LIVERPOOL, ENGLAND — The IRIS-RA study of the investigational monoclonal antibody drug nipocalimab in patients with rheumatoid arthritis (RA) did not meet its primary endpoint, but there could still be people with moderate to severe RA who might benefit from treatment with the drug, according to information reported at the British Society for Rheumatology annual meeting.
The primary endpoint for the phase 2A trial was the least squares mean change in Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) from baseline to 12 weeks of treatment. This was reduced by −1.03 with nipocalimab and by −0.58 with placebo, giving a mean difference of just −0.45 (P = .224).
However, one of the key secondary endpoints was the proportion of patients who had 20% improvement in American College of Rheumatology response criteria (ACR20). Results for this endpoint showed a greater difference in response to nipocalimab vs placebo, with a respective 45.5% and 20.0% (P = .055) of individuals achieving ACR20.
Moreover, an analysis stratifying for anti-citrullinated protein autoantibody (ACPA) levels at baseline found that people with higher levels had a better response to nipocalimab.
Choice of Endpoint
“The way this study was powered was to look at a change between the treatment groups of a DAS28-CRP reduction of 1.0,” said Peter C. Taylor, BMBCh, PhD, the Norman Collisson chair of musculoskeletal medicine at the University of Oxford in Oxford, England.
DAS28-CRP was often chosen as the primary endpoint in small proof-of-concept studies, such as IRIS-RA, because it was a “measure of continuous change [that] theoretically, would allow greater sensitivity to change,” Dr. Taylor added.
Sara Freeman/Medscape Medical News
Dr. Peter C. Taylor
“Ironically, it has to be said that had we chosen ACR20, we would have hit the primary endpoint. One lives and learns,” noted Dr. Taylor.
Proof of Concept
IRIS-RA was billed as a “proof-of-concept” study because it was the first time that a monoclonal antibody targeting the neonatal fragment crystallizable receptor (FcRn) was being tested in an RA population.
The study was a randomized double-blind trial in which 33 people with moderate to severe RA who had an inadequate response to tumor necrosis factor (TNF) inhibitors were treated with nipocalimab at a dose of 15 mg/kg given intravenously every 2 weeks, and 20 received a matching placebo. Participants were treated for 10 weeks, and then the primary follow-up was at 12 weeks, with additional follow-up for safety undertaken at 18 weeks.
Nipocalimab is a fully human, immunoglobulin G1 (IgG1) monoclonal antibody that is designed to selectively block the FcRn. By doing so, it essentially stops IgG from being recycled within the immune system, and this in turn lowers IgG levels. That includes potentially harmful ACPAs, among other pathogenic antibodies, Dr. Taylor and fellow investigators explained in their abstract.
“We’ve known for a long time that ACPA have prognostic value, but there’s been controversy about whether or not ACPA are actually pathogenic,” Dr. Taylor said. “So, one of the hypotheses that this study gives rise to is that by blocking FcRn, and thereby reducing, potentially, the concentration of ACPA in the blood, will we actually have efficacy in patients?”