(693) A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 2 Through 5 Years of Age with Cystic Fibrosis and at Least One F508del Allele

This Phase 3, 2-part (Part A and Part B) study was designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of ELX/TEZ/IVA in children 2 through 5 years of age. Dosing was based on weight at Day 1. Children who weighed < 14 kg received ELX 80 mg once daily (qd)/TEZ 40 mg qd/IVA 60 mg once daily in AM and IVA 59.5 mg once daily in PM while children who weighed ≥ 14 kg received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg every 12 hours (half adult dose). The primary endpoints for Part A were PK and safety and tolerability. The primary endpoint for Part B was safety and tolerability; secondary endpoints included PK parameters and absolute changes from baseline in sweat chloride concentration and lung clearance index_2.5 (LCI_2.5) through Week 24. Other endpoints in Part B included: absolute changes from baseline in BMI and associated z-score and fecal elastase-1 at Week 24 as well as the number of pulmonary exacerbations (PEx) and CF-related hospitalization through Week 24.  

Results:

75 children (F508del/minimal function [F/MF] genotypes, n=52; F508del/ F508del [F/F] genotype, n=23) were enrolled and dosed in Part B. Analysis of PK data from Part A confirmed the appropriateness of the Part B dosing regimen. In Part B, 74 children (98.7%) had adverse events (AEs), which for all children were either mild (62.7%) or moderate (36.0%) in severity. The most commonly reported AEs were cough, fever, and rhinorrhea. Two children (2.7%) had serious AEs (SAEs): one child had SAEs of abnormal behavior and urinary and fecal incontinence which were considered possibly related to study drug and resolved with study drug discontinuation and a second child had an SAE of PEx which was considered not related to study drug and resolved. ELX/TEZ/IVA treatment led to decreases in sweat chloride concentration (-57.9 [95% CI, -61.3, -54.6] mmol/L; n=69) and LCI_2.5 (-0.83 [95% CI, -1.01, -0.66] units; n=50) from baseline through Week 24. The estimated PEx rate per 48 weeks was 0.32 events per year. Mean BMI and BMI z-score, which were normal at baseline, remained stable at Week 24 (mean absolute change 0.03 [95% CI, -0.10, 0.17] kg/m² and 0.10 [95% CI, 0.00, 0.20], respectively). The mean absolute change in fecal elastase-1 concentration from baseline at Week 24 was 39.5 (SD, 89.2) µg/g; there were 6 children who had fecal elastase-1 concentrations ≥ 200 µg/g (normal range) at Week 24 compared with 2 children at baseline.

Conclusions:

ELX/TEZ/IVA was generally safe and well-tolerated in children 2 through 5 years of age, with a safety profile consistent with older age groups. Treatment with ELX/TEZ/IVA led to improvements in sweat chloride concentration and LCI_2.5, along with a low rate of PEx and stable nutritional status. These results show ELX/TEZ/IVA has a favorable safety profile and provides clinically meaningful benefits in CFTR function to people with CF as young as 2 years of age.

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