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 .).

Figure 1.. In Vitro Effects of VX-445 Alone or in Combination with TEZ, IVA, or TEZ–IVA.

Panel A shows the results of immunoblotting from three independent experiments involving human bronchial epithelial (HBE) cells. (HBE cells for all experiments are from four Phe508del-MF donors and three Phe508del– Phe508del donors.) Panel B shows the quantitative assessment of that data through densitometry findings pooled from three independent experiments, with six replicates each for Phe508del–minimal function (MF) HBE cells and Phe508del–Phe508del HBE cells. Data are presented as mean relative intensities normalized to calnexin, a control for protein loading. Compound concentrations used were as follows: 2 μM of VX-445, 18 μM of tezacaftor (TEZ), and 1 μM of ivacaftor (IVA) in the presence of 10 mg per milliliter of human serum albumin. The letter a represents P<0.05 for the comparison with vehicle (0.37% dimethyl sulfoxide), b P<0.05 for the comparison with tezacaftor–ivacaftor (TEZ–IVA), and c P<0.05 for the comparison with VX-445 in unpaired t-tests. Panel C represents an assessment of chloride transport in HBE cells treated with various combinations of TEZ (18 μM), IVA (1 μM), and VX-445 (3 μM) by means of an Ussing chamber. Data represent the mean of three or four donor bronchi, with three or four replicate experiments per donor. The letter x represents P<0.05 for the comparison with vehicle, y P<0.05 for the comparison with TEZ–IVA, and z P<0.05 for the comparison with VX-445–IVA in paired t-tests. T bars indicate standard errors.

Figure 2. (facing page). Absolute Change from Baseline in the Percentage of Predicted FEV1, Sweat Chloride Concentration, and CFQ-R Respiratory Domain.

Panels A and B show the respective least-squares mean absolute change in percentage of predicted forced expiratory volume in 1 second (ppFEV1), sweat chloride concentration, and Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain score in patients heterozygous for the Phe508del CFTR mutation and a minimalfunction mutation (Phe508del–MF) and in patients homozygous for the Phe508del mutation (Phe508del– Phe508del) after receiving treatment with the triple combination therapy of VX-445–tezacaftor–ivacaftor (TC) as compared with placebo. Asterisks indicate P<0.001 for all within-group comparisons, and I bars least-squares means ±SE. IVA denotes ivacaftor, and TEZ tezacaftor.