A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation
By B. Ramsey, J. Davies, N. G. Mcelvaney, Elizabeth Tullis, Scott C Bell, Pavel Drevinek, Matthias Griese, E. McKone, C. E. Wainwright, M. Konstan and 9 more. New England Journal of Medicine, 2011
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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 (FEV1). RESULTS The change from baseline through week 24 in the percent of predicted FEV1 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.
Subfields: Physiology, Pulmonary and Respiratory Medicine, Sociology and Political Science
View Paper: https://www.semanticscholar.org/paper/9ce6f6c385628df35db2e68678e67989471605e9
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Citations in the corpus
- Handbook of ion channels (2015, background): “Soon after the discovery of VX-770 on the bench, encouraging results were reported from clinical trials (Accurso et al., 2010; Ramsey et al., 2011), followed without delay by the approval of VX-770 for CF treatment by the FDA.”
- The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. (2015, positive): “Similarly, understanding the physiological effects of CFTR (cystic fibrosis transmembrane conductance regulator [MIM: 602421]) mutations responsible for cystic fibrosis has led to allele-specific therapies that significantly improve pulmonary function in affected individuals.(63) Other common-diseas”