Stimulation of PD-1: a new concept to treat RA

Peresolimab was significantly superior to placebo in reducing the Disease Activity Score-28 with C-reactive protein (DAS28-CRP) as well as Clinical Disease Activity Index (CDAI) in patients with rheumatoid arthritis (RA). The safety profile did not demonstrate a dose effect of the study drug.

The programmed cell death protein 1 (PD-1) agonist peresolimab represents a novel mode of action for the therapy of RA. “We hypothesised that peresolimab binding to PD-1, which is a checkpoint inhibitory receptor, could stimulate physiological immune pathways and restore immune homeostasis,” Prof. Paul Emery (University of Leeds, UK) informed [1].

The presented phase 2a trial (NCT04634253) enrolled participants with moderate-to-severe active RA who had a prior failure to not more than 2 conventional synthetic, biologic, or targeted synthetic DMARDs. In this study, 98 participants were randomly allocated to a high (700 mg) or low-dose (300 mg) arm of peresolimab every 4 weeks or placebo. The change in DAS28-CRP represented the primary endpoint assessed at week 12, ending the first period of the study. At week 14, a further evaluation identified participants who had reached low disease activity defined by CDAI ≤10. They entered period 2 and stayed on 1 of the dosages of the active drug until week 24. All others continued on the standard of care.

The trial population was predominantly female, had a mean age between 50.1 and 55.8 years, and their RA had been present for around 10 years. Among the participants, 36.7% to 48% were experienced in biological or targeted synthetic DMARDs, and about 60% were on corticosteroids.

At week 12, the primary endpoint was met with significantly lower DAS28-CRP in both peresolimab arms than in the placebo arm (P<0.05 for the lower and P<0.001 for the higher dose). “CDAI also produced significant improvements, showing superiority over placebo, so, at the joint level, this drug clearly works,” Prof. Emery further stated. When stratified according to prior use of DMARDs, naïve participants did not have better results than those who were experienced. “There is certainly no loss of response in the advanced therapy experienced patients,” Prof. Emery commented. He also pointed out that participants with low disease activity at week 14 largely maintained their level of change in DAS28-CRP to the end of period 2.

Overall, the safety profile of peresolimab was considered acceptable. “No adverse event was more frequent in the higher dose than in placebo or the lower dose,” Prof. Emery stated. Of note, nausea was reported in 4 participants (8.2%) on the higher dose during period 1, but it did not persist after they continued medication in period 2.

In summary, Prof. Emery pointed out that this data represents the first clinical evidence that agonism of checkpoint inhibitory receptors could be an effective approach to treating rheumatic diseases. Thus, peresolimab should be further evaluated.

 

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   1. Emery P. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. L03, ACR Convergence 2022, 10–14 November, Philadelphia, USA.

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Posted on 1 December 202215 February 2024