A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age with Cystic Fibrosis Homozygous for F508del-CFTR

Abstract

Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ⩾2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was -29.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registered with www.clinicaltrials.gov (NCT03601637).

Keywords: children; cystic fibrosis; ivacaftor; lumacaftor.

Figure 1.

Participant disposition diagram for part B. *This child had an AE of increased alanine aminotransferase and aspartate aminotransferase concentrations that led to treatment discontinuation. AE = adverse event.

Figure 2.

Predicted areas under the curve (AUCs) for LUM (A) and IVA (B) at steady state for children in part B. In each boxplot, the median is represented by the horizontal line and the box represents the interquartile range. The whiskers represent the largest and smallest values within 1.5 times the interquartile range. Gray bars represent the adult dose exposure, with the upper line of the gray box indicating the 95th percentile of adult AUC values and the lower line of the gray box indicating the 5th percentile. The horizontal dotted lines represent the adult median AUC. Blue dots represent AUC values from individual patients. IVA = ivacaftor; L75/I94 = lumacaftor 75 mg/ivacaftor 94 mg; L100/I125 = lumacaftor 100 mg/ivacaftor 125 mg; L150/I188 = lumacaftor 150 mg/ivacaftor 188 mg; LUM = lumacaftor.

Figure 3.

Mean absolute change from baseline in sweat chloride concentration by study visit in part B. Mean absolute changes from baseline are presented with 95% CIs, with numbers of children assessed at each study visit indicated on the x-axis. After the 2-week washout period (Weeks 24‒26), mean sweat chloride concentrations returned to baseline at safety follow-up visits. CI = confidence interval.

Figure 4.

Changes in biomarkers of pancreatic function and intestinal inflammation by study visit in part B. Mean concentrations of fecal elastase-1 (A), serum immunoreactive trypsinogen (B), and fecal calprotectin (C) are shown by study visit. Mean values are presented with 95% CIs, with number of children assessed at each visit indicated on the x-axis. (D) Fecal elastase-1 concentrations in each child (n = 46) at each study visit. Four children who were pancreatic insufficient at baseline (<200 μg/g) had fecal elastase-1 concentrations ⩾200 μg/g at Week 24; 200 μg/g is represented by the horizontal dotted line. CI = confidence interval.