Anti-IL-33 Antibody Shows Promise in High-Risk Patients with COPD

A NEW monoclonal antibody therapy targeting IL-33 has shown encouraging results in a subgroup of patients with COPD with frequent exacerbations, according to Phase 2a trial data from FRONTIER-4.

IL-33 is increasingly recognised as a key player in the inflammatory processes of COPD, particularly in patients with chronic bronchitis. The FRONTIER-4 study evaluated the efficacy and safety of tozorakimab, an anti-IL-33 monoclonal antibody, in 135 patients with moderate-to-severe COPD who were already receiving dual or triple inhaled maintenance therapy. Participants were randomised to receive either tozorakimab 600 mg or placebo via subcutaneous injection every 4 weeks for 24 weeks. The primary outcome was change from baseline in pre-bronchodilator FEV₁ at 12 weeks, with secondary endpoints including post-bronchodilator FEV₁, time to first composite exacerbation, and safety measures.

In the overall intent-to-treat population, the primary endpoint was not met: the difference in pre-bronchodilator FEV₁ at Week 12 between tozorakimab and placebo groups was a non-significant 24 mL (80% CI: –15 to 63 mL; p=0.216). However, tozorakimab did achieve a statistically significant improvement in post-bronchodilator FEV₁, with a mean difference of 67 mL versus placebo (p=0.044). Notably, among the predefined subgroup of patients with a history of two or more exacerbations, the benefits were more pronounced. Pre-bronchodilator FEV₁ increased by 69 mL (p=0.072) and post-bronchodilator FEV₁ by 124 mL (p=0.020) compared with placebo.

While the overall reduction in exacerbation risk did not reach significance (hazard ratio: 0.79; p=0.186), a greater effect was observed in the high-risk subgroup (hazard ratio: 0.61), approaching the threshold for statistical significance. Safety profiles were similar between groups, and tozorakimab was well tolerated in both former and current smokers.

Although the trial did not meet its primary endpoint, the subgroup analysis suggests that targeting IL-33 with tozorakimab may offer clinical benefit for patients with COPD who are prone to frequent exacerbations. These findings support further investigation in this patient population.

Reference

Singh D 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.