A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele

Abstract

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes. Methods: In this 24-week open-label phase 3 study, children (N = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV₁ (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index_2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).

Keywords: child; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor.

Figure 1.

Patient disposition diagram for part B. *Patient discontinued treatment because of erythematous rash.

Figure 2.

Pharmacokinetic exposure simulation. For each boxplot, the median is represented by a horizontal line, and the interquartile range is represented by the box. The whiskers mark the largest and smallest values within 1.5 × interquartile range. Dots represent individual empirical Bayes AUC estimate (EBE) values. In each panel, the dashed horizontal line represents the median of the ⩾18 years AUC values, and the gray shaded area indicates the 5th and 95th percentiles of the ⩾18 years AUC values. The EBE values for 6–11 years are from part B of this study. The EBE values for ⩾12 years are from studies 445-102 and 445-103 (12, 13). AUC = area under the concentration-versus-time curve; AUC_0–12 = area under the concentration-versus-time curve (0–12 h after dose); AUC_0–24 = area under the concentration-versus-time curve (0–24 h after dose); ELX = elexacaftor; IVA = ivacaftor; TEZ = tezacaftor.

Figure 3.

Efficacy results, by visit, in part B. (A) Absolute change from baseline at each visit in ppFEV₁. (B) Absolute change from baseline at each visit in the respiratory domain score on the CFQ-R, child’s version; scores are normalized to a 100-point range, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms. (C) Absolute change from baseline at each visit in LCI_2.5. (D) Absolute change from baseline at each visit in sweat chloride concentration; a reduction indicates improvement in CFTR (cystic fibrosis transmembrane conductance regulator) function. Data are least squares means based on a mixed-effects model for repeated measures, and error bars indicate SEMs; the dashed line indicates no change from baseline. Sample size shown under each x-axis is the number of patients at the time point with evaluable in-clinic data. CFQ-R = Cystic Fibrosis Questionnaire–Revised; LCI_2.5 = lung clearance index_2.5; ppFEV₁ = percentage of predicted FEV₁.

Figure 4.

Absolute change from baseline at each visit in (A) BMI, (B) BMI-for-age z-score, (C) weight, (D) weight-for-age z-score, (E) height, and (F) height-for-age z-score in part B. Data are least squares means based on a mixed-effects model for repeated measures, and error bars indicate SEMs; the dashed line indicates no change from baseline. Sample size shown under each x-axis is the number of patients at the time point with evaluable in-clinic data. BMI = body mass index.

Figure 5.

Responder analysis for sweat chloride concentration by genotype group in part B. The percentage of children in each genotype group with sweat chloride concentrations <60 mmol/L or <30 mmol/L through Week 24 is shown. No children had sweat chloride concentrations <60 mmol/L at baseline. Percentages were calculated by dividing n (the number of patients with sweat chloride concentration below the indicated threshold) by N1, where N1 is the number of patients with evaluable data. Patients with missing data were considered missing at random and were not counted in the denominator. F/F = homozygous for the F508del-CFTR mutation; F/MF = heterozygous for the F508del-CFTR mutation and a minimal function CFTR mutation.