Efficacy and Safety of the CFTR Potentiator Icenticaftor (QBW251) in COPD: Results from a Phase 2 Randomized Trial

  • Int J Chron Obstruct Pulmon Dis. 2020 Oct 5;15:2399-2409. doi: 10.2147/COPD.S257474.
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 Grant  2
Affiliations
  • 1. University of Alabama at Birmingham, Department of Medicine, Birmingham, AL, USA.
  • 2. Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 3. Enterprise Therapeutics, Brighton, UK.
  • 4. Sussex Drug Discovery Centre, University of Sussex, Brighton, UK.
PMID: 33116455 DOI: 10.2147/COPD.S257474
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 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
CFTR potentiator; chronic bronchitis; chronic obstructive pulmonary disease; cystic fibrosis transmembrane conductance regulator potentiator; icenticaftor; QBW251; mucociliary clearance.
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