title: Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation.
abstract: BACKGROUND
  Ivacaftor (VX-770) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that was approved in the United States for the treatment of cystic fibrosis (CF) in patients ≥ 6 years of age who have a G551D mutation; however, the most prevalent disease-causing CFTR mutation, F508del, causes a different functional defect. The objectives of this study were to evaluate the safety of ivacaftor in a larger population and for a longer time period than tested previously and to assess the efficacy of ivacaftor in subjects with CF who are homozygous for F508del-CFTR.
  
  
  METHODS
  This was a phase 2 study with a 16-week randomized (4:1), double-blind, placebo-controlled period (part A) and an open-label extension (part B) for subjects who met prespecified criteria.
  
  
  RESULTS
  Part A: The safety profile of ivacaftor was comparable to that of the placebo. The overall adverse event frequency was similar in the ivacaftor (87.5%) and placebo (89.3%) groups through 16 weeks. The difference in the change of FEV₁ % predicted from baseline through week 16 (primary end point) between the ivacaftor and placebo groups was 1.7% (P = .15). Sweat chloride, a biomarker of CFTR activity, showed a small reduction in the ivacaftor vs placebo groups of -2.9 mmol/L (P = .04) from baseline through week 16. Part B: No new safety signals were identified. The changes in FEV₁ or sweat chloride in part A were not sustained with ivacaftor treatment from week 16 to week 40.
  
  
  CONCLUSIONS
  These results expand the safety information for ivacaftor and support its continued evaluation. Lack of a clinical effect suggests that a CFTR potentiator alone is not an effective therapeutic approach for patients who have CF and are homozygous for F508del-CFTR.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT00953706; URL: www.clinicaltrials.gov.
authors.affiliation: Department of Medicine and Pediatrics, Medical University of South Carolina, Charleston, SC. Electronic address: flumepa@musc.edu.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Flume
authors.affiliation: University of Utah, Salt Lake City, UT.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Liou
authors.affiliation: Department of Pediatrics, State University of New York at Buffalo, Buffalo, NY.
authors.forename: Drucy S
authors.initials: DS
authors.lastname: Borowitz
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, MA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Li
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, MA.
authors.forename: Karl
authors.initials: K
authors.lastname: Yen
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, MA.
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Ordoñez
authors.affiliation: Divisions of Biomedical Research and Pediatric Pulmonology, Nemours Children's Clinic, Orlando, FL.
authors.forename: David E
authors.initials: DE
authors.lastname: Geller
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000627:Aminophenols / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D002648:Child; D002712:Chlorides / Q000032:analysis; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010597:Pharmacogenetics; D015363:Quinolones / Q000627:therapeutic use*; D013542:Sweat / Q000737:chemistry; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000627:Aminophenols; D015415:Biomarkers; D002712:Chlorides; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor