The triple combination medicine deutivacaftor/tezacaftor/vanzacaftor (brand name Alyftrek) has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) for treating eligible patients with cystic fibrosis.
This is a once-daily, next-in-class triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator treatment.
Deutivacaftor/tezacaftor/vanzacaftor is indicated for people with cystic fibrosis aged six years and older who have at least one F508del mutation or another responsive mutation in the CFTR gene, including additional mutations not previously approved with other CFTR modulator therapies.
The manufacturer Vertex Pharmaceuticals is working with the National Institute for Health and Care Excellence (NICE) and the NHS to ensure eligible patients can access this new therapy, with a decision expected during the summer.
David Ramsden, chief executive of the Cystic Fibrosis Trust, said the ‘MHRA approval is another important step in making sure as many people with CF as possible can benefit from the best available treatments’.
He added: ‘We never forget that these medicines are not a cure, and do not work for some people. Cystic Fibrosis Trust will not stop until everyone with CF can live a life that’s not limited by their condition.’
This follows the approval of deutivacaftor/tezacaftor/vanzacaftor in the US in December for the same age group. Marketing authorisation applications are ongoing with the European Medicines Agency and other markets.
Safety and efficacy of deutivacaftor/tezacaftor/vanzacaftor
The MHRA approval was based on the results of two head-to-head randomised phase 3 trials (Skyline 121-102 and 121-103) involving 480 participants aged 12 years and over, and supported by data from an additional open‑label, phase 3 trial (Ridgeline 121-105, Cohort B1).
The primary endpoint for the trials was absolute change in FEV1 percentage predicted from baseline (most recent value before treatment on Day 1) through Week 24 (with non-inferiority of deutivacaftor/tezacaftor/vanzacaftor shown if the lower bound of the 95% CI for the primary endpoint was –3.0 or higher).
Safety was assessed in all participants who received at least one dose of study drug during the treatment period.
Deutivacaftor/tezacaftor/vanzacaftor was found to be as effective at improving lung function as the standard of care ivacaftor/tezacaftor/elexacaftor (brand name Kaftrio). It was also found to be more effective at reducing sweat chloride levels than the standard of care.
The study drug also showed potential as a treatment option for people with a small number of gene mutations not covered by the license for ivacaftor/tezacaftor/elexacaftor.
The authors wrote that once-daily dosing with deutivacaftor/tezacaftor/vanzacaftor reduced treatment burden, potentially improving adherence, compared with the twice-daily regimen of the current standard of care.
The most common side effects in the clinical trials were headache (15.8%) and diarrhoea (12.1%), the MHRA noted.
‘More flexible and less burdensome regimen’
Professor Alex Horsley, who led the Skyline trials, is professor of respiratory medicine at the University of Manchester, consultant at the Manchester Adult Cystic Fibrosis Centre and medical director of the NIHR Manchester Clinical Research Facility at Wythenshawe Hospital.
Commenting on the findings, he said: ‘The deutivacaftor/tezacaftor/vanzacaftor Phase 3 trial results showed that it is possible to further improve CFTR protein function with this once-a-day, more flexible and less burdensome regimen.
‘Children and adults taking the new triple combination therapy were more likely to have carrier levels of sweat chloride compared to those on the ivacaftor/tezacaftor/elexacaftor regimen, which we hope will translate to reduced risk of developing CF-related complications in the long term.’
The license for ivacaftor/tezacaftor/elexacaftor was extended by the MHRA in November 2023 to include children aged two to five years old.
Last year, it was found that ivacaftor use was ‘safe and effective’ from one month old.
