Safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in children with cystic fibrosis aged 2-5 years (TIMBERLINE Trial VX21-121-105): a phase 3, open-label study.

Abstract

Vanzacaftor-tezacaftor-deutivacaftor was shown to be efficacious and safe in people with cystic fibrosis aged 6 years and older, providing further restoration of CFTR function compared with elexacaftor-tezacaftor-ivacaftor. We aimed to assess the safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in children aged 2-5 years. This phase 3, single-arm, open-label study (TIMBERLINE Trial VX21-121-105) consisted of two parts: part A (conducted at 11 sites in the USA) assessed the pharmacokinetics and safety and tolerability of vanzacaftor-tezacaftor-deutivacaftor over a 22-day treatment period to confirm dosing for part B; part B (conducted at 30 sites in nine countries) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of vanzacaftor-tezacaftor-deutivacaftor over a 24-week period. The study enrolled children with cystic fibrosis aged 2-5 years with an elexacaftor-tezacaftor-ivacaftor-responsive genotype. Before the 24-week vanzacaftor-tezacaftor-deutivacaftor treatment period in part B, all children were either on a stable regimen of elexacaftor-tezacaftor-ivacaftor for at least 28 days before screening or underwent a 4-week elexacaftor-tezacaftor-ivacaftor run-in. During the treatment period, children weighing less than 12 kg received vanzacaftor 8 mg once daily, tezacaftor 32 mg once daily, and deutivacaftor 100 mg once daily and children weighing 12 kg or more received vanzacaftor 12 mg once daily, tezacaftor 48 mg once daily, and deutivacaftor 150 mg once daily, orally. The primary endpoint was safety and tolerability; secondary endpoints included absolute change in sweat chloride concentration and proportion of children with sweat chloride concentrations below 60 mmol/L and below 30 mmol/L. These endpoints were assessed in children who received at least one dose of vanzacaftor-tezacaftor-deutivacaftor. This study is registered with ClinicalTrials.gov (NCT05422222) and evaluation in the 2-5-year-old cohort is complete. Part A was conducted between June 11, 2024, and Oct 2, 2024, and part B between Jan 27, 2025, and Jan 7, 2026. In part B, a total of 67 children received at least one dose of vanzacaftor-tezacaftor-deutivacaftor, all of whom completed the study. Mean exposure was 24·0 weeks (SD 0·5). 64 (96%) of 67 children had adverse events, predominantly mild (35 [52%]) or moderate (26 [39%]) in severity. Two (3%) of 67 children had serious adverse events; neither was considered related to vanzacaftor-tezacaftor-deutivacaftor. No children discontinued due to adverse events. From the elexacaftor-tezacaftor-ivacaftor baseline, mean sweat chloride concentration decreased by 9·6 mmol/L (95% CI -12·1 to -7·0) to a mean of 28·9 mmol/L by week 24, with 61 (92%) of 66 children reaching concentrations below the diagnostic threshold for cystic fibrosis (<60 mmol/L) and 43 (65%) reaching concentrations below 30 mmol/L. Vanzacaftor-tezacaftor-deutivacaftor was generally safe and well tolerated. Sweat chloride decreased, with 65% of children reaching concentrations below 30 mmol/L. These results show the safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in preschool-aged children with cystic fibrosis. Vertex Pharmaceuticals.