Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis

Abstract

Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.

Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.

Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.

Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.

Keywords: CFTR modulator; Pseudomonas aeruginosa; cystic fibrosis; ivacaftor; pH.

Figure 1.

Diagram of participants screened, eligible, enrolled in core and substudies, follow-up, and withdrawals.

Figure 2.

Clinical measures at baseline, 1, 3, and 6 months postivacaftor. (A) FEV₁ percent predicted. Change from baseline in (B) body mass index (BMI) and (C) sweat chloride. (D) Change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQR) Respiratory Score. Means and 95% confidence intervals. Horizontal hashed line in D at 4 represents minimal clinically important difference (41).

Figure 3.

Clinical measures obtained through Cystic Fibrosis Foundation National Patient Registry in 6-month intervals preivacaftor and postivacaftor. (A) Participants with at least one hospitalization and (B) Pseudomonas aeruginosa positivity among those with a recorded respiratory culture in 6-month intervals. Means and 95% confidence intervals; *P < 0.001.

Figure 4.

Substudy mucociliary clearance (A) mean particle retention curves from the whole right lung at baseline and 1 month following ivacaftor treatment. (B) Average (± SD) whole lung clearance for 60 minutes after inhaling Tc99m-SC aerosol. *P < 0.001 versus baseline.

Figure 5.

Substudy small intestinal pH profile. Mean pH readings every minute at baseline (gray) and 1 month postivacaftor (black). GE = gastric emptying.