Peresolimab superior to placebo for rheumatoid arthritis treatment
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Key takeaways:
- Peresolimab was beneficial for patients with rheumatoid arthritis, compared with placebo, in a phase 2a study.
- Doses of 700 mg were favorable regarding ACR20 responses, but not ACR50 or ACR70.
Peresolimab 700 mg is superior to placebo in the treatment of moderate-to-severe rheumatoid arthritis, according to data published in the New England Journal of Medicine.
“Immunotherapy targeting the PD-1–PD-L1 pathway has proved to be effective against various cancers, but it has also been associated with toxic effects collectively defined as immune-related adverse events,” Jay Tuttle, PhD, associate vice president of research and development at Eli Lilly & Co., and colleagues wrote. “Peresolimab, a humanized IgG1 monoclonal antibody, binds and activates PD-1.”
To investigate the safety and efficacy of peresolimab (Eli Lilly & Co.) in patients with RA, Tuttle and colleagues conducted a phase 2a, double-blind, randomized, placebo-controlled study. Patients were eligible to participate if they were aged older than 18 years and had a confirmed diagnosis of moderate-to-severe adult-onset RA. In addition, patients were required to demonstrate active synovitis in at least one joint in their hands or wrists, and to have had inadequate response to, a loss of response to, or unacceptable side effects from, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), or to biologic or targeted synthetic DMARDs.
Those who met the study criteria were randomized 2:1:1 to receive peresolimab 700 mg, 300 mg or placebo every 4 weeks throughout the study. Patients were able to continue therapy with oral methotrexate, hydroxychloroquine, oral sulfasalazine, NSAIDs and glucocorticoids throughout the study period.
The primary efficacy outcome was the measurable change from baseline to 12 weeks regarding DAS28 using C-reactive protein levels. The main comparison of concern was the 700 mg group compared with those who received a placebo. Secondary endpoints included American College of Rheumatology 20% (ACR20), ACR50 and ACR70 responses.
A total of 98 patients were enrolled in the study, including 49 in the 700 mg dose group, 25 in the 300 mg group and 24 who received a placebo. After 12 weeks, changes in DAS28-CRP were “significantly greater” in the group that received 700 mg doses vs. those in the placebo group (Difference in change = –1.09; 95% CI, –1.73 to –0.46), according to the researchers. Doses of 700 mg were favorable regarding ACR20 responses, but not ACR50 or ACR70, the researchers added. Regarding safety, there was one serious adverse event reported in the 700 mg group. However, it was deemed to be unrelated to treatment.
“In this phase 2a trial involving adults with moderate-to-severe rheumatoid arthritis, the
PD-1 agonist monoclonal antibody peresolimab, at a dose of 700 mg, was superior to placebo with respect to the change from baseline in the DAS28-CRP at week 12,” Tuttle and colleagues wrote. “Longer and larger trials are needed to assess the efficacy and safety of peresolimab in rheumatoid arthritis.”
Perspective
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In the long tradition of novel therapeutic agents inspired by the development of fortuitous accidents and medication side effects, Tuttle and colleagues present an early trial of peresolimab, a humanized monoclonal antibody to bind and activate programmed (cell) death (PD1) protein and ligand, thereby suppressing rheumatoid arthritis-associated T-cell activation and tamping down the production of proinflammatory cytokines.
The adverse effects that led to the drug’s synthesis were of course the immune-related adverse effects of the immune checkpoint inhibitor therapies used for the past decade to revolutionize the treatment of multiple types of cancers. However, it has been recognized that these agents can trigger multiple autoimmune disorders, among which is a rheumatoid-like inflammatory polyarthritis, which is often seropositive.
The 700 mg dose proved quite effective for the primary outcome of significant DAS28-CRP change from baseline vs. placebo, and successful as well in attaining ACR20 improvement from baseline in one secondary outcome. There were additional trends toward betterment in several other ancillary outcome measures. It succeeded in this task all the more impressively given that a high proportion of these patients were biologic and targeted synthetic DMARD experienced.
A notable drawback of the trial was its small size, with no African American or Hispanic patients listed as having been included, and its short duration. This limitation particularly important because of the need to assess the frequency of adverse effects and risk for cancer association, given that blocking the interaction of PD1 and its ligand result in such impressive tumor regression.
Ultimately, it appears that much more needs to be known about the use, efficacy and safety of this molecule before it becomes part of our RA treatment armamentarium, but it does appear to have a novel mechanism of action not previously explored, and therefore a welcome concept that we look forward to learning more about in future studies.
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