PD-1 agonist generates ‘a bit of excitement’ in rheumatoid arthritis
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PHILADELPHIA — A novel therapy targeting human programmed cell death protein-1 showed efficacy in rheumatoid arthritis with an attractive safety profile, according to a speaker at ACR Convergence 2022.
“Our objective was to test the efficacy of peresolimab (Eli Lilly) in moderately or severely active RA,” Paul Emery, MD, of the University of Leeds, in the United Kingdom, told attendees.
According to Emery, peresolimab is a humanized immunoglobulin G1 monoclonal antibody that stimulates human programmed cell death protein 1 (PD-1). The researchers hypothesized that the binding of peresolimab to PD-1 could stimulate physiological immune inhibitory pathways to restore immune homeostasis.
“It gives us the opportunity to tell you about another mode of action that has generated a bit of excitement,” Emery said.
The current phase 2a, double-blind, placebo-controlled, randomized clinical trial included 101 patients with RA. Among these patients, 49 received IV peresolimab 700 mg, 25 were treated with peresolimab 300 mg and 24 received a placebo. Treatment was administered every 4 weeks.
The cohort was more than 80% women, with a mean age at baseline of 51.7 years, a mean disease duration of 10 years at baseline, and a mean baseline DAS28-CRP score of 5.9. Additionally, patients demonstrated an average of six swollen joints and objective evidence of synovitis on MRI at baseline.
“The inclusion criteria are pretty standard,” Emery said.
Primary endpoint results showed significant improvements from baseline to week 12 in DAS28-CRP score in both the peresolimab 700 mg (P < .001) and 300 mg (P = .017) groups, compared with placebo.
“There is superiority for both doses of the active drug,” Emery said. “The primary endpoint was met for the superiority of this drug over placebo. At the joint level, this drug clearly works.”
CDAI score also significantly improved compared with placebo among the 700 mg (P < .001) and 300 mg (P = .008) groups.
Meanwhile, the 700-mg dose yielded significant improvement compared with placebo in terms of ACR20 response (P < .05).
Emery added that swollen joint counts also “significantly improved.”
Although the patient global assessment score showed a “continual improvement,” there was no separation between treatment and placebo for these patient-reported parameters, according to Emery.
Regarding patients who were experienced with disease-modifying anti-rheumatic drugs vs. those who were DMARD-naïve, Emery pointed out “no loss of response” in the experienced group.
“Normally, you would expect naïve patients to do better,” he said. “There was a trend toward a better response in the targeted synthetic and biologic DMARD [experienced] patients.”
Emery then highlighted an important conclusion to be drawn from this outcome.
“More refractory patients are doing well,” he said.
Safety data through 24 weeks demonstrated just two treatment-emergent adverse events in the low-dose peresolimab group, and five events in the high-dose group, according to Emery. He added that there were no treatment discontinuations in the high-dose arm at any point in the study.
“There is no adverse event that is higher in the high dose [group compared with the] lower dose or placebo,” Emery said. “There is no dose effect.”
If there was a caveat about the broader applicability of the findings, it is that the patient population is small. That said, Emery found both the efficacy and safety data to be 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,” Emery said. “They represent the first clinical evidence that agonism of checkpoint inhibitory receptors could be an effective approach to treat rheumatic disease.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Paul Emery, MD, presented a phase 2a study using peresolimab (Eli Lilly) to target the programmed cell death protein 1 (PD-1) in rheumatoid arthritis. PD-1 is an immune checkpoint that provides inhibitory signals to the immune system to modulate the activity of T cells and maintain self-tolerance in the setting of infection and inflammation.
PD-1 was discovered by Tasuku Honjo, MD, PhD — co-winner of the 2018 Nobel Prize in Physiology or Medicine — and colleagues in Japan. They demonstrated that PD-1 knockout mice were prone to autoimmune disease — lupus-like glomerulonephritis and dilated cardiomyopathy — and hence concluded that PD-1 was a negative regulator of immune responses. Suppressing T cell inflammatory activity prevents autoimmune diseases, but also prevents the immune system from killing cancer cells. Developing checkpoint inhibitors has been an ongoing successful development in cancer treatment.
PD-1 guards against autoimmunity through two mechanisms. First, it promotes apoptosis of antigen-specific T cells in lymph nodes and, second, it reduces apoptosis of regulatory T cells. It is surprising, then, that a PD-1 inhibitor is being used in an autoimmune disease. This study showed statistically significant improvement by DAS28-CRP in the peresolimab groups — 300 mg or 700 mg — every 4 weeks intravenously vs. placebo. Of particular significance was the similar efficacy of peresolimab in those with prior exposure to DMARDs.
This is always a difficult-to-treat group, as the best response in studies is always those without prior DMARD treatment. This gives optimism that peresolimab might be effective in these treatment-resistant RA patients. Specific data on safety was not presented but the treatment emergent adverse events were similar in all groups, and no one in the high dose peresolimab group discontinued treatment due to adverse events. This was a phase 2a study, and we will have to wait for further data to see if this new mechanism of action will be added to the rheumatologist’s toolbox for RA in the future.
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Emery P. Abstract L03. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
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