A phase 2a trial of the IL-33 mAb tozorakimab in patients with COPD: FRONTIER-4.

Abstract

Background: Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-IL-33 monoclonal antibody) in moderate-to-severe COPD patients with chronic bronchitis receiving dual or triple inhaled therapy.

Methods: FRONTIER-4 was a phase 2a, randomized, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary endpoint was change in pre-bronchodilator (BD) FEV₁ from baseline to week 12. Secondary outcomes included post-BD FEV₁, time-to-first COPDCompEx event and safety.

Results: The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase from baseline in pre-BD FEV₁ (least-squares mean [LSM]: 24 mL [80% confidence interval (CI): -15,63]; p=0.216) that was not statistically significant, and in post-BD FEV₁ (LSM: 67 mL [80% CI: 17,116]; p=0.044), when compared with placebo. Tozorakimab showed improvements versus placebo (LSM [80% CI]) in change from baseline in pre-BD FEV₁ (69 mL [9,130]; p=0.072) and post-BD FEV₁ (124 mL [47,201]; p=0.020) at week 12 in a pre-specified subgroup of patients with ≥2 prior exacerbations. Tozorakimab did not significantly reduce the risk of COPDCompEx events (HR: 0.79 [80% CI: 0.57,1.11]; p=0.186) in the intent-to-treat population, although there were greater effects in patients with ≥2 prior exacerbations (hazard ratio: 0.61 [80% CI: 0.37,1.00]). Results were similar in former and current smokers. Tozorakimab was well tolerated.

Conclusion: Although the primary endpoint was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals versus placebo in a subgroup of patients with COPD with a high risk of exacerbations.