In children with cystic fibrosis (CF) between the ages of 2 and 5 years, the combination of lumacaftor and ivacaftor was safe and well tolerated over a 24-week period. In addition, the CF transmembrane conductance regulator (CFTR) modulators were associated with short-term improvements in biomarkers indicative of pancreatic function. These findings were published in Lancet Respiratory Medicine.

Children between the ages of 2 and 5 years who had a confirmed CF diagnosis and were homozygous for the F508delCFTR mutation were enrolled in a clinical trial to evaluate  the safety and pharmacokinetic properties of lumacaftor/ivacaftor ( Identifier: NCT02797132). Participants with a body weight of <14 kg received oral lumacaftor 100 mg and ivacaftor 125 mg (n=4), and those with a body weight of ≥14 kg received lumacaftor 150 mg and ivacaftor 188 mg every 12 hours (n=8) for 15 days to assess pharmacokinetics and safety (part A) and for 24 weeks to assess safety, pharmacokinetics, pharmacodynamics, and efficacy (part B; n=19 and n=41, respectively). Additional secondary end points in part A included safety and pharmacokinetics of lumacaftor and ivacaftor metabolites, and secondary end points in part B were pharmacokinetics in participants who received ≥1 lumacaftor and ivacaftor dose.

The majority of children in part B (n=59, 98%) had ≥1 treatment-emergent adverse event (TEAEs) during the study period. The severity of most TEAEs was mild to moderate. Common AEs that occurred alongside treatment included cough (n=38; 63%), vomiting (n=17; 28%), pyrexia (n=17; 28%), and rhinorrhea (n=15; 25%). A total of 4 children experienced serious AEs, including infective pulmonary exacerbation of CF (n=2), gastroenteritis viral (n=1), and constipation (n=1). Treatment discontinuation occurred in 3 (5%) of the 60 children in part B, with discontinuation primarily as a result of elevated concentrations of serum aminotransferase.

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Improvements in pancreatic function biomarkers, including increases in fecal elastase-1 and decreases in serum immunoreactive trypsinogen, were observed at 24-week follow-up.

The open-label design of the study, the absence of a direct placebo comparator, as well as the small sample size represented the main limitations of this analysis.

The researchers emphasized “that although the mean change from baseline in sweat chloride concentration appears to be numerically greater in children 2-5 years of age vs older children, given the substantial overlap in the confidence intervals for this end point in the 2-5 year and 6-11 year age groups, it is not clear if the effect of CFTR modulators on CFTR function is significantly different in the younger vs older children.”

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Disclosures: This study was funded by Vertex Pharmaceuticals Incorporated.


McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study [published online January 24, 2019]. Lancet Respir Med. doi:10.1016/S2213-2600(18)30460-0