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

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dc.contributor.authorDavies, Jane C.
dc.contributor.authorMoskowitz, Samuel M.
dc.contributor.authorBrown, Cynthia
dc.contributor.authorHorsley, Alexander
dc.contributor.authorMall, Marcus A.
dc.contributor.authorMcKone, Edward F.
dc.contributor.authorPlant, Barry J.
dc.contributor.authorPrais, Dario
dc.contributor.authorRamsey, Bonnie W.
dc.contributor.authorTaylor-Cousar, Jennifer L.
dc.contributor.authorTullis, Elizabeth
dc.contributor.authorUluer, Ahmet
dc.contributor.authorMcKee, Charlotte M.
dc.contributor.authorRobertson, Sarah
dc.contributor.authorShilling, Rebecca A.
dc.contributor.authorSimard, Christopher
dc.contributor.authorVan Goor, Fredrick
dc.contributor.authorWaltz, David
dc.contributor.authorXuan, Fengjuan
dc.contributor.authorYoung, Tim
dc.contributor.authorRowe, Steven M.
dc.contributor.funderVertex Pharmaceuticalsen
dc.date.accessioned2020-02-21T12:21:17Z
dc.date.available2020-02-21T12:21:17Z
dc.date.issued2018-10-25
dc.date.updated2020-02-21T12:15:13Z
dc.description.abstractBACKGROUND: 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.sponsorshipVertex Pharmaceuticals (VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351. opens in new tab and NCT03029455)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationDavies, 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/NEJMoa1807119en
dc.identifier.doi10.1056/NEJMoa1807119en
dc.identifier.endpage1611en
dc.identifier.issn0028-4793
dc.identifier.issued17en
dc.identifier.journaltitleNew England Journal of Medicineen
dc.identifier.startpage1599en
dc.identifier.urihttps://hdl.handle.net/10468/9684
dc.identifier.volume379en
dc.language.isoenen
dc.publisherMassachusetts Medical Societyen
dc.relation.urihttps://www.nejm.org/doi/full/10.1056/NEJMoa1807119
dc.rights© 2018 Massachusetts Medical Society. All rights reserved. Reprinted with permissionen
dc.subjectAdolescenten
dc.subjectAdulten
dc.subjectAllelesen
dc.subjectAminophenolsen
dc.subjectBenzodioxolesen
dc.subjectCells, cultureden
dc.subjectChloride channel agonistsen
dc.subjectChloridesen
dc.subjectCystic fibrosisen
dc.subjectCystic fibrosis transmembrane conductance regulatoren
dc.subjectDouble-blind methoden
dc.subjectDrug combinationsen
dc.subjectFemaleen
dc.subjectForced expiratory volumeen
dc.subjectGenotypeen
dc.subjectHumansen
dc.subjectIndolesen
dc.subjectMaleen
dc.subjectMutationen
dc.subjectQuinolonesen
dc.subjectSweaten
dc.subjectYoung adulten
dc.titleVX-659–Tezacaftor–Ivacaftor in patients with cystic fibrosis and one or two Phe508del allelesen
dc.typeArticle (peer-reviewed)en
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