AERIFY: Phase 3 Data Reveal Challenges, Potential of Itepekimab in COPD

At the 2026 American Thoracic Society (ATS) International Conference, Klaus Friedrich Rabe, MD, PhD, of LungenClinic Grosshansdorf GmbH discussed new phase 3 findings evaluating itepekimab, an anti–IL-33 monoclonal antibody, in former smokers with chronic obstructive pulmonary disease (COPD), highlighting both the promise and uncertainty surrounding the investigational medication.1

The data resulted from the multinational AERIFY-1 and AERIFY-2 trials, which assessed itepekimab as an add-on therapy in patients with COPD despite dual or triple inhaler treatment. Both analyses involved evaluations of former smokers with frequent exacerbations and moderate-to-severe airflow limitation, though a smaller cohort of current smokers was also evaluated in AERIFY-2.

In AERIFY-1, itepekimab met its primary endpoint, reducing annualized moderate or severe exacerbation rates by 27.1% with every-2-week dosing and by 20.5% with every-4-week dosing compared with placebo. However, the findings were not replicated in AERIFY-2, where exacerbation reductions were considerably smaller and not statistically significant. Safety findings across both trials were generally comparable between treatment and placebo groups.

Speaking during an interview at ATS, Rabe described the results as evidence that “a new drug is on the horizon” for patients with COPD who fall outside the traditional type 2 inflammatory phenotype often associated with elevated eosinophils. He noted currently available biologic therapies in COPD largely target a minority subset of patients with type 2 inflammation, emphasizing the need for additional therapeutic pathways.

Rabe explained IL-33 acts as an epithelial-derived signaling protein released in response to airway injury and inflammation, triggering downstream inflammatory cascades implicated in COPD pathogenesis. Blocking IL-33 with a monoclonal antibody such as itepekimab, he said, may help address inflammatory mechanisms not adequately targeted by existing therapies.

He also addressed the decision to focus the primary analysis on former smokers. According to Rabe, earlier phase 2 findings suggested current smokers derived little or no benefit from itepekimab, whereas former smokers appeared more responsive. Investigators therefore designed the phase 3 program around that observation while still including a smaller cohort of current smokers to confirm prior findings.

Rabe acknowledged the most notable challenge from the program was the divergence between AERIFY-1 and AERIFY-2 despite nearly identical trial designs. He noted the therapy appeared effective through approximately 24 weeks in AERIFY-2 before the efficacy signal diminished later in the study period.

While investigators have not identified a definitive explanation, Rabe suggested pandemic-era variability during study conduct, including regional differences in masking practices, vaccination rates, infection waves, and healthcare utilization during COVID-19, may have influenced exacerbation outcomes and contributed to the discordant findings.

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.