• Jane C Davies, Samuel M Moskowitz, Cynthia Brown, Alexander Horsley, Marcus A Mall, Edward F McKone, Barry J Plant, Dario Prais, Bonnie W Ramsey, Jennifer L Taylor-Cousar, Elizabeth Tullis, Ahmet Uluer, Charlotte M McKee, Sarah Robertson, Rebecca A Shilling, Christopher Simard, Fredrick Van Goor, David Waltz, Fengjuan Xuan, Tim Young, Steven M Rowe, and VX16-659-101 Study Group.
• From Imperial College London and Royal Brompton and Harefield NHS Foundation Trust, London (J.C.D.), and the Manchester Adult Cystic Fibrosis Centre, Manchester (A.H.) - both in the United Kingdom; Vertex Pharmaceuticals (S.M.M., C.M.M., S.R., R.A.S., C.S., F.V.G., D.W., F.X., T.Y.) and Boston Children's Hospital and Brigham and Women's Hospital (A.U.) - all in Boston; Indiana University School of Medicine, Indianapolis (C.B.); Universitätsmedizin Berlin and Berlin Institute of Health, Berlin, and the German Center for Lung Research, Giessen - all in Germany (M.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.), and Cork University Hospital and University College Cork, Cork (B.J.P.) - all in Ireland; Schneider Children's Medical Center of Israel, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (D.P.) - both in Israel; Seattle Children's Hospital, Seattle (B.W.R.); National Jewish Health, Denver (J.L.T.-C.); St. Michael's Hospital, Toronto (E.T.); and the University of Alabama at Birmingham, Birmingham (S.M.R.).
• N. Engl. J. Med. 2018 Oct 25; 379 (17): 1599-1611.

BackgroundThe 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.MethodsWe 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).ResultsVX-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.ConclusionsRobust 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 .).

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