Cellular and proteomic changes following administration of peresolimab in patients with rheumatoid arthritis: a post-hoc analysis of a randomised phase 2a trial

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• Picked for Pharmacology (medical) (paper of the day, 1 October 2026): Phase 2a trial reporting peresolimab PK and biomarker data

Abstract

BACKGROUND: Peresolimab, a monoclonal antibody that stimulates human PD-1, demonstrated superiority over placebo in a phase 2a trial assessing Disease Activity Score in 28 joints using C-reactive protein over 12 weeks in adults with moderate-to-severe rheumatoid arthritis. In this post-hoc analysis, we report the pharmacokinetic and exploratory biomarker results from this trial. METHODS: We did a phase 2a double-blind, randomised, placebo-controlled trial across 26 centres in Europe, Mexico, and the USA. Eligible participants were aged 18 years or older, with a diagnosis of adult-onset rheumatoid arthritis and moderate-to-severe disease activity. Patients were randomly assigned (2:1:1) to receive peresolimab 700 mg, peresolimab 300 mg, or placebo intravenously once every 4 weeks during the 14-week placebo-controlled period. This post-hoc analysis assessed peresolimab pharmacokinetics, PD-1 coverage with peresolimab, and cellular and molecular biomarker changes from baseline to week 14 (or to week 36 for pharmacokinetics). Blood and serum samples were collected from patients who received peresolimab or placebo and from control participants without a diagnosis of rheumatoid arthritis as a baseline comparison. Cellular changes were assessed using standard flow cytometry and molecular changes were assessed with Olink proteomics and RNA sequencing. People with lived experience of rheumatoid arthritis were not involved in the design or conduct of the study. The phase 2a trial was registered with ClinicalTrials.gov (NCT04634253) and is completed. FINDINGS: Between Jan 4, 2021, and Jan 10, 2022, 172 patients were screened for eligibility of whom 98 (82 [84%] female and 16 [16%] male; mean age 51·7 [SD 12·6]) were randomly assigned to receive peresolimab 700 mg (n=49), peresolimab 300 mg (n=25), or placebo (n=24). Across the doses studied, peresolimab showed a dose-proportional increase in exposure (terminal half-life approximately 9 days); both peresolimab 300 mg and 700 mg groups had greater than 90% receptor occupancy on circulating CD4 effector memory T cells over the treatment period. From baseline to 12 weeks, PD-1 high-expressing CD4 T cell count for the peresolimab group decreased between -52·2% and -57·1%. No meaningful differences were seen for PD-1 low-expressing T cells or any other major cell types or subsets. Neutrophil count decreased by more than 10% in the peresolimab group, corroborated by RNA-sequencing results. Proteomic data analysis identified multiple pathways showing differences between peresolimab and placebo starting at week 8, including treatment-induced down-modulation of cytokines and chemokines in interleukin signalling pathways, including IL-6. INTERPRETATION: PD-1 agonism with peresolimab resulted in reduction of peripheral PD-1 high-expressing CD4 T cells and neutrophils, as well as normalisation of numerous molecular pathways associated with inflammation in patients with moderate-to-severe rheumatoid arthritis. Peresolimab treatment was evaluated in a subsequent phase 2b dose ranging study (NCT05516758), after which further development of peresolimab was discontinued. FUNDING: Eli Lilly and Company.

Abstract as published, via PubMed.