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Checkpoint Stimulator Passes Mid-Stage Test in Rheumatoid Arthritis

— Novel approach to normalizing immune activity

MedpageToday

PHILADELPHIA -- Aimed at treating rheumatoid arthritis, an investigational antibody drug that stimulates checkpoint activity yielded good results in a reported here.

After 12 weeks, patients assigned to the drug, called peresolimab, achieved significantly greater improvement in symptoms as assessed through the 28-joint Disease Activity Score (DAS28) and the Clinical Disease Activity Index (CDAI) than did a placebo group, said Paul Emery, MD, of the University of Leeds in England.

In a second phase of the study with no placebo control, which was limited to participants who attained low disease activity in the first 12 weeks, clinical responses were maintained for an additional 12 weeks, Emery told attendees at the American College of Rheumatology's (ACR) annual meeting at a late-breaking abstract session.

Checkpoint-modulating drugs have taken the oncology world by storm in recent years. They seek to counteract tumors' ability to shut down immune attack through the programmed death-1 (PD-1) receptor on immune cells. Those drugs, epitomized by pembrolizumab (Keytruda) and nivolumab (Opdivo), inhibit this pathway.

Peresolimab has the opposite aim: it stimulates the PD-1 receptor as a means of preventing pathogenic immune cells from replicating. This, Emery explained, should rein in the overactivity and "restore normal homeostasis."

His multicenter study appears to be the first to test the hypothesis in rheumatoid arthritis patients.

A total of 98 patients were enrolled, randomized in a 1:2:1 ratio to 300 mg or 700 mg of peresolimab or placebo, each given by infusion every 4 weeks. Participants were typical for such trials: mostly women, mean age of about 50, with disease duration averaging 10 years and substantial current disease activity despite treatment. About 60% were using corticosteroids and nearly half had previously taken a biologic or other targeted agent for rheumatoid arthritis. Mean disease severity scores at baseline were about 5.9 on the DAS28 and 40 with CDAI.

During the initial 12-week phase, similar improvements in all three arms were seen for DAS28 total score and the CDAI up to week 8. At that point, the placebo group had no further improvement while scores on both measures continued to decline (indicating less disease activity) in the two peresolimab groups. Most of the DAS28's individual components showed a similar pattern, except for patients' global assessments, for which no difference was apparent among the three arms.

In general, efficacy was similar for the two peresolimab doses, although trends favored the higher dose on many measures. During the second phase, in which 42 patients in the peresolimab groups who had achieved CDAI scores ≤10 in the first phase continued with dosing for another 12 weeks, CDAI scores remained low with no difference between the dosage groups.

Safety findings were encouraging, Emery said, with no major differences between the active drug and placebo. Infections were numerically greater with peresolimab. Some 8% of the high-dose peresolimab group experienced nausea, which did not occur in the other groups, but there were no discontinuations because of nausea and the effect appeared to be confined to the first few doses.

Following Emery's talk, an audience member asked whether the approach could increase cancer risk, helping early malignancies escape "immune surveillance" and grow more rapidly. Emery replied that this will be evaluated in larger studies, but "there are reasons to believe" that it will not occur; the hypothesized mechanism of action does not suppress normal immune function but rather targets only the overactivity in rheumatoid arthritis, he explained.

in rheumatoid arthritis with planned enrollment of 420 patients recently got underway. Sponsor Eli Lilly had conducted an early trial in psoriasis patients but it was quietly terminated and the company appears to have no further plans for peresolimab in that condition.

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    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The study was sponsored by Eli Lilly. Several authors were Lilly employees. Emery reported relationships with the firm and numerous others.

Primary Source

American College of Rheumatology

Tuttle J, et al "A phase 2 trial of peresolimab for adults with rheumatoid arthritis" ACR 2022; Abstract L03.