• Dominic Keating, Gautham Marigowda, Lucy Burr, Cori Daines, Marcus A Mall, Edward F McKone, Bonnie W Ramsey, Steven M Rowe, Laura A Sass, Elizabeth Tullis, Charlotte M McKee, Samuel M Moskowitz, Sarah Robertson, Jessica Savage, Christopher Simard, Fredrick Van Goor, David Waltz, Fengjuan Xuan, Tim Young, Jennifer L Taylor-Cousar, and VX16-445-001 Study Group.
• From Alfred Hospital, Melbourne, VIC (D.K.), and Mater Hospital, Brisbane, QLD (L.B.) - both in Australia; Vertex Pharmaceuticals, Boston (G.M., C.M.M., S.M.M., S.R., J.S., C.S., F.V.G., D.W., F.X., T.Y.); Banner University Medical Center, Tucson, AZ (C.D.); Universitätsmedizin Berlin and Berlin Institute of Health, Berlin, and the German Center for Lung Research, Giessen - both in Germany (M.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); Seattle Children's Hospital, Seattle (B.W.R.); University of Alabama at Birmingham, Birmingham (S.M.R.); Children's Hospital of the King's Daughters, Norfolk, VA (L.A.S.); St. Michael's Hospital, Toronto (E.T.); and National Jewish Health, Denver (J.L.T.-C.).
• N. Engl. J. Med. 2018 Oct 25; 379 (17): 1612-1620.

BackgroundVX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor).MethodsWe evaluated the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline.ResultsIn vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P<0.001). In patients in the Phe508del-Phe508del group, who were already receiving tezacaftor-ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised.ConclusionsThe use of VX-445-tezacaftor-ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).

48 keywords...

hide…