Triple Combo Regimens May Address Cause of Cystic Fibrosis

FRIDAY, Oct. 19, 2018 — Triple therapy with VX-659 or VX-445 combined with tezacaftor-ivacaftor shows promise for the treatment of adult patients with cystic fibrosis who have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), according to two studies published online Oct. 18 in the New England Journal of Medicine. The studies were published to coincide with presentation at the annual North American Cystic Fibrosis Conference, held from Oct. 18 to 20 in Denver.

Jane C. Davies, M.D., from Imperial College London, and colleagues examined the effects of VX-659-tezacaftor-ivacaftor in cystic fibrosis. A range of doses were assessed in randomized trials involving patients with cystic fibrosis, heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del). The researchers observed significant improvement in the processing and trafficking of the Phe508del CFTR protein with VX-659-tezacaftor-ivacaftor, as well as improved chloride transport in vitro. Significant mean increases in the percentage of predicted forced expiratory volume in one second (FEV₁) were seen through day 29.

Dominic Keating, M.D., from Alfred Hospital in Melbourne, Australia, and colleagues examined the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial cells. A phase 2 trial was conducted in patients with Phe508del-MF and Phe508del-Phe508del. The researchers found that VX-445-tezacaftor-ivacaftor improved Phe508fel CTFR protein processing, trafficking, and chloride transport in vitro to a greater extent than any two of these agents in dual combination. The treatment resulted in an increased percentage of predicted FEV₁ of up to 13.8 points in the Phe508del-MF group.

“These reports represent a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common CFTR mutation,” write the authors of an accompanying editorial.

Both studies were funded by Vertex Pharmaceuticals.

Abstract/Full Text – Davies
Abstract/Full Text – Keating
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Posted: October 2018

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