RESEARCHERS have found that peresolimab, a PD-1 agonist antibody, was associated with reductions in PD-1 high-expressing CD4 T cells and neutrophils in patients with moderate-to-severe rheumatoid arthritis, according to a post-hoc analysis of a randomised phase 2a trial.
Peresolimab, a monoclonal antibody that stimulates human PD-1, has demonstrated superiority over placebo on Disease Activity Score in 28 joints using C-reactive protein over 12 weeks in moderate-to-severe rheumatoid arthritis. Until now, the underlying pharmacokinetic and biomarker data remained unreported.
This double-blind, randomised, placebo-controlled phase 2a trial enrolled adults aged 18 years or older with moderate-to-severe rheumatoid arthritis across 26 centres in Europe, Mexico and the USA. Participants were 84% female, with a mean age of 51.7 years (SD 12.6).
Of 172 patients screened between January 2021 and January 2022, 98 were randomised 2:1:1 to intravenous peresolimab 700 mg (n=49), 300 mg (n=25), or placebo (n=24) every 4 weeks during a 14-week placebo-controlled period.
This post-hoc analysis assessed pharmacokinetics, PD-1 coverage and biomarker changes from baseline to Week 14 (Week 36 for pharmacokinetics) using flow cytometry, Olink proteomics and RNA sequencing in samples from patients and from control participants without rheumatoid arthritis.
Peresolimab showed a dose-proportional increase in exposure (terminal half-life approximately 9 days), and both doses achieved greater than 90% receptor occupancy on circulating CD4 effector memory T cells.
From baseline to Week 12, PD-1 high-expressing CD4 T cell count decreased by 52.2% to 57.1% in the peresolimab group, with no meaningful differences in PD-1 low-expressing T cells or other major cell types.
Neutrophil count decreased by more than 10%, corroborated by RNA sequencing. Proteomic analysis showed differences versus placebo from Week 8, including down-modulation of interleukin signalling cytokines and chemokines, such as IL-6.
These findings have shown that PD-1 agonism with peresolimab reduced peripheral PD-1 high-expressing CD4 T cells and neutrophils and normalised inflammatory molecular pathways in rheumatoid arthritis.
Further development of peresolimab was discontinued after a subsequent phase 2b dose-ranging study. These data provide mechanistic insight that may inform future PD-1-targeted approaches in rheumatoid arthritis.
Reference
Benschop RJ et al. Cellular and proteomic changes following administration of peresolimab in patients with rheumatoid arthritis: a post-hoc analysis of a randomised phase 2a trial. Lancet Rheumatol. 2026;DOI:10.1016/S2665-9913(26)00218-3.
Featured image: Khunatorn on Adobe Stock
Khunatorn on Adobe Stock
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