VX-659-Tezacaftor-Ivacaftor in Patients With Cystic Fibrosis and One or Two Phe508del Alleles

N Engl J Med. 2018 Oct 25;379(17):1599-1611. doi: 10.1056/NEJMoa1807119. Epub 2018 Oct 18.

Abstract

Background: The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.

Methods: We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1).

Results: VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations.

Conclusions: Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Aminophenols / adverse effects
  • Aminophenols / therapeutic use*
  • Benzodioxoles / adverse effects
  • Benzodioxoles / therapeutic use*
  • Cells, Cultured
  • Chloride Channel Agonists / adverse effects
  • Chloride Channel Agonists / therapeutic use*
  • Chlorides / analysis
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Forced Expiratory Volume / drug effects
  • Genotype
  • Humans
  • Indoles / adverse effects
  • Indoles / therapeutic use*
  • Male
  • Mutation
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Pyrrolidines / adverse effects
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use*
  • Quinolones / adverse effects
  • Quinolones / therapeutic use*
  • Sweat / chemistry
  • Young Adult

Substances

  • Aminophenols
  • Benzodioxoles
  • CFTR protein, human
  • Chloride Channel Agonists
  • Chlorides
  • Drug Combinations
  • Indoles
  • Pyrazoles
  • Pyrrolidines
  • Quinolones
  • tezacaftor
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor
  • VX-659

Associated data

  • ClinicalTrials.gov/NCT03224351
  • ClinicalTrials.gov/NCT03029455