<p>Efficacy and Safety of the CFTR Potentiator Icenticaftor (QBW251) in COPD: Results from a Phase 2 Randomized Trial</p>
Steven M. Rowe, Ieuan Jones, Mark T. Dransfield, Nazmul Haque, Stephen Gleason, Katy Hayes, Kenneth Kulmatycki, Denise P. Yates, Henry Danahay, Martin Gosling, David J. Rowlands, Sarah Schmidt Grant
Abstract
Rationale: Excess mucus plays a key role in COPD pathogenesis. Cigarette smoke-induced cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction may contribute to disease pathogenesis by depleting airway surface liquid and reducing mucociliary transport; these defects can be corrected in vitro by potentiating CFTR. Objective: To assess the efficacy of the CFTR potentiator icenticaftor in improving airflow obstruction in COPD patients with symptoms of chronic bronchitis. Methods: In this double-blind, placebo-controlled study, COPD patients were randomized (2:1) to either icenticaftor 300 mg or placebo b.i.d. This non-confirmatory proof of concept study was powered for lung clearance index (LCI) and pre-bronchodilator FEV 1 , with an estimated sample size of 90 patients. The primary endpoint was change from baseline in LCI for icenticaftor versus placebo at Day 29; key secondary endpoints included change from baseline in pre- and post-bronchodilator FEV 1 on Day 29. Key exploratory endpoints included change from baseline in sweat chloride, plasma fibrinogen levels, and sputum colonization. Results: Ninety-two patients were randomized (icenticaftor, n=64; placebo, n=28). At Day 29, icenticaftor showed no improvement in change in LCI (treatment difference: 0.28 [19% probability of being better than placebo]), an improvement in pre-bronchodilator FEV 1 (mean: 50 mL [84% probability]) and an improvement in post-bronchodilator FEV 1 (mean: 63 mL [91% probability]) over placebo. Improvements in sweat chloride, fibrinogen and sputum bacterial colonization were also observed. Icenticaftor was safe and well tolerated. Conclusion: The CFTR potentiator icenticaftor increased FEV 1 versus placebo after 28 days and was associated with improvements in systemic inflammation and sputum bacterial colonization in COPD patients; no improvements in LCI with icenticaftor were observed. Keywords: chronic obstructive pulmonary disease, chronic bronchitis, cystic fibrosis transmembrane conductance regulator potentiator, CFTR potentiator, mucociliary clearance, icenticaftor; QBW251