Dose response of icenticaftor in patients with COPD and chronic bronchitis on triple inhaled therapy

Background: CF Transmembrane Conductance Regulator (CFTR) dysfunction disrupts airway homeostasis and is associated with COPD symptom worsening. This Phase 2b dose finding study compared the novel, oral CFTR potentiator icenticaftor (QBW251) in patients with COPD and chronic bronchitis (CB) and history of exacerbations, with placebo, when added to standardized inhaled triple therapy (LABA/LAMA/ICS) using a model-based approach (NCT04072887). Methods: 974 patients were randomized to 6 BID treatment arms (450mg, 300mg, 150mg, 75mg, 25mg, placebo), in a 24-week, multi-centre, parallel-group, double-blind study. Primary endpoint was trough FEV₁ change from baseline after 12 weeks. Secondary endpoints included FEV₁, EXACT-Respiratory Symptoms (E-RS) total score and E-RS cough and sputum (C&S) score after 24 weeks. Rescue medication use (RM) after 6 months was an exploratory endpoint. Results: While no dose response in FEV₁ was observed after 12 weeks, it was observed after 24 weeks, for FEV₁, E-RS C&S and total scores, and RM, with 300mg BID consistently the most effective dose. Consistent improvements for 300 mg BID were also seen in pairwise comparisons for these endpoints (Figure). All treatments were well-tolerated. Conclusion: Icenticaftor improved symptoms over 24 weeks with associated improvements in FEV₁, E-RS total score, and RM in COPD patients with CB on triple therapy.