Positive early results with new generation CFTR corrector triple therapy are a “major breakthrough” for most cystic fibrosis patients, researchers say.
Published in the NEJM, two parallel trials of triple therapy regimens of the small-molecule CFTR correctors VX-659 or VX445 in combination with tezacaftor–ivacaftor showed significant improvements for patients with the most common CFTR mutations.
The novel molecules bind to different parts of the CFTR protein than current therapies and appear to have synergistic effects when used in combination with tezacaftor–ivacaftor dual therapy in adult CF patients who have the Phe508del–MF or Phe508del–Phe508del genotypes.
In one trial, four weeks of therapy with the next-generation CFTR corrector VX-659 was compared to placebo in combination with tezacaftor–ivacaftor in 29 patients with the Phe508del–Phe508del genotype and 25 patients with the Phe508del–MF genotype.
For these genotypes, triple therapy significantly increased the primary endpoint of predicted percentage FEV1 by an average of 9.7% and 13.3% respectively, compared to placebo.
Patients taking triple therapy also showed improvements in sweat chloride concentration, and CF quality of life respiratory scores compared to dual therapy.
In a parallel trial using VX-445 in 28 patients with the Phe508del–Phe508del genotype and 95 patients with Phe508del–MF genotypes, triple therapy significantly increased FEV1 for these genotypes by 11% and 13.8%, compared to placebo.
The study authors say these phase 1 and 2 trials of the molecules – developed by Vertex Pharmaceuticals – will pave the way for larger and longer trials that could potentially offer treatment for many patients with CF.
“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, approximately 9 of every 10 patients with the disease,” they said.
An accompanying editorial noted that the trials showed no dose-limiting toxicity and said the findings “represent a major breakthrough in cystic fibrosis therapeutics.”
Dr Martin Donnelley, Co-Director of the Cystic Fibrosis Airway Research Group at Adelaide University said that if confirmed in phase 3 trials, the triple therapy combination would potentially work for 90% of patients with CF, in contrast to current therapies such as ivacaftor (Kalydeco) which works for about 10% of the Australian CF population.
“The improvements they saw in these clinical trials were impressive, even more so considering a group of patients were already receiving an existing modulator therapy,” he said.
“[And] while it’s great to see lung function improvements, importantly the patients on the new drug also recorded improvements in their quality of life, suggesting these therapies can have a huge impact for patients.”
However, Dr Donnelly noted that some patients did have adverse events, with three of 122 discontinuing treatment due to side effects in one trial “highlighting that these therapies are not suitable for all CF patients.”
“The cost of these pharmaceutical therapies remains an important consideration, and this will need to be assessed in the future by the PBAC,” he added.