VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles

Dominic Keating, Gautham Marigowda, Lucy Burr, Cori Daines, Marcus A. Mall, Edward F. McKone, Bonnie W. Ramsey, Steven M. Rowe, Laura A. Sass, Elizabeth Tullis, Charlotte M. McKee, Samuel M. Moskowitz, Sarah Robertson, Jessica Savage, Christopher Simard, Fredrick Van Goor, David Waltz, Fengjuan Xuan, Tim Young, Jennifer L. Taylor-Cousar

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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.

Original languageEnglish
Pages (from-to)1612-1620
Number of pages9
JournalNew England Journal of Medicine
Volume379
Issue number17
DOIs
Publication statusPublished - 25 Oct 2018
Externally publishedYes

Cite this

Keating, D., Marigowda, G., Burr, L., Daines, C., Mall, M. A., McKone, E. F., ... Taylor-Cousar, J. L. (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. https://doi.org/10.1056/NEJMoa1807120
Keating, Dominic ; Marigowda, Gautham ; Burr, Lucy ; Daines, Cori ; Mall, Marcus A. ; McKone, Edward F. ; Ramsey, Bonnie W. ; Rowe, Steven M. ; Sass, Laura A. ; Tullis, Elizabeth ; McKee, Charlotte M. ; Moskowitz, Samuel M. ; Robertson, Sarah ; Savage, Jessica ; Simard, Christopher ; Van Goor, Fredrick ; Waltz, David ; Xuan, Fengjuan ; Young, Tim ; Taylor-Cousar, Jennifer L. / VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. In: New England Journal of Medicine. 2018 ; Vol. 379, No. 17. pp. 1612-1620.
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title = "VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles",
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.",
author = "Dominic Keating and Gautham Marigowda and Lucy Burr and Cori Daines and Mall, {Marcus A.} and McKone, {Edward F.} and Ramsey, {Bonnie W.} and Rowe, {Steven M.} and Sass, {Laura A.} and Elizabeth Tullis and McKee, {Charlotte M.} and Moskowitz, {Samuel M.} and Sarah Robertson and Jessica Savage and Christopher Simard and {Van Goor}, Fredrick and David Waltz and Fengjuan Xuan and Tim Young and Taylor-Cousar, {Jennifer L.}",
year = "2018",
month = "10",
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doi = "10.1056/NEJMoa1807120",
language = "English",
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pages = "1612--1620",
journal = "New England Journal of Medicine",
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Keating, D, Marigowda, G, Burr, L, Daines, C, Mall, MA, McKone, EF, Ramsey, BW, Rowe, SM, Sass, LA, Tullis, E, McKee, CM, Moskowitz, SM, Robertson, S, Savage, J, Simard, C, Van Goor, F, Waltz, D, Xuan, F, Young, T & Taylor-Cousar, JL 2018, 'VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles', New England Journal of Medicine, vol. 379, no. 17, pp. 1612-1620. https://doi.org/10.1056/NEJMoa1807120

VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. / Keating, Dominic; Marigowda, Gautham; Burr, Lucy; Daines, Cori; Mall, Marcus A.; McKone, Edward F.; Ramsey, Bonnie W.; Rowe, Steven M.; Sass, Laura A.; Tullis, Elizabeth; McKee, Charlotte M.; Moskowitz, Samuel M.; Robertson, Sarah; Savage, Jessica; Simard, Christopher; Van Goor, Fredrick; Waltz, David; Xuan, Fengjuan; Young, Tim; Taylor-Cousar, Jennifer L.

In: New England Journal of Medicine, Vol. 379, No. 17, 25.10.2018, p. 1612-1620.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles

AU - Keating, Dominic

AU - Marigowda, Gautham

AU - Burr, Lucy

AU - Daines, Cori

AU - Mall, Marcus A.

AU - McKone, Edward F.

AU - Ramsey, Bonnie W.

AU - Rowe, Steven M.

AU - Sass, Laura A.

AU - Tullis, Elizabeth

AU - McKee, Charlotte M.

AU - Moskowitz, Samuel M.

AU - Robertson, Sarah

AU - Savage, Jessica

AU - Simard, Christopher

AU - Van Goor, Fredrick

AU - Waltz, David

AU - Xuan, Fengjuan

AU - Young, Tim

AU - Taylor-Cousar, Jennifer L.

PY - 2018/10/25

Y1 - 2018/10/25

N2 - 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.

AB - 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.

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U2 - 10.1056/NEJMoa1807120

DO - 10.1056/NEJMoa1807120

M3 - Article

VL - 379

SP - 1612

EP - 1620

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 17

ER -