PD-1 checkpoint in play for RA

3 minute read

NEJM publishes an “exciting therapeutic mechanism” for RA treatment, beating usual standards for bDMARD-IR.

A phase IIa study of peresolimab has reported encouraging efficacy and safety findings in refractory rheumatoid arthritis patients.

Peresolimab is a humanised IgG1 monoclonal antibody designed to stimulate the programmed cell death protein 1 (PD-1) inhibitory pathway, with the aim of suppressing T-cell activation. The PD-1 inhibitory pathway is thought to be involved in the pathogenesis of rheumatoid arthritis and targeting it represents a novel approach to treating patients with autoimmune disease.

The multicentre trial involved patients with moderate to severe rheumatoid arthritis who had not responded to previous treatment, had stopped responding or had experienced unacceptable side effects.

Patients taking peresolimab were more likely than those in the placebo group to achieve low disease activity at the end of the trial period and had a greater change from baseline in DAS28-CRP.

The study was presented at ACR 2022 as a late breaking abstract and has now been published in the NEJM.

Speaking at ACR, co-author Dr Paul Emery told delegates the efficacy and safety data were encouraging, particularly in patients with treatment experience.

“This could be more effective or certainly useful in refractory patients, for which we have a really great unmet need still in rheumatoid arthritis,” he said.

“They represent the first clinical evidence that agonism of checkpoint inhibitory receptors could be an effective approach to treat rheumatic disease.”

In an accompanying editorial, Dr Ellen Gravallese and Professor Ranjeny Thomas wrote:

“Many of the current therapies for rheumatoid arthritis act by blocking proinflammatory pathways, and disease often recurs when these therapies are discontinued. Peresolimab has the potential instead to reset the immune response or restore immune tolerance.

“This novel approach provides an exciting therapeutic mechanism for the treatment of rheumatoid arthritis and potentially other autoimmune diseases in which antigen-activated lymphocytes play a pathogenic role.”

A total of 98 patients in the double-blind randomised placebo-controlled trial were assigned 2:1:1 to receive 700mg peresolimab, 300mg or placebo, administered intravenously every four weeks. Patients with low disease activity at 14 weeks continued treatment for up to 24 weeks, with the remaining patients receiving standard of care.

The primary outcome was change from baseline to week 12 in DAS28-CRP, with secondary outcomes including percentage of patients with ACR20, ACR50 and ACR70 responses.

The change in DAS28-CRP from baseline to week 12 was significantly greater in the 700mg peresolimab group than placebo, with a between-group difference in change from baseline of −1.09 (95% CI −1.73 to −0.46; P<0.001). This was mainly due to tender joint and swollen joint counts; there was no difference in the serum CRP and patient self-assessment components.

There was also a better ACR20 response in the 700mg group vs placebo, but not ACR50 or ACR70.

Among other secondary outcomes, there was no difference in patient’s global assessment of disease activity or the scores on the mental and physical components of the SF-36.

Around half the patients in the peresolimab groups achieved CDAI low disease activity at week 14, compared with only a quarter of the placebo group.

The safety profiles were similar in the three different groups and no serious adverse events were reported. Mild or moderate adverse events were mainly infections and skin disorders.

The main limitations of the study were the small numbers and short follow up – in particular with respect to potential cancer risks.

“Because this therapeutic approach is not antigen-specific, one of the biggest concerns about the treatment relates to the development of cancer, an adverse event that probably would not have been identified during the short timeframe of the trial,” wrote Dr Gravallese and Professor Thomas.

NEJM 2023, 18 May

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