Efficacy and Safety of the CFTR Potentiator Icenticaftor (QBW251) in COPD: Results from a Phase 2 Randomized Trial
Authors Rowe SM, Jones I, Dransfield MT, Haque N, Gleason S, Hayes KA, Kulmatycki K, Yates DP, Danahay H, Gosling M, Rowlands DJ, Grant SS
Received 8 April 2020
Accepted for publication 15 July 2020
Published 5 October 2020 Volume 2020:15 Pages 2399—2409
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Richard Russell
Steven M Rowe,1 Ieuan Jones,2 Mark T Dransfield,1 Nazmul Haque,2 Stephen Gleason,2 Katy A Hayes,2 Kenneth Kulmatycki,2 Denise P Yates,2 Henry Danahay,3 Martin Gosling,3,4 David J Rowlands,2 Sarah S Grant2
1University of Alabama at Birmingham, Department of Medicine, Birmingham, AL, USA; 2Novartis Institutes for BioMedical Research, Cambridge, MA, USA; 3Enterprise Therapeutics, Brighton, UK; 4Sussex Drug Discovery Centre, University of Sussex, Brighton, UK
Correspondence: Sarah S Grant
Novartis Institutes for BioMedical Research, 250 Massachusetts Ave, Cambridge, MA 02139, USA
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 FEV1, 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 FEV1 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 FEV1 (mean: 50 mL [84% probability]) and an improvement in post-bronchodilator FEV1 (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 FEV1 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
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]