VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

Abstract

Background: The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.

Methods: We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV₁).

Results: VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV₁ through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV₁. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations.

Conclusions: Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).

Figure 1 (facing page).. Trial Design and Randomization and Follow-up of Patients.

Panel A shows the design of the phase 1 trial (VX16-659-001) and phase 2 trial (VX16-659-101) involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-minimal function genotypes) and patients who were homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). In the phase 1 trial, the dose of VX-659 was 120 mg every 12 hours; tezacaftor-ivacaftor (TEZ-IVA) was administered at a dose of 100 mg of TEZ once daily and 150 mg of IVA every 12 hours. In the phase 2 trial, the dose of VX-659 shown is the dose that was administered once daily; TEZ-IVA was administered at the same dose as in the phase 1 trial. A subgroup of patients with the Phe508del-minimal function genotype received VX-561 once daily instead of IVA every 12 hours. In the phase 2 trial, period 1 is the 4-week intervention period; period 2 is a wash-out of VX-659, as applicable. Panel B shows the number of patients in each intervention group who received at least one dose of the trial regimen and the number who completed the intervention period of 2 weeks (phase 1 trial) or 4 weeks (phase 2 trial).

Figure 2.. In Vitro Effect of VX-659 Alone or in Combination with TEZ, IVA, or TEZ-IVA.

Panels A and B show the effect of VX-659 on the processing and trafficking of Phe508del CFTR protein in human bronchial epithelial (HBE) cells derived from patients with Phe508del-minimal function (Phe508del-MF) or Phe508del-Phe508del genotypes. Panel A shows the results of representative immunoblotting from three independent experiments. Panel B shows the quantitative assessment of that data through densitometry findings pooled from three independent experiments, with six replicates in each experiment. Data are presented as mean relative intensities normalized to calnexin, a control for protein loading. The compound concentrations used were as follows: 1.4 μM of VX-659, 18 μM of TEZ, and 1 μM of 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, b P<0.05 for the comparison with TEZ-IVA, and c P<0.05 for the comparison with VX-659 in unpaired t-tests. Panel C shows an assessment of chloride transport in HBE cells treated with various combinations of TEZ (18 μM), IVA (1 μM), and VX-659 (1 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<0.05for the comparison with vehicle, y P<0.05 for the comparison with TEZ-IVA, and z P<0.05 for the comparison with VX-659-IVA in paired t-tests. In Panels B and C,T bars indicate standard errors.

Figure 3 (facing page).. Absolute Change from Baseline in the Percentage of Predicted FEV₁, Sweat Chloride Concentration, and CFQ-R Respiratory Domain Score.

Shown is the least-squares mean change in the percentage of predicted forced expiratory volume in 1 second (FEV₁) though day 29, sweat chloride concentration through day 29, and score on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), without adjustment for baseline scores, at day 29 in patients with Phe508del-minimal function genotypes (Panel A) and those with the Phe508del-Phe508del genotype (Panel B). CFQ-R respiratory domain scores range from 0 to 100, with higher scores indicating a higher patient-reported quality of life with respect to respiratory status (minimal clinically important difference, 4 points). I bars indicate standard errors. Asterisks indicate a within-group P value of less than 0.001 for the comparison with baseline. TC denotes triple-combination therapy with VX-659-TEZ-IVA; the dose in milligrams represents the dose of VX-659 administered once daily.