• Steven M Rowe, Sonya L Heltshe, Tanja Gonska, Scott H Donaldson, Drucy Borowitz, Daniel Gelfond, Scott D Sagel, Umer Khan, Nicole Mayer-Hamblett, Jill M Van Dalfsen, Elizabeth Joseloff, Bonnie W Ramsey, and GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network.
• 1 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
• Am. J. Respir. Crit. Care Med. 2014 Jul 15; 190 (2): 175-84.

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

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