Safety, Pharmacokinetics, and Pharmacodynamics of Lumacaftor/Ivacaftor Combination Therapy in Children Aged 2-5 Years with Cystic Fibrosis Homozygous for F508del-CFTR : An Open-Label Phase 3 Study

Background: Efficacy, safety, and tolerability of lumacaftor/ivacaftor are established in patients aged ≥6 years with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation. This openlabel Phase 3 study evaluated safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor/ivacaftor in children aged 2-5 years homozygous for F508del-CFTR. Methods: In this two-part study, we enrolled children aged 2-5 years, weighing ≥8 kg. Part A evaluated pharmacokinetics and safety of lumacaftor/ivacaftor for 15 days (N=12). Part B evaluated safety, pharmacodynamics, and efficacy for 24 weeks (N=60). Children received lumacaftor 100 mg/ivacaftor 125 mg every 12 hours (q12h; weight <14 kg) or lumacaftor 150 mg/ivacaftor 188 mg q12h (weight ≥14 kg). Findings: Safety and pharmacokinetics were consistent with the wellcharacterized safety profile of lumacaftor/ivacaftor. In Part B, most children (98·3%) had ≥1 treatment-emergent adverse event (AE); most were mild to moderate in severity. The most common AEs were cough (63·3%), vomiting (28·3%), pyrexia (28·3%), and rhinorrhea (25·0%). Three (5·0%) children discontinued due to elevated transaminases. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function (fecal elastase-1 and serum immunoreactive trypsinogen) improved, and growth parameters increased at week 24. Interpretation: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 2-5 years with CF for 24 weeks. Sustained reductions in sweat chloride, improvements in biomarkers of pancreatic function, and increases in growth parameters indicate that early intervention with lumacaftor/ivacaftor has the potential to modify the course of disease. Clinical Trial Number: This study is registered with ClinicalTrials.gov, identifier NCT02797132. Funding Statement: Vertex Pharmaceuticals Incorporated. Declaration of Interests: JJM received grant support from Vertex Pharmaceuticals Incorporated for participation in clinical trials. SAM received personal fees from Novartis, AbbVie, Vertex Pharmaceuticals Incorporated, and Gilead Sciences outside of the submitted work. GM, FL, ST, CAO, DS, CL, DW, and LTW are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. GSS is a member of the US Cystic Fibrosis Foundation Patient Registry Committee, and his institution has received funding from Vertex Pharmaceuticals Incorporated for participation in clinical trials. Ethics Approval Statement: The study was conducted with ethics board approval at each participating site. Written informed consent was obtained from each child’s parent/legal guardian. Data were reviewed by an independent data monitoring committee.