B14-03 Efficacy and Safety of Itepekimab in Former Smokers With Chronic Obstructive Pulmonary Disease: AERIFY-1 and AERIFY-2 Trials

Abstract Rationale Interleukin-33 (IL-33) is a key cytokine that initiates and amplifies inflammation in chronic obstructive pulmonary disease (COPD). Itepekimab, a fully human monoclonal antibody, inhibits IL-33 signaling and reduced moderate or severe exacerbations in former smokers in a proof-of-concept study. AERIFY-1 and AERIFY-2 investigated itepekimab efficacy and safety in patients with COPD who were former smokers. Methods AERIFY-1 (NCT04701983) and AERIFY-2 (NCT04751487), two phase 3, multinational, randomized, double-blind, placebo-controlled trials, enrolled former smokers (smoking cessation ≥6 months before screening) aged 40-85 years with physician-diagnosed COPD for ≥1 year (GOLD standard definition), ≥2 moderate or ≥ 1 severe exacerbations in the previous year, and moderate-to-severe airflow limitation (post-bronchodilator percent predicted forced expiratory volume in 1 second [FEV1] ≥30% to < 80%), despite being on triple or dual inhaler therapy, irrespective of screening blood eosinophil counts. Patients received subcutaneous add-on itepekimab 300 mg every 2 or 4 weeks (q2w, q4w), or placebo, for 52 weeks. Primary endpoint: annualized moderate or severe exacerbation rate; key secondary endpoint: change in pre-bronchodilator FEV1 at Week 24. A secondary population of current smokers receiving itepekimab 300 mg q2w or placebo was also evaluated in AERIFY-2. Results In AERIFY-1, former smokers received itepekimab q2w (n = 375), q4w (n = 377), or placebo (n = 375). Itepekimab vs placebo reduced moderate or severe exacerbation rates by 27.1% (q2w; P=0.0019) and 20.5% (q4w; P=0.0213). In AERIFY-2, former smokers were randomized to itepekimab q2w (n = 326), q4w (n = 303), or placebo (n = 324). Itepekimab vs placebo reduced exacerbations by 1.6% (q2w; P=0.8781) and 12.4% (q4w; P=0.2176). In AERIFY-1, no meaningful improvements were observed in pre-bronchodilator FEV1 at Week 24 (least squares mean difference vs placebo was 6 mL [q2w; P=0.7453] and 10 mL [q4w; P=0.5962]). In contrast, itepekimab vs placebo significantly improved pre-bronchodilator FEV1 at Week 24 in AERIFY-2 (least squares mean difference vs placebo) by 38 mL (q2w; Pnominal=0.0311) and 75 mL (q4w; Pnominal