Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials.

Summary

Across two double-blind, active‑controlled phase 3 trials (n=398 and n=573 randomized), once‑daily vanzacaftor‑tezacaftor‑deutivacaftor was non‑inferior to elexacaftor‑tezacaftor‑ivacaftor for FEV1 over 52 weeks, with a comparable safety profile. The regimen simplifies dosing to morning tablets only and supports normalizing CFTR function.

Key Findings

• Two randomized, double‑blind, active‑controlled phase 3 trials enrolled 398 and 573 participants after a 4‑week ETI run‑in.
• Vanzacaftor‑tezacaftor‑deutivacaftor met non‑inferiority versus ETI for FEV1 change over 52 weeks.
• Safety profiles were broadly comparable between regimens; dosing is once‑daily in the morning for vanzacaftor‑based therapy.

Clinical Implications

Vanzacaftor‑tezacaftor‑deutivacaftor offers a non‑inferior, once‑daily alternative to ETI for eligible genotypes, supporting regimen simplification in routine CF care.

Limitations

• Non‑inferiority framework without superiority; details of secondary outcomes not fully specified in abstract
• Generalisability limited to genotypes eligible for CFTR modulation

Future Directions

Head‑to‑head comparisons on patient‑reported outcomes, adherence, and long‑term exacerbation risk; evaluation in broader age ranges and comorbid populations.