title: Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
abstract: BACKGROUND
  A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro.
  
  
  METHODS
  We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study).
  
  
  RESULTS
  At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770.
  
  
  CONCLUSIONS
  This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).
authors.affiliation: University of Colorado Denver and Children's Hospital, Aurora, CO 80045, USA. accurso.frank@tchden.org
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Accurso
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: J P
authors.initials: JP
authors.lastname: Clancy
authors.forename: Michael P
authors.initials: MP
authors.lastname: Boyle
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Dunitz
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Hornick
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.forename: Scott H
authors.initials: SH
authors.lastname: Donaldson
authors.forename: Richard B
authors.initials: RB
authors.lastname: Moss
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pilewski
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Rubenstein
authors.forename: Ahmet Z
authors.initials: AZ
authors.lastname: Uluer
authors.forename: Moira L
authors.initials: ML
authors.lastname: Aitken
authors.forename: Steven D
authors.initials: SD
authors.lastname: Freedman
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Rose
authors.forename: Nicole
authors.initials: N
authors.lastname: Mayer-Hamblett
authors.forename: Qunming
authors.initials: Q
authors.lastname: Dong
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Zha
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Stone
authors.forename: Eric R
authors.initials: ER
authors.lastname: Olson
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Ordoñez
authors.forename: Preston W
authors.initials: PW
authors.lastname: Campbell
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Ashlock
authors.forename: Bonnie W
authors.initials: BW
authors.lastname: Ramsey
mesh_terms: D000328:Adult; D000627:Aminophenols / Q000009:adverse effects / Q000627:therapeutic use*; D002712:Chlorides / Q000032:analysis; D018592:Cross-Over Studies; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009154:Mutation; D009297:Nasal Mucosa / Q000502:physiology; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D013542:Sweat / Q000737:chemistry; D055815:Young Adult
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D002712:Chlorides; D007473:Ion Channels; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor