May 02, 2019
2 min read

Combination lumacaftor, ivacaftor improves clinical outcomes in young children with cystic fibrosis

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Lumacaftor and ivacaftor combination therapy was generally safe and well-tolerated over 24 weeks of treatment in children aged 2 to 5 years with cystic fibrosis who were homozygous for the F508del-CFTR mutation, according to a study.

This study served as the basis for FDA approval in August 2018 of lumacaftor/ivacaftor (Orkambi, Vertex Pharmaceuticals) in children aged 2 to 5 years with cystic fibrosis who have two copies of the F508del-CFTR mutation. The data are now published in The Lancet Respiratory Medicine. In October 2016, Orkambi was approved for the 6- to 11-year age group.

“These data highlight the potential of early intervention with lumacaftor and ivacaftor to improve clinically relevant outcomes and support the use of lumacaftor and ivacaftor combination therapy in children aged 2-5 years homozygous for the F508del-CFTR mutation,” researchers wrote in the study.

In part A of the two-part, multicenter, phase 3, open-label study, 11 of 12 children completed 15 days of treatment with combination lumacaftor 100 mg and ivacaftor 125 mg. Ten children experienced adverse events, including cough (42%), rhinorrhea (17%), soft feces (17%) and vomiting (17%). All were considered mild or moderate. One child discontinued treatment due to increased respiratory rate, but the event was deemed moderate and resolved without treatment after 4 days.

In part B of the study, 56 of 60 children completed 24 weeks of treatment with combination lumacaftor and ivacaftor. Of all 60 children, 59 had at least one adverse event, with cough (63%) being the most commonly reported event. Most adverse events were considered mild or moderate. However, four experienced adverse events, including infective pulmonary exacerbation of cystic fibrosis, viral gastroenteritis and constipation — the only serious adverse event deemed potentially attributable to the treatment.

Six children also had respiratory adverse events, which were defined as respiration abnormal, chest discomfort, dyspnea, asthma, bronchial hyperreactivity, bronchospasm and wheezing. The median time to onset was 9 days and events lasted for a median 4.5 days. All events were mild or moderate in severity, the researchers noted.

Elevated serum aminotransferase concentrations prompted discontinuation of treatment in three of 60 patients.

From baseline to 24 weeks, lab studies showed a mean 31.7-mmol/L decrease in sweat chloride concentration, a mean 52.6-g/g increase in fecal elastase-1 concentrations and a mean 130.2-ng/mL reduction in serum immunoreactive trypsinogen concentrations. After a 2-week washout period, sweat chloride concentrations tended to reverse toward baseline, the researchers reported.


Mean growth parameters, including weight, stature and BMI, also increased at week 24.

“Pharmacokinetic and safety profiles were consistent with previous studies of lumacaftor and ivacaftor in children aged 6 years and older, and no new safety concerns were identified,” the researchers wrote.

The study was performed from 2016 to 2017 at sites in the United States and Canada and included children aged 2 to 5 years with cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children who participated in part A were eligible to participate in part B, and after a 2-week washout period, children who completed part B visits were eligible to enroll in a 96-week extension study. – by Melissa Foster

Disclosures: The study was funded by Vertex Pharmaceuticals, and most of the authors are employees of Vertex Pharmaceuticals. Please see the study for all of the authors’ relevant financial disclosures.