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Peresolimab for Adults with Rheumatoid Arthritis

In a phase 2a trial, the humanized IgG1 monoclonal antibody peresolimab demonstrated potential efficacy in 98 adults with rheumatoid arthritis. This agent stimulates the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway; the investigators conclude that “these results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis.”

Study participants, all of whom had moderate-to-severe rheumatoid arthritis that was not successfully treated with conventional synthetic disease-modifying antirheumatic drugs (DMARDs), were randomized to double-blinded peresolimab 700 mg, peresolimab 300 mg, or placebo intravenously once every 4 weeks. Based on a primary outcome of the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP), the investigators found: “At week 12, the change from baseline in the DAS28-CRP was significantly greater in the 700-mg peresolimab group than in the placebo group (least-squares mean change [± SE], −2.09 ± 0.18 vs. −0.99 ± 0.26; difference in change, −1.09 [95% confidence interval, −1.73 to −0.46]; P <0.001). The results of the analyses of secondary outcomes favored the 700-mg dose over placebo with respect to the [American College of Rheumatology (ACR) 20] response but not with respect to the ACR50 and ACR70 responses. Adverse events were similar in the peresolimab and placebo groups.”

Editorial: “Many of the current therapies for rheumatoid arthritis act by blocking proinflammatory pathways, and disease often recurs when these therapies are discontinued,” editorialists write. “Peresolimab has the potential instead to reset the immune response or restore immune tolerance. Although this trial is a promising step forward, many questions remain. Will mechanistic studies validate the prediction that PD-1 agonism enhances T-cell anergy and regulation in rheumatoid arthritis? How long will the effects of peresolimab persist after treatment is withdrawn, and will these effects create a better immune environment for response to other DMARDs? Will administration of peresolimab during the early stage of disease result in a more prolonged immunosuppressive effect than administration in patients with established disease? Although the answers to these questions are unknown, this trial opens a refreshing new chapter in the treatment of rheumatoid arthritis and introduces an approach that might also be applied to the treatment of other autoimmune diseases that are driven by antigen-activated lymphocytes.”

Source: New England Journal of Medicine