VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.
Davies, Jane C. M.D.; Moskowitz, Samuel M. M.D.; Brown, Cynthia M.D.; Horsley, Alexander Ph.D.; Mall, Marcus A. M.D.; McKone, Edward F. M.D.; Plant, Barry J. M.D.; Prais, Dario M.D.; Ramsey, Bonnie W. M.D.; Taylor-Cousar, Jennifer L. M.D., M.S.C.S.; Tullis, Elizabeth M.D.; Uluer, Ahmet D.O.; McKee, Charlotte M. M.D.; Robertson, Sarah Pharm.D.; Shilling, Rebecca A. M.D.; Simard, Christopher M.D.; Van Goor, Fredrick Ph.D.; Waltz, David M.D.; Xuan, Fengjuan Ph.D.; Young, Tim Ph.D.; Rowe, Steven M. M.D., M.S.P.H.; the VX16-659-101 Study Group
[Article]
New England Journal of Medicine.
379(17):1599-1611, October 25, 2018.
(Format: HTML, PDF)
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.)
Copyright (C) 2018 Massachusetts Medical Society. All rights reserved.
