Twice-yearly Depemokimab Reduces Exacerbations and Improves Quality of Life in Patients With Uncontrolled Asthma Symptoms at Baseline: Subgroup Analyses of the Phase III SWIFT-1/2 Studies

Abstract Rationale: Depemokimab is the first ultra-long-acting biologic with enhanced interleukin-5 binding affinity, high potency, and extended half-life, potentially enabling twice-yearly dosing in patients with asthma. In the Phase III SWIFT-1/2 studies, depemokimab significantly reduced exacerbations with sustained inhibition of type 2 inflammation observed in patients with type 2 asthma characterized by blood eosinophils.1 Uncontrolled asthma symptoms were not required for inclusion, so patients with any baseline Asthma Control Questionnaire-5 (ACQ-5) score were eligible. This post hoc subgroup analysis of pooled SWIFT-1/2 data investigated outcomes by ACQ-5 score <1.5 versus ≥1.5, with ≥1.5 indicating uncontrolled asthma symptoms. Methods: Patients ≥12 years of age with asthma receiving medium- to high-dose inhaled corticosteroids and ≥1 additional controller, who had ≥2 exacerbations in the past year and blood eosinophil count (BEC) ≥150 cells/µL (screening) or ≥300 cells/µL (past year) were randomized 2:1 to receive depemokimab 100 mg subcutaneously or placebo once every 26 weeks, plus standard of care. The primary endpoint was annualized exacerbation rate at 52 weeks; secondary endpoints included change from baseline to Week 52 in St George's Respiratory Questionnaire (SGRQ) score and ACQ-5. SGRQ response was classed as reduction of ≥4 points versus baseline. Results: Of 744 SWIFT-1/2 patients with baseline ACQ-5 scores (depemokimab, n=490; placebo, n=254), 25% (n=185) had a baseline ACQ-5 score <1.5 (depemokimab, n=127; placebo, n=58) and 75% (n=559) had a baseline ACQ-5 score ≥1.5 (depemokimab, n=363; placebo, n=196); mean baseline ACQ-5 score was 2.21 for depemokimab and 2.24 for placebo. Annualized exacerbation rate reduction was 53% and 54% for ACQ <1.5 and ≥1.5, respectively (Figure A). Depemokimab-treated patients with uncontrolled asthma symptoms (ACQ ≥1.5) at baseline had clinically meaningful improvement in SGRQ at Week 52 (Figure B), with 69% classed as responders based on SGRQ score versus 63% of placebo-treated patients. For patients with ACQ-5 <1.5 at baseline, 51% of depemokimab-treated patients and 55% of placebo-treated patients were classified as responders. There was also a trend toward greater ACQ-5 improvement versus placebo in depemokimab-treated patients with uncontrolled asthma symptoms at baseline (Figure C). Conclusions: Twice-yearly depemokimab consistently reduced exacerbations versus placebo regardless of baseline asthma control, suggesting uncontrolled asthma symptoms are not required to experience an exacerbation reduction in patients with a history of exacerbations. Depemokimab-treated patients who were symptomatic at baseline trended toward sustained clinical improvement in quality of life and better asthma control. Reference: 1. Jackson DJ et al. NEJM 2024;10.1056/NEJMoa2406673.