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Sirukumab effective for anti-TNF intolerant RA
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Sirukumab was effective for patients with rheumatoid arthritis who were intolerant to other anti-tumor necrosis factor inhibitors, according to recently published data.
“The phase 3 SIRROUND-T study results, as published in The Lancet, demonstrated the significant efficacy of sirukumab, an interleukin-6– (IL-6) targeted therapy, in the treatment of moderate to severe rheumatoid arthritis (RA) in patients whose disease is still active, despite prior treatment with anti-tumor necrosis factor (TNF) therapy or other biological compounds,” Daniel Aletaha, MD, at the Medical University of Vienna, told Healio Rheumatology.
Aletaha and colleagues performed a randomized, double-blind, placebo-controlled, parallel-group study of 878 patients at 183 hospitals and private rheumatology clinics in 20 countries between 2012 and 2016. Patients had at least four tender joints and at least four swollen joints and had an inadequate response to, or were intolerant to, previous treatment with at least one anti-TNF drug.
Patients received subcutaneous placebo every 2 weeks (n = 294), 50 mg of sirukumab every 4 weeks (n = 292) or 100 mg of sirukumab every 2 weeks (n = 292).
Sixty percent of patients had previously used two or more biologics and 19% did not use a disease-modifying antirheumatic drug at baseline. In addition, patients could continue to use any concomitant disease-modifying antirheumatic drug.
Researchers stratified the randomization schedule by methotrexate use at baseline: zero mg, between zero mg and 12.5 mg per week or at least 12.5 mg per week.
Patients who showed less than 20% improvement in swollen and tender joint counts after 18 weeks were randomly reassigned at week 24 to either 50 mg or 100 mg of sirukumab. Patients in the placebo group were randomly assigned to the sirukumab groups at week 23.
The primary outcome was proportion of patients who achieved ACR20 in the intention-to-treat population.
The ACR20 response rate was 40% in the 50-mg group, 45% in the 100-mg group and 24% in the placebo group. The safety analysis showed at least one adverse event occurred for 182 patients in the placebo group, 194 of the 50-mg group and 207 in the 100-mg group. The most common adverse events at both 24 weeks and 52 weeks were injection-site erythema.
“These findings are important in a progressive inflammatory musculoskeletal disease like rheumatoid arthritis, especially for those patients who are very difficult to treat,” Aletaha said. – by Will Offit
Disclosure: Aletaha has served as a consultant for, or received grant or research support from Abbvie, Grünenthal, Janssen, Merck Medac, Mitsubishi/Tanabe, Pfizer, Roche and UCB.
Perspective
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Josef S. Smolen, MD
TNF alpha and IL-6 are two cytokines that are pivotally involved in the pathogenesis of rheumatoid arthritis (RA). Hitherto, five TNF-inhibitors, but only one IL-6 pathway blocker have been used in clinical practice. The latter is tocilizumab, a humanized monoclonal antibody to the IL-6-receptor (IL-6R); currently, a human IL-6R antibody, sarilumab, is under regulatory review. However, no antibody to the IL-6 cytokine has yet been approved. Sirukumab is a human monoclonal antibody to the IL-6 ligand which has shown efficacy in patients with RA in a prior phase 2 trial.
Now, Aletaha and colleagues present the first phase 3 trial of sirukumab which was tested at a 50-mg dose every 4 weeks and a 100-mg dose every 2 weeks. The present study involved RA patients who were highly refractory to prior therapies, since they not only had responded insufficiently to conventional synthetic disease-modifying antirheumatic drugs (DMARDs), but also to biologic agents; indeed, about 60% of the patients had not responded sufficiently to two or more biological DMARDs. These biologics spanned from TNF-inhibitors to biologics of all other modes of action.
The study was well designed and led to important results. Not only did it meet its primary endpoint, an ACR20 response of 40% and 45% for the two doses, respectively, compared with 24% on placebo, but also other important endpoints. The ACR70 response amounted to about 10%, in line with results of other biologic DMARDs in similar populations. The 100-mg dose (every 2 weeks) had generally slightly better efficacy than the 50-mg dose (every 4 weeks) and on this dose, even 7% of patients achieved stringent ACR-EULAR remission criteria and 19% arrived at a HAQ-DI of 0.5 or less. Adverse events were within the expectations for an IL-6 pathway inhibitor. Importantly, Aletaha and colleagues also presented a post-hoc analysis of a small subgroup of patients who had previously been treated with tocilizumab and the ACR20 response in this population was similar to the one seen in the overall population, suggesting that — like with TNF-inhibitors — IL-6 inhibition may be efficacious if prior IL-6 R inhibition has not led to the expected results.
These data suggest sirukumab is an effective biologic with a somewhat new mode of action and an acceptable tolerability profile for the treatment of RA patients who had an insufficient response to biological DMARDs. This is a nice study.
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