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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
Tel +16178717812

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

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