VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
Open accessAbstract
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: ). RESULTS: . 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 .).
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In proof-of-concept trials, elexacaftor-tezacaftor-ivacaftor led to improvements in spirometry, patient-reported respiratory symptoms, and sweat chloride concentration in patients with cystic fibrosis with a single Phe508del allele.
“In proof-of-concept trials that evaluated this therapeutic approach,16,18 elexacaftor–tezacaftor–ivacaftor led to improvements in spirometry, patient-reported respiratory symptoms, and sweat chloride concentration, a marker of CFTR activity, in patients with cystic fibrosis with a single Phe508del allele.18”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [16]
The Results (Phase 2 Efficacy; page not provided) report improved FEV1, sweat chloride concentration, and CFQ-R respiratory scores in patients with a single Phe508del allele. But the Methods (Clinical Development; page not provided) identify the treatment as VX-659–tezacaftor–ivacaftor, not elexacaftor–tezacaftor–ivacaftor. This source therefore supports the outcomes and patient group, but not the named regimen. (LLM, conf=0.88)
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Cites
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
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Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
Middleton, P. G., Mall, M. A., Dřevínek, P., Lands, L. C., McKone, E. F., Polineni, D., Ramsey, B. W., Taylor-Cousar, J. L., Tullis, E., Vermeulen, F., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908639 · Cited by 2,198 · see citing works
Self-citationRamos, K. J., Smith, P. J., McKone, E. F., Pilewski, J. M., Lucy, A., Hempstead, S. E., Tallarico, E., Faro, A., Rosenbluth, D. B., Gray, A. L., et al. (2019) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2019.03.002 · Cited by 227 · see citing works
Self-citationPutman, M. S., Norris, A. W., Hull, R. L., Rickels, M. R., Sussel, L., Blackman, S. M., Chan, C. L., Ode, K. L., Daley, T., Stecenko, A. A., et al. (2023) · Diabetes Care · doi:10.2337/dc23-0380 · Cited by 35 · see citing works
Outcomes following lung re-transplantation in patients with cystic fibrosis
Chan, E. G., Hyzny, E. J., Ryan, J. P., Morrell, M. R., Pilewski, J., & Sanchez, P. G. (2022) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2021.12.002 · Cited by 23 · see citing works
Worth a Double Take? An In-Depth Review of Lung Retransplantation
Dawodu, G., Gulati, S., Bugacov, H., Laskey, D., Housman, B., Seethamraju, H., & Scheinin, S. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12237418 · Cited by 4 · see citing works
- Authors
- 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., & Rowe, S. M.
- Affiliations
- Brigham and Women's Hospital (US)
- 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...
- University College Dublin (IE)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-10-25
- Volume
- 379
- Issue
- 17
- Pages
- 1599-1611
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6277022
- OpenAlex
- W2917538474
- Cited by
- 331
- References
- 2
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 20 · 2023: 24 · 2022: 37 · 2021: 61 · 2020: 61 · 2019: 89 · 2018: 11 · 2017: 1 · 2014: 1
- FWCI
- 41.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Cork Open Research Archive (University College Cork, Ireland) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Vertex Pharmaceuticals Incorporated
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- cystic fibrosis, CFTR correctors, tezacaftor, ivacaftor, triple combination therapy, F508del mutation, sweat chloride, Cystic Fibrosis Questionnaire-Revised, CFTR function restoration
- MeSH terms
- Adolescent, Adult, Alleles, Aminophenols, Cells, Cultured, Chlorides, Cystic Fibrosis, Double-Blind Method, Drug Combinations, Female, Forced Expiratory Volume, Genotype, Humans, Indoles, Male, Mutation, Pyrazoles, Pyrrolidines, Sweat, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles, Young Adult, Chloride Channel Agonists
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