title: Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.
abstract: Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation.
  
  
  
  We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24.
  
  
  
  A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo.
  
  
  
  These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.).
authors.affiliation: From Queensland Children's Medical Research Institute, Royal Children's Hospital, Lady Cilento Children's Hospital, and University of Queensland School of Medicine, Brisbane, Australia (C.E.W.); Queens University of Belfast, Belfast (J.S.E.), and Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London (J.C.D.) - all in the United Kingdom; Seattle Children's Hospital and University of Washington School of Medicine, Seattle (B.W.R.); Vertex Pharmaceuticals, Boston (G.M., X.H., D.W.); Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona (M.C.), and Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan (C.C.) - both in Italy; University Hospital Gasthuisberg, Leuven, Belgium (K.D.B.); Medical University of South Carolina, Charleston (P.A.F.); Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland (M.W.K.), and the Department of Pediatrics, Pulmonary Division, Nationwide Children's Hospital and Ohio State University, Columbus (K.M.) - both in Ohio; Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, Chicago (S.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); Hôpital Robert Debré, Paediatric Gastroenterology and Respiratory Department, CF Center, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris (A.M.); Division of Respiratory Medicine, Department of Pediatrics, Physiology, and Experimental Medicine, Hospital for Sick Children, University of Toronto, Toronto (F.R.); University of Alabama at Birmingham, Birmingham (S.M.R.); and Johns Hopkins Medicine, Baltimore (M.P.B.).
authors.forename: Claire E
authors.initials: CE
authors.lastname: Wainwright
authors.forename: J Stuart
authors.initials: JS
authors.lastname: Elborn
authors.forename: Bonnie W
authors.initials: BW
authors.lastname: Ramsey
authors.forename: Gautham
authors.initials: G
authors.lastname: Marigowda
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Huang
authors.forename: Marco
authors.initials: M
authors.lastname: Cipolli
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
authors.forename: Kris
authors.initials: K
authors.lastname: De Boeck
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Flume
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.forename: Susanna A
authors.initials: SA
authors.lastname: McColley
authors.forename: Karen
authors.initials: K
authors.lastname: McCoy
authors.forename: Edward F
authors.initials: EF
authors.lastname: McKone
authors.forename: Anne
authors.initials: A
authors.lastname: Munck
authors.forename: Felix
authors.initials: F
authors.lastname: Ratjen
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: David
authors.initials: D
authors.lastname: Waltz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Boyle
mesh_terms: D000293:Adolescent; D000328:Adult; D000627:Aminophenols / Q000008:administration & dosage* / Q000009:adverse effects; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006720:Homozygote; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; C569105:lumacaftor