Lumacaftor-ivacaftor combo benefits children with cystic fibrosis
A combined therapy of lumacaftor and ivacaftor improves lung ventilation inhomogeneity, preserves spirometric lung function, and decreases sweat chloride concentrations with a well-tolerated safety profile in children with cystic fibrosis who harbour the F508del mutation on both CFTR* alleles (F508del-CFTR), according to the VX14-809-109** study.
“Lung damage starts very early [although infants and children may appear asymptomatic] … our current treatment strategies are insufficient to prevent irreversible structural damage,” according to Dr Carla Colombo from the Cystic Fibrosis Centre at University of Milan, Italy, in an accompanying commentary. “[C]hildren with cystic fibrosis … could benefit even more than adult patients from treatment [with CFTR modulators] as it might prevent the progression of lung disease.” [Lancet Respir Med 2017;5:536-537]
“It is not uncommon for patients in this age group to have normal spirometry, even when structural abnormalities [associated with impaired ventilation are present on CT scans and MRI],” said the researchers.
Lung clearance index [LCI2.5#] ─ which has been shown to be a more sensitive measure of early structural lung abnormalities related with cystic fibrosis and ventilation inhomogeneity ─ was chosen as the primary endpoint, and shown to be responsive even in children with normal spirometry. [Lancet Respir Med 2017;5:557-567]
At 24 weeks, LCI2.5 significantly improved from baseline in the lumacaftor-ivacaftor vs the placebo arms (least square [LS] mean, -1.01 vs 0.08 units; p<0.0001).
“[P]atients in this study were permitted to continue receiving their existing medications during the study period … This suggests that the effect of lumacaftor and ivacaftor on LCI2.5 would have occurred over and above any improvement caused by [the existing medications],” said the researchers.
Sweat chloride concentration, a biomarker of CFTR function, was also significantly decreased (ie, improved) at day 15 and week 4 (combined) from baseline in the lumacaftor-ivacaftor vs the placebo groups (LS mean, -20.0 vs 0.8 mmol/L; p<0.0001).
Although the absolute change in ppFEV1## from baseline through week 24 was not significant within either group, the between-group difference in the change from baseline was significant in favour of lumacaftor-ivacaftor (LS mean, 1.1 vs -1.3; p=0.0182), with the mean ppFEV1 in the placebo group falling below the baseline at all study visits but never below baseline among the lumacaftor- and ivacaftor-treated patients.
The multinational double-blind phase III study included 206 children aged 6–11 years with cystic fibrosis who weighed ≥15 kg, had predicted FEV1 of ≥70, LCI2.5 ≥7.5, and were tested positive for F508del-CFTR mutation on both alleles. They were randomized 1:1 to receive lumacaftor 200 mg and ivacaftor 250 mg Q12H or placebo for 24 weeks.
Incidence of adverse events (AEs) occurred at similar rates between the two groups, of which a majority were mild (43 percent) or moderate (48 percent) in severity, with cough being the most frequently reported AE in both groups (45 percent vs 47 percent). Compared with placebo, lumacaftor-ivacaftor was associated with more frequent productive cough, nasal congestion, rhinorrhoea, oropharyngeal pain, upper abdominal pain, and increased sputum.
Elevated liver enzymes (ALT and AST###) were also detected in more patients in the lumacaftor-ivacaftor arm than the placebo arm (13 percent vs 8 percent).
“In children, particularly those with a history of liver enzyme elevation or those exposed to other risk factors (antibiotic therapy, malnutrition, antioxidant deficiency), liver biochemistry should be closely monitored,” advised Colombo.