Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2-5 Years with Cystic Fibrosis and at Least One F508del Allele

Abstract

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ⩾6 years with at least one F508del-CFTR allele but has not been studied in younger children. Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2-5 years. Methods: In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ⩾14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours. Measurements and Main Results: The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk 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 index_2.5 (LCI_2.5, defined as the number of lung turnovers required to reduce the end tidal N₂ concentration to 2.5% of its starting value) 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 LCI_2.5 (-0.83 U; 95% CI, -1.01 to -0.66; n = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24. Conclusions: In this open-label study in children 2-5 years of age, ELX/TEZ/IVA 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 LCI_2.5. Clinical trial registered with www.clinicaltrials.gov (NCT04537793).

Keywords: CF; ELX; IVA; TEZ; preschool children.

Figure 1.

Patient disposition diagram for part B of the study. AE = adverse event.

Figure 2.

Pharmacokinetic exposure simulations. In each box plot, the median is represented by the horizontal line and the interquartile range by the box. Whisker marks indicate the largest and smallest within 1.5× the interquartile range. The gray area represents the 5th percentile (bottom border) and 95th percentile (top border), the green line represents the 50th percentile of the adult area under the curve values, and the red line represents the no observable adverse events level. AUC = area under the curve; ELX = elexacaftor; IVA = ivacaftor; M1 = metabolite 1; M23 = metabolite 23; NOAEL = no observable adverse events level; q12h = once every 12 hours; qd = once daily; TEZ = tezacaftor. *Children received ivacaftor 60 mg in the morning and ivacaftor 59.5 mg in the evening.

Figure 3.

Secondary efficacy results by visit in part B. (A) Mean (SE) change from baseline in sweat chloride concentration is shown for each visit. (B) Mean (SE) change from baseline in LCI_2.5 is shown for each visit. LCI_2.5 = lung clearance index_2.5; LS = least squares.

Figure 4.

Changes in growth parameters and fecal elastase-1 concentrations by visit in part B of the study. Mean (SE) absolute change from baseline in the growth parameters (A) BMI-for-age z-score, (B) weight-for-age z-score, and (C) height-for-age z-score for each study visit. (D) Spaghetti plot showing individual changes from baseline in fecal elastase-1 concentration at each visit. Blue lines indicate children with at least one fecal elastase-1 measurement >200 µg/g at a study visit. BMI = body mass index; LS = least squares.

Figure 5.

Sweat chloride responder analysis by genotype group. The percentage of children in each genotype group (F/F and F/MF) with sweat chloride concentrations <60 mmol/L and <30 mmol/L at Week 24 is shown. Percentages were calculated by dividing the number of children with sweat chloride concentrations below the indicated threshold at Week 24 by the total number of children with evaluable data. Children with missing data were considered to be missing at random and were not counted in the denominator. F/F = homozygous for the F508del–cystic fibrosis transmembrane conductance regulator (CFTR) mutation; F/MF = heterozygous for the F508del-CFTR mutation and a minimal-function CFTR mutation.