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

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:

• chronic obstructive pulmonary disease
• chronic bronchitis
• cystic fibrosis transmembrane conductance regulator potentiator
• CFTR potentiator
• mucociliary clearance
• icenticaftor; QBW251

Acknowledgments

The study was supported and funded by Novartis. We thank the patients who participated in the trial. Phani Tejasvi Dantu and Rahul Lad, professional scientific writers at Novartis (Hyderabad, India), provided editorial and technical support in the preparation of the manuscript. MedQIA, including Jonathan Goldin and Grace Hyun Kim, provided assistance with imaging acquisition and analysis. We also had infrastructure support from two NIH grants, which also informed the basis of the study: R35 HL135816, P30 DK072482.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.The study was funded by Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

Disclosure

Steven M Rowe reports grants and personal fees from Novartis during the conduct of the study; grants and personal fees from Bayer, grants from Translate Bio, grants from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants, personal fees and in kind support for research from Synedgen/Synspira, grants from Eloxx, grants and personal fees from Celtaxsys, grants, personal fees, non-financial support from Vertex Pharmaceuticals Inc, grants, personal fees and stock options from Renovion, grants and personal fees from Arrowhead, grants, personal fees and in kind support for research from Ionis, grants from AstraZeneca, grants from N30/Nivalis, grants from PTC Therapeutics, personal fees from Genentech, personal fees, non-financial support from Boehringer Ingelheim, grants from Janssen, Vivus, Actelion, Johnson and Johnson, and other related entities, outside the submitted work. Mark T Dransfield reports grants from the NIH, Department of Defense and American Lung Association; consulting fees from AstraZeneca, GlaxoSmithKline, Mereo, Quark and Teva; travel support from Pulmonx; and contracted clinical trial support from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Gala, Nuvaira, PneumRx/BTG, Pulmonx and Yungjin. Ieuan Jones, Katy A Hayes, David J Rowlands and Sarah S Grant have patent 8247436 issued and are employees of Novartis. Nazmul Haque, Stephen Gleason and Denise P Yates are employees of Novartis. Kenneth Kulmatycki have a patent issued and is an employee of Novartis. Martin Gosling was an employee of Novartis between 2001 and 2014. He is now affiliated with Enterprise Therapeutics. Henry Danahay was an employee of Novartis between 1997 and 2014. He is now affiliated with Enterprise Therapeutics. The authors report no other conflicts of interest in this work.