The therapeutic triple combo elexacaftor (VX-445), tezacaftor, and ivacaftor leads to marked improvements in lung function and quality of life in people with cystic fibrosis (CF) carrying the F508del mutation, data from a Phase 3 trial show.
The findings were reported in a study, “Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial,” published in the journal The Lancet.
CF is a genetic disorder caused by mutations in the CFTR gene, which provides instructions to make the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Although several mutations can cause CF, the F508del mutation is the most common, with up to 90% of CF patients worldwide estimated to carry at least one copy of this mutation.
In people with CF, the F508del mutation leads to the incorrect folding and premature degradation of the CFTR protein, effectively preventing it from reaching the cell membrane and performing its normal function of transporting molecules and water in and out of cells.
Over the past few years, several therapies designed to correct the defects caused by mutations in the CFTR gene, known as CFTR correctors, have been developed. These include Vertex Pharmaceuticals’ lumacaftor, tezacaftor, and elexacaftor, which have been found to be more effective when used in combination with CFTR potentiators, such as ivacaftor (sold under the brand name Kalydeco).
Of note, CFTR potentiators are designed to keep the CFTR protein in a stable conformation to facilitate the transport of molecules in and out of cells.
“Elexacaftor (VX-445) is a next-generation CFTR corrector that was shown, in vitro, to substantially increase the amount of mature CFTR protein and CFTR activity when added to the combination of tezacaftor plus ivacaftor. The triple combination of elexacaftor plus tezacaftor plus ivacaftor showed encouraging results in a phase 2 study [NCT03227471] of a small sample of people with cystic fibrosis [who carried two copies of] the F508del mutation,” the researchers wrote.
Now, investigators have reported the findings from a Phase 3 trial (NCT03525548), sponsored by Vertex, evaluating the efficacy of the triple combo in CF patients with two copies of the F508del mutation.
The multicenter, randomized, double-blind trial enrolled a total of 113 CF patients, 12 and older, who were recruited from 44 clinical sites across four countries — the U.S., Belgium, the Netherlands, and the United Kingdom.
After receiving tezacaftor plus ivacaftor in an initial run-in period of four weeks, participants were randomly assigned to complete one of two four-week treatment regimens: oral elexacaftor (200 mg once-a-day) plus oral tezacaftor (100 mg once-a-day) plus oral ivacaftor (150 mg every 12 hours); or oral tezacaftor (100 mg once-a-day) plus oral ivacaftor (150 mg every 12 hours) alone.
The study’s main goal was to assess the effects of treatment on participants’ lung function, which was measured by the percentage predicted forced expiratory volume in 1 second (ppFEV₁), from baseline to the end of the four-week treatment period.
Secondary goals included assessing changes in the levels of sweat chloride, which is a measure of CFTR activity, and in the Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score, which is a measure of quality of life.
From the 113 CF patients initially enrolled in the study, 107 completed the entire treatment regimen.
Findings revealed that patients who received the triple combination treatment had marked improvements in lung function (improvement of 10 percentage points in ppFEV1), CFTR protein function (sweat chloride levels dropped by 45.1 mmol/L), and quality of life (increase of 17.4 points in CFQ-R RD scores), compared to those who received tezacaftor and ivacaftor alone.
The triple combination therapy was considered safe and well-tolerated, with no patient discontinuing treatment due to adverse events. Most adverse events reported were mild or moderate in severity. The incidence of serious adverse events was slightly higher among patients receiving the triple combination therapy (4%) compared to those receiving tezacaftor and ivacaftor alone (2%).
“The introduction of the triple combination of elexacaftor plus tezacaftor plus ivacaftor could extend highly effective CFTR modulator therapy to those [who carry two copies of] the F508del mutation — a large proportion of people with cystic fibrosis,” the researchers wrote.
“This advance in therapy is likely to modify the natural course of the disease, leading to meaningful improvements in the lives of people with cystic fibrosis, and profoundly affecting the face of cystic fibrosis care,” they added.
Of note, the U.S. Food and Drug Administration approved this triple combo in October 2019 as a treatment for CF patients with at least one F508del mutation. The therapy is marketed as Trikafta by Vertex Pharmaceuticals.