A CFTR potentiator in patients with cystic fibrosis and the G551D mutation

Abstract

Background: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.

Methods: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)).

Results: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).

Conclusions: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).

Figure 1. Changes from Baseline in Percent of Predicted FEV₁, Respiratory Symptoms, and Weight, and Time to the First Pulmonary Exacerbation, According to Study Group

Panel A shows the absolute mean change from baseline in the percent of predicted forced expiratory volume in 1 second (FEV₁), through week 48. Panel B shows the time to the first pulmonary exacerbation, expressed as estimates of the proportion of subjects free from events. Panel C shows the absolute mean change from baseline in the score on the respiratory domain of the Cystic Fibrosis Questionnaire–revised (CFQ-R), a quality-of-life questionnaire that is scored on a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient’s quality of life. The established minimum clinically important difference for the CFQ-R respiratory domain is 4 points. Panel D shows the absolute mean change from baseline in weight, through week 48. The values and the 95% confidence intervals (indicated by I bars) in Panels A, C, and D are unadjusted. The first data points in Panels A, C, and D are baseline data.

Figure 2. Changes from Baseline through Week 48 in Sweat Chloride, According to Study Group

Panel A shows the mean change from baseline in the concentration of sweat chloride. Panel B shows the actual mean concentrations of sweat chloride over time; the dashed line at 60 mmol per liter represents the cutoff point for the diagnosis of cystic fibrosis. The values and 95% confidence intervals (indicated by I bars) in both panels are unadjusted. The first data points in both panels are baseline data.