In a recent IRIS-RA clinical trial study published in Rheumatic and Musculoskeletal Diseases Open, the innovative monoclonal antibody, nipocalimab, has demonstrated encouraging results for patients with moderate to severe rheumatoid arthritis (RA) who have not responded well to anti-TNF therapy. Despite not reaching statistical significance for the primary endpoint, the study revealed significant potential for this novel treatment.
A total of 53 participants were enrolled in the study, with 33 receiving nipocalimab and 20 receiving a placebo intravenously every 2 weeks, or placebo from Weeks 0 to 10. While the primary efficacy endpoint—change from baseline in Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12—did not achieve statistical significance, there was a notable numerical improvement for those treated with nipocalimab. The least squares mean change from baseline in DAS28-CRP was -1.03 for nipocalimab compared to -0.58 for placebo. Additionally, secondary efficacy outcomes and patient-reported outcomes also showed numerical improvements. Three participants experienced serious adverse events, including burn infection, infusion-related reactions, and deep vein thrombosis. However, nipocalimab was found to significantly and reversibly reduce serum immunoglobulin G, anticitrullinated protein antibodies (ACPA), and circulating immune complex levels. Interestingly, this reduction did not extend to serum inflammatory markers such as CRP.
Nipocalimab is a high-affinity, fully human, effectorless IgG1 monoclonal antibody specifically engineered to block the neonatal Fc receptor (FcRn). By inhibiting FcRn, nipocalimab prevents IgG recycling, thereby lowering IgG levels. This reduction potentially decreases levels of ACPA and other pathogenic antibodies involved in the pathogenesis of RA. FcRn plays a crucial role in both cell-mediated and humoral immune responses by regulating IgG trafficking and recycling. Nipocalimab is designed with an aglycosylated Fc domain to eliminate its effector functions, even when presented in immune complexes. Consequently, nipocalimab does not induce complement-mediated cytotoxicity or facilitate antibody-dependent cellular cytotoxicity/phagocytosis. Beyond IgG trafficking and recycling, FcRn may directly influence the functions of FcRn-expressing immune cells, such as monocytes and B cells, through mechanisms independent of IgG recycling. Nipocalimab’s targeted action on FcRn offers a novel therapeutic approach for managing RA by mitigating the effects of pathogenic antibodies without triggering undesirable immune responses.
Studies are exploring the role of nipocalimab in other complement-driven diseases such as atypical hemolytic uremic syndrome and antibody-mediated rejection in organ transplantation. The current findings suggest that nipocalimab offers consistent, numerical efficacy benefits for RA patients, particularly those with higher baseline ACPA levels. While the primary endpoint was not statistically significant, the overall results highlight the potential of nipocalimab as a promising therapeutic option for individuals with moderate to severe active RA. As RA continues to affect millions worldwide, the development of new treatments like nipocalimab provides hope for better management and improved quality of life for patients battling this chronic condition. Further research and larger clinical trials are essential to confirm these findings and potentially pave the way for new, effective RA therapies.
Reference
- Taylor PC, Schett G, Huizinga TW, Wang Q, Ibrahim F, Zhou B et al. Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study. RMD Open. 2024 Jun 28;10(2):e004278.