Authors: Dave Singh, Patricia Guller, Fred Reid, Sarah Doffman, Ulla Seppälä, Ioannis Psallidas, Rachel Moate, Rebecca Smith, Joanna Kiraga, Eulalia Jimenez, Dennis Brooks, Aoife Kelly, Lars H. Nordenmark, Muhammad Waqas Sadiq, Luis Mateos Caballero, Chris Kell, Maria G Belvisi, Hitesh Pandya
Published: 2025-03-28
DOI: 10.1183/13993003.02231-2024
Source: Full article
BackgroundInterleukin-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.MethodsFRONTIER-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) FEV1from baseline to week 12. Secondary outcomes included post-BD FEV1, time-to-first COPDCompEx event and safety.ResultsThe 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 improvementsversusplacebo (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.ConclusionAlthough the primary endpoint was not met in the intent-to-treat population, tozorakimab showed positive efficacy signalsversusplacebo in a subgroup of patients with COPD with a high risk of exacerbations.