RATIONALE
Elexacaftor/tezacaftor/ivacaftor has been shown to be safe and effective in people with cystic fibrosis (CF) aged ≥6 years with ≥1 F508del-CFTR allele but has not been studied in younger children.
OBJECTIVES
To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of elexacaftor/tezacaftor/ivacaftor in children with CF aged 2 through 5 years.
METHODS
In this Phase 3, open-label, two-part study (Parts A and B), children weighing <14 kg (on Day 1) received elexacaftor 80 mg once daily, tezacaftor 40 mg once daily, and ivacaftor 60 mg each morning and 59.5 mg each evening; children weighing ≥14 kg received elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, and ivacaftor 75 mg every 12 hours.
MEASUREMENTS AND MAIN RESULTS
The primary endpoints for Part A (15-day treatment period) were pharmacokinetics and safety and tolerability. For Part B (24-week treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in Part A confirmed the appropriateness of the Part B dosing regimen. In Part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L [95% confidence interval [CI], -61.3 to -54.6]; n = 69) and LCI2.5 (-0.83 units [95% CI, -1.01 to -0.66]; n = 50) were observed from baseline through Week 24. Mean BMI was within the normal range at baseline and remained stable at Week 24.
CONCLUSIONS
In this open label study in children 2 through 5 years of age, elexacaftor/tezacaftor/ivacaftor treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and lung clearance index. Clinical trial registration available at www.
CLINICALTRIALS
gov, ID: NCT04537793.