Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis

• Published in: American journal of respiratory and critical care medicine Vol. 190; no. 2; pp. 175 - 184
• Main Authors: Rowe, Steven M., Heltshe, Sonya L., Gonska, Tanja, Donaldson, Scott H., Borowitz, Drucy, Gelfond, Daniel, Sagel, Scott D., Khan, Umer, Mayer-Hamblett, Nicole, Van Dalfsen, Jill M., Joseloff, Elizabeth, Ramsey, Bonnie W.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 15.07.2014
• Subjects: Adolescent; Adult; Age; Aminophenols - pharmacology; Aminophenols - therapeutic use; Biomarkers - metabolism; Child; Cohort analysis; Cystic fibrosis; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - microbiology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; FDA approval; Female; Follow-Up Studies; Forced Expiratory Volume - drug effects; Genetic Markers; Hospitalization - statistics & numerical data; Humans; Hydrogen-Ion Concentration - drug effects; Infections; Inflammation; Intestine, Small - drug effects; Intestine, Small - metabolism; Lung - drug effects; Lung - metabolism; Lung - microbiology; Lung - physiopathology; Male; Microbiota - drug effects; Mucociliary Clearance - drug effects; Mutation; Original; Patients; Pseudomonas aeruginosa - isolation & purification; Pseudomonas Infections - complications; Pseudomonas Infections - diagnosis; Pseudomonas Infections - prevention & control; Quinolones - pharmacology; Quinolones - therapeutic use; Respiratory System Agents - pharmacology; Respiratory System Agents - therapeutic use; Spirometry; Sputum - metabolism; Sputum - microbiology; Sweat - drug effects; Sweat - metabolism; Treatment Outcome; Young Adult; pH; Pseudomonas aeruginosa; CFTR modulator; ivacaftor; cystic fibrosis
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201404-0703OC

Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. 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. 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.