Peresolimab phase IIa rheumatoid arthritis trial published in The New England Journal of Medicine.- Eli Lilly

These data represent the first clinical evidence that stimulating the endogenous PD-1 inhibitory pathway could be an effective approach to treat rheumatologic disease.

The phase IIa clinical trial (NCT04634253) evaluated the safety and efficacy of peresolimab in adult participants with moderate-to-severe RA who had an inadequate response to prior conventional, biologic or synthetic disease modifying antirheumatic drugs (DMARDs).

"In the study, peresolimab showed meaningful results in refractory RA patients," said Jay Tuttle, Ph.D, study first author and associate vice president, 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."

Peresolimab is an investigational humanized immunoglobulin G1 monoclonal antibody that stimulates human programmed cell death protein 1 (PD-1), a checkpoint inhibitory receptor, that may induce physiological immune inhibitory pathways to restore immune homeostasis. RA, a form of rheumatologic disease, is a systemic autoimmune disease characterized by inflammation and progressive destruction of joints.

These data were first presented as a late-breaking abstract at the American College of Rheumatology (ACR) annual Convergence in November 2022.

In this phase IIa, double-blind, randomized, placebo-controlled trial, adult patients with moderate-to-severe RA who had an inadequate response to, a loss of response to, or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or to biologic or targeted synthetic DMARDs to receive 700 mg of peresolimab, 300 mg of peresolimab, or placebo intravenously once every 4 weeks. The primary outcome was 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 primary comparison was between the 700-mg group and the placebo group.

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 acr20 response, but not with respect to the acr50 and acr70 responses — defined as improvements from baseline of 20%, 50%, and 70% or more, respectively, in the numbers of tender and swollen joints and in at least three of five important domains — at week 12. noted improvements were seen in the clinical disease activity index (cdai) in participants treated with both peresolimab doses compared to placebo. in addition, low disease activity was maintained through week 24 in most patients achieving cdai low disease activity at week 14.></0.001).>

Adverse events were similar in the peresolimab and placebo groups. Treatment emergent events were mild or moderate in severity, with the most common events being infections and infestations, in addition to skin and subcutaneous tissue disorders. A single serious adverse event (worsening of hypothyroidism, 700 mg) was reported during the treatment period, which did not result in participant discontinuation from the study. There were no deaths reported in the study, and no reports of malignancy in participants receiving peresolimab.

The results support further clinical evaluation of peresolimab in rheumatologic diseases. Future studies will continue evaluating peresolimab as treatment for RA, including the ongoing RESOLUTION-1 (NCT05516758) clinical trial, a phase IIb study of peresolimab in adult participants with moderate-to-severe RA. Additionally, Lilly is considering evaluating peresolimab in other autoimmune diseases.

See-"A Phase II Trial of Peresolimab for Adults with Rheumatoid Arthritis"; Jay Tuttle, Ph.D., Edit Drescher, M.D., Jesus Abraham Simón-Campos, M.D., Paul Emery,et al. 18 May 2023 N Engl J Med 2023; 388:1853-1862. DOI: 10.1056/NEJMoa2209856.