Lumacaftor–ivacaftor combination shows promise in young children with cystic fibrosis
medwireNews: Trial findings published in The Lancet Respiratory Medicine support the use of combination therapy with lumacaftor and ivacaftor in children aged 2–5 years with cystic fibrosis homozygous for the F508del-CFTR mutation.
“Lumacaftor and ivacaftor is the first combination CFTR [cystic fibrosis transmembrane conductance regulator] modulator therapy approved to treat patients homozygous for F508del-CFTR”, and the pharmacokinetic, safety and efficacy profiles “are established in patients aged 6 years and older”, explain the investigators.
Patrick Flume (Medical University of South Carolina, Charleston, USA) says in an accompanying comment that “[t]he study […] has satisfied the FDA, who has approved the product for children aged 2–5 years”, adding that this is “some welcome news for affected families.”
The open-label phase III trial included 60 children who were treated with lumacaftor 100 mg plus ivacaftor 125 mg every 12 hours (for those weighing <14 kg) or lumacaftor 150 mg plus ivacaftor 188 mg every 12 hours (for those weighing ≥14 kg).
The first part of the study – completed by 11 of the participants – demonstrated that average plasma concentrations of the two drugs and their metabolites “were consistent with those previously reported”, say John McNamara (Children’s Respiratory and Critical Care Specialists, Minneapolis, Minnesota, USA) and co-investigators. Ten (83%) of the 12 patients who enrolled in this part of the study experienced adverse events (AEs) at the 10-day follow-up, all of which were mild or moderate in severity, and there were no serious AEs.
In the second part of the study, which involved all 60 participants, 98% of patients experienced treatment-emergent AEs over 26 weeks of follow-up, the majority of which were mild to moderate. The most frequently reported AE was cough (63%), followed by vomiting (28%) and pyrexia (28%). Serious AEs occurred in four children, including two cases of infective pulmonary exacerbation of cystic fibrosis and one case each of viral gastroenteritis and constipation, while three children discontinued treatment due to elevated serum aminotransferase concentrations.
These safety data are “consistent with the well characterised safety profile of lumacaftor and ivacaftor”, summarise McNamara and team.
In the efficacy analysis, the researchers observed a “substantial” reduction in sweat chloride levels among children treated with lumacaftor–ivacaftor, with an average decrease of 31.7 mmol/L over 24 weeks from a baseline mean of 105.8 mmol/L.
Levels of fecal elastase-1 – a biomarker of pancreatic exocrine function – increased by a mean of 52.6 µg/g over 24 weeks, while average serum levels of the pancreatic inflammatory marker immunoreactive trypsinogen decreased by 130.2 ng/mL. Significant increases in measures of growth, including BMI, weight and height, also occurred from baseline to week 24.
“The improvements in CFTR and pancreatic function, and increases in growth parameters, suggest that early treatment could alter the course of the disease”, conclude McNamara et al.
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