VX-445-tezacaftor-ivacaftor, which targets the Phe508del cystic fibrosis transmembrane conductance regulator (CFTR) protein, was associated with an increase in in vitro CFTR function as well as improvements in patients with cystic fibrosis with 1 or 2 Phe508del alleles, according to study results published in the New England Journal of Medicine.

Human bronchial epithelial cells were used to assess the effect of VX-445-tezacaftor-ivacaftor on the processing, trafficking, and chloride transport of Phe508del CFTR protein. Using the information in this assessment, researchers performed a randomized double-blind phase 2 trial (VX16-445-001; ClinicalTrials.gov Identifier: NCT03227471) to test the effect of oral VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–MF). 

In addition, the treatment was tested in patients homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del) following a run-in phase of tezacaftor-ivacaftor. Safety and absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) comprised the primary end points.

A total of 122 patients were included. In the in vitro analysis, VX-445-tezacaftor-ivacaftor led to noticeable improvements in Phe508del CFTR protein function. Patients with the Phe508del-MF and Phe508del-Phe508del genotypes experienced significant improvements in the percentage of predicted FEV1 from baseline. In patients with the Phe508del-MF genotype, treatment was associated with a 13.8-point increase in predicted FEV1 (P <.001), whereas patients in the Phe508del-Phe508del group had an 11.0-point increase (P <.001).

Treatment with VX-445-tezacaftor-ivacaftor was relatively safe, with most adverse events reported as mild or moderate in severity. Both genotype groups experienced a decrease in the concentrations of sweat chloride and improvements in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised.

Limitations of this study include the lack of long-term follow-up as well as the relatively small number of patients included in the phase 2 trial.

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According to the researchers, the findings from this study “provide support for further development of both CFTR modulator combinations, which have the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients with the disease.”

Disclosures: This study was funded by Vertex Pharmaceuticals.

Reference

Keating D, Marigowda G, Burr L, et al; for the VX16-445-001 Study Group. VX-445–tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018;379(17):1599-1611.