Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf GmbH. 

Klaus F. Rabe, MD, PhD

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

2026 American Thoracic Society (ATS) International Conference

, Klaus Friedrich Rabe, MD, PhD, of LungenClinic Grosshansdorf GmbH further discussed with 

 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.

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.

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.

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

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Klaus Friedrich Rabe, MD, PhD, spoke at ATS about the mixed phase 3 AERIFY trial findings on itepekimab, an anti–IL-33 monoclonal antibody, in COPD.

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

, 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.

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.

At ATS, Klaus Friedrich Rabe, MD, PhD, discussed phase 3 data on itepekimab in former smokers with chronic obstructive pulmonary disease (COPD).

Klaus F. Rabe, MD, PhD

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