Dupilumab Efficacy on Chronic Obstructive Pulmonary Disease (COPD) Exacerbations and Lung Function by Cough and Sputum Score: Pooled Results From Phase 3 BOREAS and NOTUS

Abstract RATIONALE: Chronic cough and sputum production are prevalent in patients with chronic obstructive pulmonary disease (COPD) and are associated with increased risk of exacerbations and morbidity. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation. In BOREAS and NOTUS trials, add-on dupilumab reduced exacerbations and improved lung function in patients with COPD and type 2 inflammation. Safety was consistent with the known dupilumab safety profile. This post-hoc pooled analysis investigated dupilumab efficacy based on baseline cough and sputum scores in patients with COPD from BOREAS and NOTUS. METHODS: BOREAS (NCT03930732) and NOTUS (NCT04456673) both were phase 3 randomized, double-blind, placebo-controlled trials of patients with COPD, moderate-to-severe airflow limitation, and type 2 inflammation (blood eosinophils ≥300 cells/µL at screening) on triple therapy (inhaled corticosteroids, long-acting β2-agonists, and long-acting muscarinic antagonists) unless contraindicated, with investigator reported chronic cough/chronic bronchitis (emphysema not excluded). Patients were randomized 1:1 to receive dupilumab 300 mg or placebo subcutaneously every 2 weeks for 52 weeks. The Evaluating Respiratory Symptoms in COPD tool (E-RS:COPD) was used to evaluate baseline cough and sputum scores (range 0−11, with lower scores indicating less severe symptoms). Assessed endpoints included the moderate or severe exacerbation rates and pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Week 12, in patients dichotomized by median baseline cough and sputum score. RESULTS: Median baseline cough and sputum score was 3.4 points. Of 1,851 patients with cough and sputum scores at baseline, 914 (dupilumab n=449; placebo n=465) had a baseline score equal to median or higher, and 937 (dupilumab n=475; placebo n=462) scored below the median. Compared with placebo, dupilumab reduced moderate or severe exacerbations by 29% (relative risk, RR [95% CI]: 0.71 [0.59, 0.87]) in patients with baseline cough and sputum score equal to median or higher, and by 33% (RR [95% CI]: 0.67 [0.54, 0.83]) in those who scored below the median. Dupilumab improved pre-bronchodilator FEV1 at Week 12 compared with placebo by least squares mean difference (95% CI) of 91 (51, 131) mL (baseline score equal to median or higher) and 81 (36, 125) mL (below median baseline score). CONCLUSION: In this pooled analysis of BOREAS and NOTUS, dupilumab significantly reduced exacerbation rates and improved lung function compared to placebo irrespective of high or low E-RS:COPD cough and sputum score at baseline.