VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

Background: VX-445 is an advanced cystic fibrosis transmembrane conductance regulator (CFTR) corrector, developed to restore the function of Phe508del CFTR protein in cystic fibrosis patients when combined with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor).

Methods: The effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport were assessed in human bronchial epithelial cells. Based on in vitro results, a phase 2, randomized, placebo-controlled, double-blind, dose-ranging trial was conducted to evaluate the oral administration of VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and those homozygous for the Phe508del mutation (Phe508del-Phe508del) after a run-in period with tezacaftor-ivacaftor. The primary endpoints were safety and the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline.

Results: In vitro, VX-445-tezacaftor-ivacaftor significantly enhanced Phe508del CFTR protein processing, trafficking, and chloride transport, outperforming any two of the individual agents in dual combinations. In cystic fibrosis patients, VX-445-tezacaftor-ivacaftor demonstrated an acceptable safety profile, with most adverse events being mild or moderate. Treatment led to an increase in the percentage of predicted FEV1 by up to 13.8 points in the Phe508del-MF group (P<0.001). In the Phe508del-Phe508del group, who were already on tezacaftor-ivacaftor, adding VX-445 resulted in an 11.0-point improvement in predicted FEV1 (P<0.001). Both groups also showed a reduction in sweat chloride levels and an improvement in the respiratory domain score of the Cystic Fibrosis Questionnaire-Revised.

Conclusions: VX-445-tezacaftor-ivacaftor enhanced CFTR function in vitro and led to significant clinical improvements in patients with one or two Phe508del alleles. This combination therapy has the potential to address the underlying cause of cystic fibrosis in approximately 90% of patients.