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New Treatment Approach for Rheumatoid Arthritis Shows Promise in Trial

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Results of a Phase 2a clinical trial suggest that peresolimab, an antibody that stimulates the human programmed cell death protein 1 (PD-1) pathway, could be a promising new approach for the treatment of rheumatoid arthritis (RA). The study is published in The New England Journal of Medicine.

Exploring new options for rheumatoid arthritis

RA is a type of autoimmune disease, meaning it is caused by the immune system mistakenly attacking the body’s own healthy tissues. It mainly affects the joints – primarily the hands, wrists and knees – causing painful inflammation and swelling that damages the tissue and leads to deformity and limited mobility.


Treatment options for RA are limited, but medications and supportive treatments such as physiotherapy can go some way toward managing this chronic disease. Medication typically consists of disease-modifying antirheumatic drugs (DMARDs) – such as methotrexate – as well as biologics – protein-based drugs such as therapeutic antibodies.


However, many patients fail to respond to treatment or can lose their response to previously effective therapies over time. This underlies the need for the development of new, effective therapies for RA. One such drug, peresolimab, has been developed by Eli Lilly and Company (Lilly) and is now under evaluation in clinical trials.

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Peresolimab is a humanized G1 monoclonal antibody that binds to and stimulates the immune checkpoint protein PD-1. These proteins act as a “brake” on the immune system by preventing T-cell activation and have an important role in preventing autoimmunity. In this latest Phase 2a clinical trial, findings suggest that peresolimab for the treatment of RA is safe and effective.

Trial shows some early promise

Ninety-eight patients with moderate-to-severe RA were enrolled in this double-blind, randomized and placebo-controlled trial. These participants had either failed to respond to previous therapies, their response had reduced over time or had experienced unacceptable side effects with other therapies.


The participants were separated into 3 groups, receiving intravenous doses of either 700 mg peresolimab, 300 mg peresolimab or placebo once every 4 weeks.


The responses were primarily measured by changes in Disease Activity Score for 28 joints based on C-reactive protein level (DAS28-CRP) – this describes the severity of RA using a combination of the number of swollen and tender joints as well as laboratory tests for the inflammatory marker CRP.


After 12 weeks of treatment, the 700 mg peresolimab group had a significantly greater change in DAS28-CRP from baseline compared to the placebo group.


American College of Rheumatology 20 (ACR20), ACR50 and ACR70 were also used to measure response – defined as improvements from baseline of 20%, 50% and 70% or more in the number of tender and swollen joints and in at least 3 of 5 important domains. The 700 mg group had better ACR20 responses compared to placebo, though this was not the case for ACR50 or ACR70 responses.


“In the study, peresolimab showed meaningful results in refractory RA patients,” said Dr. Jay Tuttle, first author of the study and associate vice president of research and development at Lilly. “Refractory patients make up approximately 21% of the RA population, having tried and failed multiple treatments, and are often hesitant to try new options. While still early, these data signify an important potential new therapeutic approach for RA patients, including both refractory and biologic-naïve patients.”


Adverse events were mild or moderate and were similar in the peresolimab and placebo groups, with the most common events being infections and skin disorders. A single serious adverse event (worsening of hypothyroidism in the 700 mg group) was reported, but the patient was not discontinued from the study.

Larger and longer follow-up trials are needed

“Lilly is proud to share these results in The New England Journal of Medicine, which reinforce our commitment to discoveries that may transform care for patients. Our ultimate objective in treating immunologic conditions is to achieve not only symptom reduction, but to also induce immune homeostasis and achieve longstanding resolution of disease,” said Dr. Ajay Nirula, senior vice president of immunology at Lilly and senior author of the study. “These early data for peresolimab in RA reflect our commitment to develop first-in-class therapeutic options for patients.”


Overall, the findings from this trial provide initial evidence that stimulating PD-1 may be a promising new approach to treating RA, though longer and larger trials are needed to examine this effect in more detail. Now, Lilly is now considering investigating peresolimab in further clinical trials for other autoimmune diseases.


Reference: Tuttle J, Drescher E, Simón-Campos JA, et al. A Phase 2 trial of peresolimab for adults with rheumatoid arthritis. NEJM. 2023;388(20):1853-1862. doi: 10.1056/NEJMoa2209856


This article is a rework of a press release issued by Eli Lilly and Company. Material has been edited for length and content.

Meet the Author
Sarah Whelan, PhD
Sarah Whelan, PhD
Science Writer
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