Prospecting the IL-33 Pathway for COPD Care, with Nicola Hanania, MD, MS

Mepolizumab (Nucala) and dupilumab (Dupixent) made history as the first biologic therapies indicated to treat eligible patients with COPD in the last 2 years.1,2 The recency of those pharmaceutical breakthroughs highlights not only the previous dearth of treatment advancement for patients with obstructive lung disease — it also showed how much more clinicians must uncover about the pathophysiology of COPD.

As one leading expert explains, similar pathway-targeting agents may be on the horizon for an even wider population of patients with COPD.

In an interview with HCPLive during the 2025 Global Initiative for Chronic Obstructive Lung Disease (GOLD) International COPD Conference in Philadelphia, PA, Nicola Hanania, MD, MS, professor of medicine and director of the Asthma Clinical Research Center at Baylor College of Medicine, discussed the potential of IL-33 inhibitors to treat patients with COPD.

COPD is driven by 3 epithelial cytokines, Hanania explained: interleukin 33, 25 (IL-33; IL-25), and thymic stromal lymphopoietin (TSLP). IL-33 is released when the epithelium is harmed.

“And we know COPD patients [suffer] exposure to smoke, exposure to microbes and pollution, and all these can trigger injury to the epithelium,” Hanania said. “And thus, IL-33 has been shown to be expressed at a higher level in COPD and actually correlates with increased risk of exacerbation.”

IL-33 is associated with the trigger of type 1, 2, and 3 inflammation in patients with COPD. Whereas the IL-4 and IL-13-targeting dupilumab solely benefits exacerbations in patients with type 2 inflammation, an IL-33 inhibitor hypothetically may positively impact most patients with COPD.

Early clinical trials assessing 3 different IL-33 inhibitors — including itepekimab, tozorakimab and the ST2 receptor inhibitor astegolimab — suggest this approach may particularly benefit COPD exacerbations in patients who previously smoked.3-5 But late-stage assessments are ongoing.

“I think the jury is still out regarding blocking IL-33, but certainly it's a plausible pathway,” Hanania said. “I think there's been lots of discussion here and excitement that we're looking outside the box now for COPD. Certainly, type 2 pathway [targeting]…is very important, but blocking other inflammatory pathways is also very plausible.”

References

1. Johnson V, Iapoce C. FDA Approves Mepolizumab for Eosinophilic COPD. HCPLive. Published online May 22, 2025. https://www.hcplive.com/view/fda-approves-mepolizumab-for-eosinophilic-copd
2. Smith T. FDA Approves Dupilumab (Dupixent) for Treatment of COPD. HCPLive. Published online September 27, 2024. https://www.hcplive.com/view/fda-approves-dupilumab-dupixent-for-treatment-of-copd
3. Rabe KF, Martinez FJ, Bhatt SP, et al. AERIFY-1/2: two phase 3, randomised, controlled trials of itepekimab in former smokers with moderate-to-severe COPD. ERJ Open Res. 2024;10(5):00718-2023. Published 2024 Sep 23. doi:10.1183/23120541.00718-2023
4. Singh D, Guller P, Reid F, et al. A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4. Eur Respir J. 2025;66(1):2402231. Published 2025 Jul 14. doi:10.1183/13993003.02231-2024
5. Greening N, Brightling C, Tal-Singer R, et alS1 Randomised, placebo-controlled trial of astegolimab for COPD with frequent exacerbations: ALIENTOThorax 2025;80:A7.