VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
Open accessAbstract
BACKGROUND: VX-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). METHODS: ) from baseline. RESULTS: (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. CONCLUSIONS: The 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 .).
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The triple-combination regimen includes the next-generation corrector elexacaftor plus the corrector tezacaftor and the potentiator ivacaftor to more fully restore the function of Phe508del CFTR.
“The combination includes the next-generation corrector elexacaftor plus the corrector tezacaftor and the potentiator ivacaftor to more fully restore the function of Phe508del CFTR.18”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [18]
The Background identifies VX-445 as a next-generation corrector used with tezacaftor and ivacaftor to restore Phe508del CFTR function. The in vitro Results report greater chloride transport with the triple combination than with one- or two-drug treatments. Our copy does not identify VX-445 by the name elexacaftor, so that specific identification cannot be verified from this source alone. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn 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 [18]
The efficacy and safety findings of this trial are consistent with those of the phase 2 trial of elexacaftor-tezacaftor-ivacaftor.
“In this 24-week trial of triple-combination CFTR modulator therapy in patients with cystic fibrosis who have a single Phe508del allele, elexacaftor–tezacaftor–ivacaftor treatment resulted in improvements in lung function, the rate of pulmonary exacerbations, sweat chloride concentration, CFQ-R respiratory domain scores, and BMI and was generally safe with an acceptable side-effect profile,”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [18]
Elexacaftor (ELX; VX-445) is a next-generation CFTR corrector that, in vitro, significantly increases the amount of mature CFTR protein and CFTR activity when added to TEZ/IVA.
“Elexacaftor (ELX; VX-445) is a next-generation CFTR corrector that was shown, in vitro, to significantly increase the amount of mature CFTR protein and CFTR activity when added to the combination of TEZ/IVA.15”
ELX/TEZ/IVA improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for F508del.
“The addition of elexacaftor (ELX; VX-445), a next-generation CFTR corrector, to tezacaftor/ivacaftor (TEZ/IVA) further improved F508del-CFTR function and clinical outcomes in a phase 2 study in pwCF homozygous for F508del.”
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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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- Authors
- Keating, D., Marigowda, G., Burr, L., Daines, C., Mall, M. A., McKone, E. F., Ramsey, B. W., Rowe, S. M., Sass, L. A., Tullis, E., McKee, C. M., Moskowitz, S. M., Robertson, S., Savage, J., Simard, C., Van Goor, F., Waltz, D., Xuan, F., Young, T., & Taylor-Cousar, J. L.
- Affiliations
- The Alfred Hospital (AU)
- University College Dublin (IE)
- Seattle Children's Hospital (US)
- St. Michael's Hospital (CA)
- 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.);...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-10-25
- Volume
- 379
- Issue
- 17
- Pages
- 1612-1620
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6289290
- OpenAlex
- W2897626245
- Cited by
- 726
- References
- 1
- Citations by year
- 2026: 47 · 2025: 92 · 2024: 69 · 2023: 96 · 2022: 102 · 2021: 111 · 2020: 100 · 2019: 94 · 2018: 12 · 2017: 1 · 2014: 1
- FWCI
- 59.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Radboud Repository (Radboud University) (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, CFTR function, sweat chloride, Cystic Fibrosis Questionnaire-Revised, respiratory symptoms, CFTR modulator therapy
- MeSH terms
- Adolescent, Adult, Alleles, Aminophenols, Chlorides, Cystic Fibrosis, Double-Blind Method, Drug Combinations, Female, Forced Expiratory Volume, Genotype, Humans, Indoles, Male, Mutation, Pyrazoles, Pyridines, Pyrrolidines, Sweat, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles, Young Adult, Chloride Channel Agonists
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