Triple combination CFTR modulator therapy shows potential for cystic fibrosis
medwireNews: Combination therapy with a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector, together with tezacaftor and ivacaftor, may be a promising treatment option for cystic fibrosis, suggest findings from two studies published in The New England Journal of Medicine.
“Among patients with the Phe508de–Phe508del mutation, dual-combination therapy with a CFTR corrector (lumacaftor or tezacaftor) and [the potentiator] ivacaftor are the current standard of care”, explains Fernando Holguin (University of Colorado, Aurora, USA) in an accompanying editorial.
“However, this combination does not fully restore function to the CFTR protein and is not effective in patients with the Phe508del–minimal function (MF) mutation”, he adds.
Both studies began with in vitro investigations that led to randomised controlled trials. Using human bronchial epithelial cells taken from patients with Phe508del–Phe508del or Phe508del–MF genotypes, the researchers demonstrated that two next-generation CFTR correctors, VX-445 and VX-659, in combination with tezacaftor and ivacaftor, increased processing and trafficking of the CFTR protein, and improved chloride transport to a greater extent than any two of the agents in a dual combination. This provided “molecular and biologic rationale” for the clinical trials, say the researchers.
In the first trial, Jennifer Taylor-Cousar (National Jewish Health, Denver, Colorado, USA) and co-investigators randomly assigned participants with Phe508del–MF genotypes to receive 4 weeks of treatment with oral VX-445 at a dose of 50, 100 or 200 mg once daily, in combination with tezacaftor 100 mg once daily and ivacaftor 150 mg every 12 hours, or to receive placebo. Patients with the Phe508del–Phe508del genotype were pretreated with tezacaftor and ivacaftor for 4 weeks, after which time they were randomly assigned to receive the triple combination regimen or to receive tezacaftor, ivacaftor and placebo.
In all, 92% of 74 patients given the triple combination regimen experienced adverse events (AEs), as did 71% of seven patients given tezacaftor and ivacaftor and 100% of 12 patients treated with placebo. Three patients receiving the triple combination discontinued treatment as a result of rash, elevated bilirubin level or chest pain (each occurring in a different patient). Taylor-Cousar and team note that the majority of AEs were mild or moderate in severity.
Treatment with the triple combination at all doses of VX-445 resulted in a significant improvement in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline to week 29 among patients with both genotypes, with average improvements of 7.9–13.8 percentage points with the Phe508del–MF genotype, and 11.0 percentage points in patients with the Phe508del–Phe508del genotype who were already receiving tezacaftor and ivacaftor. The mean improvement was 0.0–0.4 percentage points for those in the control groups.
In accordance with these findings, the authors of the second trial – with the same design as the first – report that oral VX-659 had “an acceptable safety and side-effect profile” in patients with both genotypes, with the majority of AEs being mild or moderate in severity.
Steven Rowe (University of Alabama at Birmingham, USA) and team demonstrated that the percentage of predicted FEV1 improved significantly from baseline to week 29 among the 71 patients who were randomly assigned to receive a combination of tezacaftor, ivacaftor and VX-659 (80, 240 or 400 mg, given at the same dosing schedule as the first trial), with average improvements of 10.2–13.3 percentage points for patients with the Phe508del–MF genotypes, and 9.7 percentage points for those with the Phe508del–Phe508del genotype. By comparison, the 21 patients receiving the control regimens experienced an average improvement of 0.0–0.4 percentage points.
Moreover, in both trials, sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised also improved with the triple therapy combination in both genotype groups.
“These trials provide proof of the concept that targeting the Phe508del CFTR protein with a triple-combination corrector–potentiator regimen can restore CFTR function and has the potential to represent a clinical advance for patients with cystic fibrosis who harbor either one or two Phe508del alleles”, conclude Rowe and colleagues.
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