Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial

Abstract

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV₁ after 12 weeks. Secondary endpoints included change from baseline in trough FEV₁ and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV₁ was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV₁, E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV₁ over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV₁; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Keywords: CFTR dysfunction; CFTR potentiator; COPD; chronic bronchitis; icenticaftor.

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram. b.i.d. = twice daily.

Figure 2.

(A–F) Icenticaftor dose–response relationship after 12 (A) and 24 (B) weeks for trough FEV₁ and after 24 weeks, measured by Evaluating Respiratory Symptoms in chronic obstructive pulmonary disease (E-RS) cough and sputum score (C), E-RS total score (D), fibrinogen (E), and rescue medication use (F) in patients with chronic obstructive pulmonary disease. Trough FEV₁ was measured at Day 85 of Week 12 and Day 169 of Week 24. E-RS scores are weekly scores, fibrinogen was measured on Day 169 of Week 24, and rescue medication use was averaged across Month 6 (Weeks 21–24). CI = confidence interval; MMRM = mixed model for repeated measures.

Figure 3.

(A and B) Changes from baseline at (A) 12 weeks and (B) 24 weeks in trough FEV₁ with icenticaftor 300 mg twice daily versus placebo in patients with chronic obstructive pulmonary disease. Trough FEV₁ was measured at Day 85 of Week 12 and Day 169 of Week 24. All patients were on background triple therapy (fluticasone furoate, umeclidinium, and vilanterol). CI = confidence interval; LS = least squares; TD = treatment difference.

Figure 4.

(A–F) Changes from baseline in (A) Evaluating Respiratory Symptoms in chronic obstructive pulmonary disease (E-RS) cough and sputum score, (B) E-RS total score, (C) E-RS chest symptoms score, (D) rescue medication use, (E) fibrinogen, and (F) St. George’s Respiratory Questionnaire (SGRQ) total score for icenticaftor 300 mg twice daily versus placebo at Week 24 in patients with chronic obstructive pulmonary disease. E-RS scores are weekly scores, SGRQ total score and fibrinogen were measured on Day 169 of Week 24, and rescue medication use was averaged across Month 6 (Weeks 21–24). All patients were on background triple therapy (fluticasone furoate, umeclidinium, and vilanterol). CI = confidence interval; LS = least squares; TD = treatment difference.

Figure 5.

(A–D) Endpoint responders in Evaluating Respiratory Symptoms in chronic obstructive pulmonary disease (E-RS) cough and sputum score (A), E-RS total score (B), trough FEV₁ (C), and St. George’s Respiratory Questionnaire (SGRQ) total score (D): icenticaftor 300 mg twice daily and placebo. All patients were on background triple therapy (fluticasone furoate, umeclidinium, and vilanterol). The number needed to treat is 9 for E-RS cough and sputum score, 12 for E-RS total score, 8 for trough FEV₁, and 14 for SGRQ total score. CI = confidence interval; OR = odds ratio; WK = week.