Itepekimab Shows Mixed Results in Phase 3 COPD Trials

Itepekimab, an investigational monoclonal antibody for chronic obstructive pulmonary disease (COPD), demonstrated mixed results in a pair of phase 3 studies evaluating the treatment in former smokers with inadequately controlled disease, according to a press release from Sanofi and Regeneron Pharmaceuticals.¹

Itepekimab met the primary end point in the phase 3 AERIFY-1 (NCT04701983) trial by generating a statistically significant reduction in moderate or severe COPD exacerbations after 52 weeks. However, in a second phase 3 trial, AERIFY-2 (NCT04751487), it failed to meet the primary end point despite showing a benefit at 24 weeks.

The use of IL-33 as a target has been an active area of research in COPD. | Image credit: Ahmad - stock.adobe.com

Itepekimab is a fully humanized monoclonal antibody that inhibits interleukin-33 (IL-33). The cytokine is believed to amplify inflammation in COPD and has been shown to be elevated in the lungs of former smokers.

“While we are encouraged by the results of AERIFY-1, the results of both studies merit further exploration to have a full understanding of the data and the role that IL-33 plays in this complex disease,” Houman Ashrafian, MD, PhD, Sanofi’s head of research and development, said in a press release announcing the trial results.¹

In AERIFY-1, patients were randomized to receive itepekimab every 2 weeks (Q2W; 375 participants), every 4 weeks (Q4W; 377 participants), or placebo (375 participants), in addition to inhaled triple or double standard-of-care therapy. The primary end point was the reduction in the annualized rate of acute moderate or severe COPD exacerbations.

At 24 weeks, the therapy led to a 30% reduction in exacerbations in the Q2W group and a 34% reduction in the Q4W group. At 52 weeks, the reduction was 27% in the Q2W group and 21% in the Q4W group, meeting the trial’s primary end point.

In AERIFY-2, 326 patients were randomized into the Q2D group, 303 patients were given itepekimab on a Q4W basis, and 324 patients were given placebo. At 24 weeks, patients in the Q2W group saw an 18% reduction in annualized moderate or severe exacerbations, and those in the Q4W group saw a 21% reduction. At 52 weeks, though, the Q2W group had just a 2% reduction, and the Q4W group had a 12% reduction.

The companies noted that the total number of exacerbations in the trials was lower than they had anticipated, which had the effect of decreasing the power of both trials. They noted that enrollment for the trials took place during the COVID-19 pandemic, which they said might have contributed to lower exacerbation rates.

The use of IL-33 as a target has been an active area of research in COPD. In previous research, the benefits of the therapy were only apparent when data from former and current smokers were segregated.² That is, there was no meaningful benefit in current smokers, but there was a benefit in former smokers. A 2023 study suggested a possible reason for the discrepancy.³ It found that cigarette smoke led to a reduction in expression of IL-33 in the lungs, which may explain why current smokers did not benefit from the therapy.

The safety data for itepekimab were similar across both studies and suggested that the therapy was generally well tolerated. Adverse event rates ranged from 64% to 71% across treatment arms, and the rates were similar in the placebo arms.

George D. Yancopoulos, MD, PhD, the president and chief scientific officer at Regeneron, said they were encouraged by the AERIFY-1 results and will continue to evaluate the data to help determine their next steps.¹ “We remain committed to our broader itepekimab development program,” he said in the press release. “The learnings will be invaluable as we continue to advance itepekimab in respiratory diseases with unmet need.”

References

1. Sanofi and Regeneron. Press Release: Itepekimab met the primary endpoint in one of two COPD phase 3 studies. Sanofi. May 30, 2025. Accessed June 26, 2025. https://www.sanofi.com/en/media-room/press-releases/2025/2025-05-30-05-00-00-3090818

2. Rabe KF, Celli BR, Wechsler ME, et al. Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial. Lancet Respir Med. 2021;9(11):1288-1298. doi:10.1016/S2213-2600(21)00167-3

3. Faiz A, Mahbub RM, Boedijono FS, et al. IL-33 Expression Is lower in current smokers at both transcriptomic and protein levels. Am J Respir Crit Care Med. 2023;208(10):1075-1087. doi:10.1164/rccm.202210-1881OC