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.)

Cystic Fibrosis–Associated Liver Disease in Lung Transplant Recipients

“…The 2018 guidelines for the use of CFTR modulator therapy made a strong recommendation for the use of ivacaftor/lumacaftor in patients homozygous for Phe508del and with a forced expiratory volume in 1 second (FEV 1 ) <90% predicted . In October 2018, 2 breakthrough studies involving a triple combination of CFTR modulators were published . Both studies demonstrated improvement over the predicted percentage for FEV 1 , above what was already achieved by dual therapy in patients homozygous for Phe508del and with a Phe508del‐MF mutation.…”

Cystic fibrosis: novel therapies, remaining challenges

“…Although the current available combinations of potentiator (ivacaftor) and corrector (lumacaftor or tezacaftor) have provided some, albeit modest, improvement in lung function, individuals with Phe508del mutations remain a challenge. Among those who have at least one such mutation, approximately half are homozygous and approximately one‐third have a minimal function (MF) CFTR mutation as the second allele . MF mutations either produce no CFTR or a protein that is not responsive to CFTR modulators.…”

“…The initial results of two small studies using the triple CFTR approach are now available . Both studies were conducted in adults who were either Phe508del homozygous or heterozygous for the Phe508del and an MF mutation, and were already receiving dual therapy with ivacaftor and tezacaftor.…”

Cystic fibrosis: triple drug regimens that target defective ion channel improve lung function, studies show

“…Triple drug combinations that improve the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), the anion channel that is defective or deficient in the condition, significantly improve lung function in patients with cystic fibrosis who have the most common CFTR gene mutations, two early stage randomised trials have reported 12…”

“…The results, reported in the New England Journal of Medicine ,12 showed that patients treated with the VX-659-combination showed significant increases in the percentage of predicted forced expiratory volume in one second (FEV 1 ) at day 29. At the highest dose, FEV 1 increased by an average of 13.3% ± standard error 1.9% (95% confidence interval 9.5% to 17.1%; P<0.001), compared with no change in the placebo group.…”