Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3B, Randomized, Placebo-Controlled Study

Science and Research

RATIONALE: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis (CF) and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. OBJECTIVES: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. METHODS: Children were randomized to receive either ELX/TEZ/IVA (N = 60) or placebo (N = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ≥30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was absolute change in lung clearance index2.5 (LCI2.5) from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in LCI2.5 of 2.29 units (95% CI, 1.97 to 2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81, P<0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1), and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95%, CI 6.9 to 15.1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0 to 10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. CONCLUSIONS: In this first randomized, controlled study of a CFTR modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and CFTR function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT04353817.