Mixed AERIFY Data May Delay Itepekimab Approval Pathway in COPD, With Klaus F. Rabe, MD, PhD

At the 2026 American Thoracic Society (ATS) International Conference, Klaus Friedrich Rabe, MD, PhD, of LungenClinic Grosshansdorf GmbH further discussed with HCPLive the implications of the phase 3 AERIFY program evaluating itepekimab in former smokers with chronic obstructive pulmonary disease (COPD), emphasizing both the scientific promise of IL-33 inhibition and the uncertainty surrounding the drug’s future regulatory pathway.1,2

The AERIFY-1 and AERIFY-2 trials evaluated itepekimab, an anti–IL-33 monoclonal antibody, as add-on therapy in patients with COPD despite dual or triple inhaler therapy. While AERIFY-1 met its primary endpoint with significant reductions in moderate or severe exacerbations, AERIFY-2 failed to replicate those findings despite nearly identical trial designs.

During his interview, Rabe addressed additional questions surrounding the studies’ lung function findings, eosinophil-independent design, and next steps for the investigational therapy.

Discussing forced expiratory volume in 1 second (FEV1) outcomes, Rabe acknowledged the data were difficult to interpret. AERIFY-1 demonstrated reductions in exacerbations but minimal improvement in lung function, whereas AERIFY-2 showed more substantial FEV1 signals despite failing on exacerbation endpoints. He cautioned clinicians against overinterpreting the lung function data at this stage, noting the inconsistent dose-response patterns across the studies.

Rabe emphasized itepekimab remains in the development phase and is unlikely to become clinically available in the near term. According to Rabe, had both phase 3 studies produced concordant positive results, sponsors likely would have pursued immediate regulatory submission to the FDA. Instead, he suggested additional clinical evidence may now be required before potential approval.

He also highlighted the rationale behind enrolling patients regardless of baseline eosinophil count. Unlike currently approved biologic therapies for COPD, which primarily benefit patients with type 2 inflammation and elevated eosinophils, anti-alarmin therapies such as itepekimab are being developed for broader COPD populations. Rabe noted the trials intentionally included a wide range of eosinophil levels and that analyses did not demonstrate a clear efficacy signal tied to eosinophil counts, supporting the hypothesis that IL-33 inhibition may work independently of traditional type 2 biomarkers.

Looking ahead, Rabe pointed to ongoing extension data from AERIFY-1 and AERIFY-2, as well as additional mechanistic findings expected from the AERIFY-3 biopsy study later this year. Although he personally anticipates regulators may require another confirmatory study, he stressed the broader importance of IL-33 as an emerging therapeutic target in COPD.

Despite the mixed trial results, Rabe said the overall findings reinforce growing interest in anti-alarmin therapies and suggest IL-33 inhibition may ultimately provide a treatment option for a wider spectrum of patients with COPD beyond eosinophilic disease.

References

1. Rabe K, Martinez F, Mouded M, et al. Efficacy and Safety of Itepekimab in Former Smokers With Chronic Obstructive Pulmonary Disease: AERIFY-1 and AERIFY-2 Trials. Poster presented at ATS 2026 on May 17.

2. Rabe K. AERIFY: Phase 3 Data Reveal Challenges, Potential of Itepekimab in COPD. HCPLive. May 20, 2026. Accessed May 21, 2026. https://www.hcplive.com/view/aerify-phase-3-data-reveal-challenges-potential-itepekimab-copd.