9) 179 (32.1) 173 (31.1) 535 (32.0)
≥ 2 DMARDs 373 (67.1) 378 (67.9) 384 (68.9) 1,135 (68.0)
MTX 547 (98.4) 550 (98.7) 548 (98.4) 1,645 (98.5)
Sulfasalazine 174 (31.4 167 (30.0) 152 (27.3) 493 (29.5)
Systemic corticosteroids 422 (75.9) 407 (73.1) 418 (75.0) 1,247 (74.7)
Baseline medication use, n (%)
DMARDs 508 (91.4) 517 (92.8) 511 (91.7) 1,536 (92.0)
NSAIDs 434 (78.1) 420 (75.4) 454 (81.5) 1,308 (78.3)
Corticosteroids 341 (61.3) 331 (59.4) 360 (64.6) 1,032 (61.8)
Results
Endpoint Placebo (n= 556) Sirukumab 50 mg every 4 weeks (n= 557) Sirukumab 100 mg every 2 weeks (n= 557)
ACR20 at week 16, % of patients 26 55 54
ACR20 at week 52, % of patients 27 50 55
SHS change from baseline at week 24, mean 1.96 0.35 0.30
SHS change from baseline at week 52, mean 3.69 0.50 0.46
HAQ-DI change from baseline at week 24, mean (SD) -0.22 (0.53) -0.43 (0.58) -0.46 (0.57)
ACR50 at week 16, n (%) 60 (10.8) 167 (30.0) 146 (26.2)
ACR50 at week 24 , n (%) 69 (12.4) 168 (30.2) 185 (33.2)
ACR50 at week 52, n (%) 77 (13.8) 169 (30.3) 198 (35.5)
ACR70 at week 16, n (%) 22 (4.0) 75 (13.5) 75 (13.5)
ACR70 at week 24, n (%) 19 (3.4) 83 (14.9) 91 (16.3)
ACR70 at week 52, n (%) 30 (5.6) 92 (16.5) 103 (18.5)
DAS28-CRP < 2.6 at week 24, n (%) 31 (5.6) 145 (26.0) 142 (25.5)
Major clinical response by week 52, n (%) 10 (1.8) 30 (5.4) 50 (9.0)
Adverse Events Common Adverse Events (≥ 5% frequency with sirukumab treatment groups): elevated liver enzymes, upper respiratory tract infection, bronchitis, nasopharyngitis, injection site erythema and pruritus, leukopenia, neutropenia, headache, and hypertension
Serious Adverse Events:

Sirukumab 50 mg every four weeks: 11.0% total (7 deaths, serious infection 4.1%, gastrointestinal perforation in one patient)

Sirukumab 100 mg every two weeks: 9.8% total (3 deaths, serious infection 3.3%)

Placebo: 6.8% total (one death, serious infection 1.8%, one gastrointestinal perforation)

Percentage that Discontinued due to Adverse Events:

Sirukumab 50 mg every four weeks: 8%

Sirukumab 100 mg every two weeks: 7.7%

Placebo: 3.2%

Study Author Conclusions Both sirukumab treatment groups (100 mg every two weeks and 50 mg every four weeks) provided significant reduction in RA symptoms as well as RA progression for patients refractory to DMARD treatment. Both doses provided similar effectiveness and provided an improved quality of life with an acceptable safety profile.

 

This study provides data for multiple outcomes on the use of sirukumab for RA treatment and affirms the conclusion from the previous phase II trial where patients experienced improvement in RA symptoms. Patients in the sirukumab treatment groups showed a decrease in RA progression as seen by radiographic data (SHS) and an improvement in overall RA symptoms (HAQ-DI, ACR criteria, and DAS28-CRP). [6] However long term efficacy as well as safety and tolerability remains to be seen with sirukumab injections. There were several common adverse events (≥ 5%) in this study such as elevated liver enzymes, upper respiratory infections, hypertension and bronchitis that are of concern. Also the rates of death and serious infections are higher in the sirukumab treatment groups, which should be taken into consideration.

Moderate to severe RA patients who are refractory to ≥ 1 DMARD treatment (azathioprine, MXT, sulfasalazine, etc.) were included in this study, and based on the data, this patient population may benefit from sirukumab treatment. However, the burden associated with cost and bi-weekly or monthly injections should be considered by patient and provider, as well as the uncertain long-term effects of sirukumab treatment.

 

References

[1] Takeuchi T, Thorne C, Karpouzas G, et al. Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis. 2017;76(12):2001-2008.

[2] Flannery CR, Little CB, Hughes CE, et al. IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage. Matrix Biol 2000;19:549–53.
[3] Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67:1516–23.

[4] Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69:88–96.

[5] Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 2007;66:1162–7.

[6] Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol 2015;67:1424–37.

[7] Smolen JS, Weinblatt ME, Sheng S, et al. 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. Ann Rheum Dis 2014;73:1616–25.

 

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