Icenticaftor treatment improved trough forced expiratory volume in 1 second (FEV1) at 24 weeks and rescue medication use at 6 months in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB), according to a study in the American Journal of Respiratory and Critical Care Medicine.
Investigators compared treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) icenticaftor with placebo in patients with symptomatic COPD aged 40 years and older in a randomized, double-blind, dose-range-finding, phase 2 study (Clinicaltrials.gov Identifier: NCT04072887). According to study authors, “This trial is the largest and longest prospective randomized controlled trial to study a CFTR potentiator in patients with COPD and CB being treated with standardized, triple inhaled therapy.” The primary study objective was to determine the dose-response relationship for icenticaftor when added to LABA/LAMA/ICS; the primary endpoint was change from baseline in trough FEV1 after 12 weeks.
All 974 participants (mean [SD] age, 66.6 [7.55] years; 62% male) had symptomatic COPD (a score of ≥10 on the COPD Assessment Test), a history of exacerbations, a documented history of CB, and were receiving triple inhaled maintenance therapies (long-acting β2-agonist/long-acting muscarinic antagonist/inhaled corticosteroid [LABA/LAMA/ICS]) for at least 3 months prior to inclusion in the study. The trial was conducted from September 12, 2019, to February 1, 2022.
Participants were randomly assigned to 1 of 6 treatment arms, including icenticaftor administered orally twice a day (bid) at 5 different dosing levels — 450 mg, 300 mg, 150 mg, 75 mg, or 25 mg — or placebo. The treatment duration was 24 weeks.
This trial is the largest and longest prospective randomized controlled trial to study a CFTR potentiator in patients with COPD and CB being treated with standardized, triple inhaled therapy.
The clinical trial’s primary objective was not achieved: a dose-response for trough FEV1 at week 12 was not observed. However, investigators observed a dose-response at week 24, with the icenticaftor 300-mg bid arm having the greatest effect (least squares mean treatment difference, 0.035; 90% CI, 0.008-0.062).
A dose-response was observed in scores for cough and sputum on the Evaluating Respiratory Symptoms in COPD (E-RS) subscale at weeks 12 and 24, and for the E-RS total score at week 24, but not week 12, with icenticaftor 300 mg bid having the greatest effect.
Post-hoc analyses indicated a dose-response for serum fibrinogen at week 24 and for rescue medication use at 6 months, with icenticaftor 300 mg bid showing the greatest effect.
The icenticaftor arms had a higher percentage of patients with serious adverse events (4.8% to 13.2% of patients) compared with 6.0% of patients in the placebo group, with the highest percentage occurring in the icenticaftor 300-mg arm (13.2%). A higher discontinuation rate occurred in the icenticaftor arms vs placebo (3.2%-8.1% vs 4.0%, respectively). In the icenticaftor arms, 7 deaths were reported, and no deaths occurred in the placebo arm.
“Although the primary endpoint of this study was not met, our study suggests benefits in numerous pre-defined endpoints, including lung function, symptom, quality of life outcomes, and fibrinogen levels for patients with COPD and CB who are treated with maximal inhaled therapy,” stated the investigators. “Moreover, the consistency of results suggests a potential dose (300 mg bid) for future development of icenticaftor.”
Disclosure: The study was funded by Novartis. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.