NEW YORK (Reuters Health) – Triple combination therapy with elexacaftor, ivacaftor, and tezacaftor has advantages over tezacaftor plus ivacaftor in people with cystic fibrosis (CF) homozygous for the F508del mutation in the CF transmembrane conductance regulator (CFTR) gene, according to results of a phase-3b trial.
“The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population,” the study teamin The Lancet Respiratory Medicine.
Vertex Pharmaceuticals, which markets the triple-drug combo as Trikafta and the two-drug combo as Symdeko in the U.S., funded the study.
The study included 175 patients aged 12 and older with CF and two F508del-CFTR alleles, stable disease, and percent predicted FEV1 of 40%-90%.
Following a 4-week run-in period in which all participants received tezacaftor plus ivacaftor, 87 were randomly assigned to elexacaftor plus tezacaftor plus ivacaftor and 88 to tezacaftor plus ivacaftor for 24 weeks.
From baseline through 24 weeks, the mean Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain score – the primary endpoint – increased by 17.1 points in the triple therapy group versus 1.2 points in the two-drug group (P < .0001).
In addition, mean percent predicted FEV1 – a key secondary endpoint – increased by 11.2 percentage points with elexacaftor-tezacaftor-ivacaftor therapy versus 1.0 percentage points with tezacaftor-ivacaftor (P < .0001).
Triple therapy also led to improvement in sweat chloride concentration, a clinical indicator of CFTR function that is directly related to disease severity and is predictive of mortality, lung function and BMI.
The mean sweat chloride concentration decreased by 46.2 mmol/L with triple therapy versus 3.4 mmol/L with dual therapy (P < .0001).
In post hoc analysis, 79% of participants on triple therapy had sweat chloride concentrations of less than 60 mmol/L (the diagnostic threshold for CF) and 23% had concentrations less than 30 mmol/L, which corresponds to that generally seen in the population of asymptomatic carriers with a single CFTR mutation.
By contrast, only 2% of participants given tezacaftor plus ivacaftor had sweat chloride concentrations of less than 60 mmol/L and none had concentrations of less than 30 mmol/L.
“These results indicate the potential for durable normalisation of CFTR function in people with cystic fibrosis homozygous for the F508del-CFTR mutation with elexacaftor plus tezacaftor plus ivacaftor treatment,” wrote Dr. Sivagurunathan Sutharsan of the University of Duisburg-Essen, in Germany, and colleagues.
Eighty percent of participants in the elexacaftor-tezacaftor-ivacaftor group and 84% in the tezacaftor plus ivacaftor group had adverse events that were mild or moderate in severity; serious adverse events occurred in 6% and 16%, respectively.
This study shows that treatment with elexacaftor plus tezacaftor plus ivacaftor “provides robust and durable lung function, nutritional, and quality-of-life benefits in people with cystic fibrosis homozygous for the F508del-CFTR mutation, exceeding those reported with previous CFTR modulator therapies. These results further substantiate elexacaftor plus tezacaftor plus ivacaftor as a superior treatment option for this patient population,” the study team concluded.
Several authors have financial relationships with Vertex Pharmaceuticals.
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