VX-659–Tezacaftor–Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles

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dc.contributor.author Davies, Jane C.
dc.contributor.author Moskowitz, Samuel M.
dc.contributor.author Brown, Cynthia
dc.contributor.author Horsley, Alexander
dc.contributor.author Mall, Marcus A.
dc.contributor.author McKone, Edward F.
dc.contributor.author Plant, Barry J.
dc.contributor.author Prais, Dario
dc.contributor.author Ramsey, Bonnie W.
dc.contributor.author Taylor-Cousar, Jennifer L.
dc.contributor.author Tullis, Elizabeth
dc.contributor.author Uluer, Ahmet
dc.contributor.author McKee, Charlotte M.
dc.contributor.author Robertson, Sarah
dc.contributor.author Shilling, Rebecca A.
dc.contributor.author Simard, Christopher
dc.contributor.author Van Goor, Fredrick
dc.contributor.author Waltz, David
dc.contributor.author Xuan, Fengjuan
dc.contributor.author Young, Tim
dc.contributor.author Rowe, Steven M.
dc.date.accessioned 2020-02-21T12:21:17Z
dc.date.available 2020-02-21T12:21:17Z
dc.date.issued 2018-10-25
dc.identifier.citation Davies, J. C., Moskowitz, S. M., Brown, C., Horsley, A., Mall, M. A., McKone, E. F., Plant, B. J., Prais, D., Ramsey, B. W., Taylor-Cousar, J. L., Tullis, E., Uluer, A., McKee, C. M., Robertson, S., Shilling, R. A., Simard, C., Van Goor, F., Waltz, D., Xuan, F., Young, T. and Rowe, S. M. (2018) 'VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles', New England Journal of Medicine, 379(17), pp. 1599-1611. doi: 10.1056/NEJMoa1807119 en
dc.identifier.volume 379 en
dc.identifier.issued 17 en
dc.identifier.startpage 1599 en
dc.identifier.endpage 1611 en
dc.identifier.issn 0028-4793
dc.identifier.uri http://hdl.handle.net/10468/9684
dc.identifier.doi 10.1056/NEJMoa1807119 en
dc.description.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. opens in new tab and NCT03029455. opens in new tab.) en
dc.description.sponsorship Vertex Pharmaceuticals (VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351. opens in new tab and NCT03029455) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Massachusetts Medical Society en
dc.relation.uri https://www.nejm.org/doi/full/10.1056/NEJMoa1807119
dc.rights © 2018 Massachusetts Medical Society. All rights reserved. Reprinted with permission en
dc.subject Adolescent en
dc.subject Adult en
dc.subject Alleles en
dc.subject Aminophenols en
dc.subject Benzodioxoles en
dc.subject Cells, cultured en
dc.subject Chloride channel agonists en
dc.subject Chlorides en
dc.subject Cystic fibrosis en
dc.subject Cystic fibrosis transmembrane conductance regulator en
dc.subject Double-blind method en
dc.subject Drug combinations en
dc.subject Female en
dc.subject Forced expiratory volume en
dc.subject Genotype en
dc.subject Humans en
dc.subject Indoles en
dc.subject Male en
dc.subject Mutation en
dc.subject Quinolones en
dc.subject Sweat en
dc.subject Young adult en
dc.title VX-659–Tezacaftor–Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Barry Plant, Medicine Department, University College Cork, Cork, Ireland. +353-21-490-3000 Email: b.plant@ucc.ie en
dc.internal.availability Full text available en
dc.date.updated 2020-02-21T12:15:13Z
dc.description.version Published Version en
dc.internal.rssid 503503443
dc.contributor.funder Vertex Pharmaceuticals en
dc.description.status Peer reviewed en
dc.identifier.journaltitle New England Journal of Medicine en
dc.internal.copyrightchecked Yes
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress b.plant@ucc.ie en

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