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VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

(2018) NEW ENGLAND JOURNAL OF MEDICINE. 379(17). p.1612-1620
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Abstract
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 We 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. RESULTS In 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. 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.
Keywords
TEZACAFTOR-IVACAFTOR, G551D MUTATION, CFTR

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Chicago
Keating, Dominic, Gautham Marigowda, Lucy Burr, Cori Daines, Marcus A. Mall, Edward F. McKone, Bonnie W. Ramsey, et al. 2018. “VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.” New England Journal of Medicine 379 (17): 1612–1620.
APA
Keating, D., Marigowda, G., Burr, L., Daines, C., Mall, M. A., McKone, E. F., Ramsey, B. W., et al. (2018). VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. NEW ENGLAND JOURNAL OF MEDICINE, 379(17), 1612–1620.
Vancouver
1.
Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, et al. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. NEW ENGLAND JOURNAL OF MEDICINE. Waltham: Massachusetts Medical Soc; 2018;379(17):1612–20.
MLA
Keating, Dominic et al. “VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.” NEW ENGLAND JOURNAL OF MEDICINE 379.17 (2018): 1612–1620. Print.
@article{8603564,
  abstract     = {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 We 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. RESULTS In 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{\textlangle}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{\textlangle}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.},
  author       = {Keating, Dominic and Marigowda, Gautham and Burr, Lucy and Daines, Cori and Mall, Marcus A. and McKone, Edward F. and Ramsey, Bonnie W. and Rowe, Steven M. and Sass, Laura A. and Tullis, Elizabeth and McKee, Charlotte M. and Moskowitz, Samuel M. and Robertson, Sarah and Savage, Jessica and Simard, Christopher and Van Goor, Fredrick and Waltz, David and Xuan, Fengjuan and Young, Tim and Taylor-Cousar, Jennifer L. and Van Braeckel, Eva},
  issn         = {0028-4793},
  journal      = {NEW ENGLAND JOURNAL OF MEDICINE},
  language     = {eng},
  number       = {17},
  pages        = {1612--1620},
  publisher    = {Massachusetts Medical Soc},
  title        = {VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles},
  url          = {http://dx.doi.org/10.1056/NEJMoa1807120},
  volume       = {379},
  year         = {2018},
}

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