Treatment with the next-generation triple combination CFTR modulator vanzacaftor–tezacaftor–deutivacaftor shows promise in further improving CFTR function beyond the standard of care of elexacaftor–tezacaftor–ivacaftor (ETI).

International phase 3 studies, published simultaneously in The Lancet Respiratory Medicine, evaluated the new once-daily treatment in children 6-11 years [link here] and in adolescents ≥12 years and adults [link here].

The paediatric study, RIDGELINE trial VX21-121-105, enrolled 78 children with CF from 33 sites in Australia, France, Germany, Netherlands, Sweden, Switzerland, the UK, and the US.

Eligible children had a confirmed diagnosis of CF with at least one ETI-responsive CFTR variant, FEV₁ % predicted of ≥60%, and stable cystic fibrosis on ETI. Participants then received vanzacaftor–tezacaftor–deutivacaftor, dose adjusted for bodyweight, for 24 weeks. 

The single-arm study found the combination treatment was safe and well tolerated with mostly mild or moderate severity AEs including cough (46%), pyrexia (21%) and headache (18%).

Only one participant discontinued vanzacaftor–tezacaftor–deutivacaftor due to adverse events of cough and fatigue.

The study also reported that participants maintained normal baseline FEV₁ % predicted through week 24 while sweat chloride concentrations reduced.

Nearly all participants (94.9%) had sweat chloride concentrations <60 mmol/L and more than half (52·6%) had concentrations <30 mmol/L through week 24.

“Results from post-hoc genotype subgroup analyses show stable FEV₁ % predicted and improved CFTR function in all genotype categories,” the study said.

Vanzacaftor–tezacaftor–deutivacaftor treatment also led to improvements in CFQ-R respiratory domain score.

Results from cohorts of younger children 1 year to <2 years and 2–5 years will be reported elsewhere.

Adolescents and adults 

Meanwhile, the SKYLINE RCTs VX20-121-102 and VX20-121-103, reported outcomes after 52-weeks of treatment with either vanzacaftor–tezacaftor–deutivacaftor or ETI.

Trial VX20-121-102 randomised 398 participants from 126 sites across 12 countries including Australia. Trial VX20-121-103 randomised 573 participants from 159 sites across 20 countries including Australia and New Zealand.

In both trials, vanzacaftor–tezacaftor–deutivacaftor was non-inferior to ETI in the primary endpoint of absolute change in FEV₁ % predicted from baseline through week 24.

As well, vanzacaftor–tezacaftor–deutivacaftor was superior to ETI in the key secondary endpoint of absolute change from baseline in the sweat chloride concentration through week 24.

“Treatment with vanzacaftor–tezacaftor–deutivacaftor led to 2·2 times greater odds of having sweat chloride concentrations below 60 mmol/L and 2·9 times greater odds of having sweat chloride concentrations below 30 mmol/L compared with elexacaftor–tezacaftor–ivacaftor,” the study said.

 “These results show that vanzacaftor–tezacaftor–deutivacaftor treatment might lead to more people with cystic fibrosis attaining levels of CFTR function either below the diagnostic threshold or in the normal range.”

Again, vanzacaftor–tezacaftor–deutivacaftor was generally safe and well tolerated. 

“The occurrence of serious adverse events and events that led to treatment discontinuation were low and similar between groups.” 

The investigators said the results of in-vitro analyses have shown that 31 additional CFTR variants are responsive to vanzacaftor–tezacaftor–deutivacaftor but not to ETI.

“Vanzacaftor–tezacaftor–deutivacaftor may have the potential to further restore CFTR function in a broader population compared with elexacaftor-tezacaftor-ivacaftor; however, these in-vitro findings will need to be confirmed in real-world studies to establish benefits in people with cystic fibrosis with these variants,” they said.

The studies were sponsored by Vertex Pharmaceuticals.

Vanzacaftor/tezacaftor/deutivacaftor (Alyftrek) was FDA-approved in December 2024 for people with CF six years and older who have at least one F508del mutation or another mutation in the CFTR gene that is responsive to Alyftrek.