Late Breaking Abstract - FRONTIER-4: a phase 2a study to investigate tozorakimab (anti-IL-33 mAb) in COPD

<bold>Introduction:</bold> FRONTIER-4 (<ext-link>NCT04631016</ext-link>) examined the effect of tozorakimab on lung function in COPD patients with chronic bronchitis on dual- or triple-inhaled maintenance therapy. <bold>Methods:</bold> Patients were randomized 1:1 to receive tozorakimab 600 mg or placebo (PBO) s.c. Q4W. The primary endpoint was change in pre-BD FEV1 from baseline to week 12. Secondary outcomes included post-BD FEV1, time-to-first COPDCompEx event and safety. <bold>Results:</bold> The ITT population included 135 patients (tozorakimab, n=67; PBO, n=68). Baseline mean (SD) % predicted pre-BD FEV1 was 44.0% (15.2) for tozorakimab; 45.2% (12.9) for PBO. Former smokers comprised 64.2% (n=43) for tozorakimab; 52.9% (n=36) for PBO. Most patients (>88%) had baseline blood eosinophil counts (BEC) <300 cells/μL. Although the primary endpoint was not met, at week 12 tozorakimab numerically improved pre-BD FEV1 vs PBO (LS mean: 24mL [80% CI −15, 63] p=0.216). Greater effects were observed in patients with ≥2 exacerbations in the prior 12 months (LS mean: 69mL [80% CI 9, 130] n=59) and in those with BEC ≥150 cells/μL (LS mean: 82mL [80% CI 26, 138] n=62). Tozorakimab improved post-BD FEV1 vs PBO at week 12 (LS mean: 67mL [80% CI 17, 116] p=0.044). In a time-to-event analysis, tozorakimab numerically reduced risk of COPDCompEx events vs PBO at week 28 (HR=0.79 [80% CI 0.57, 1.11] p=0.186), with greater effect in patients with ≥2 exacerbations in the prior 12 months (HR=0.61 [80% CI 0.37, 1.00]). Numerical improvements in all endpoints presented here were seen in both former and current smokers. Tozorakimab was well tolerated. <bold>Conclusion:</bold> Tozorakimab may improve lung function and reduce COPD exacerbations, especially in patients with frequent exacerbation history.