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. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).

• Authors: 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, VX16-445-001 Study Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 379 Issue 17 Pg. 1612-1620 (10 25 2018) ISSN: 1533-4406 [Electronic] United States
• PMID: 30334692 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Aminophenols
• Benzodioxoles
• CFTR protein, human
• Chloride Channel Agonists
• Chlorides
• Drug Combinations
• Indoles
• Pyrazoles
• Pyridines
• Pyrrolidines
• Quinolones
• tezacaftor
• Cystic Fibrosis Transmembrane Conductance Regulator
• ivacaftor
• elexacaftor

Topics

• Adolescent
• Adult
• Alleles
• Aminophenols (adverse effects, therapeutic use)
• Benzodioxoles (adverse effects, therapeutic use)
• Chloride Channel Agonists (adverse effects, therapeutic use)
• Chlorides (analysis, metabolism)
• Cystic Fibrosis (drug therapy, genetics)
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, metabolism)
• Double-Blind Method
• Drug Combinations
• Female
• Forced Expiratory Volume (drug effects)
• Genotype
• Humans
• Indoles (adverse effects, therapeutic use)
• Male
• Mutation
• Pyrazoles (administration & dosage, pharmacology, therapeutic use)
• Pyridines (administration & dosage, pharmacology, therapeutic use)
• Pyrrolidines (administration & dosage, pharmacology, therapeutic use)
• Quinolones (adverse effects, therapeutic use)
• Sweat (chemistry)
• Young Adult