Elexacaftor/tezacaftor/ivacaftor improves CFTR function to near-normal levels in children with cystic fibrosis.

Background

The CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves CFTR function in adolescents and adults with cystic fibrosis (CF) carrying at least one F508del allele to around 40% of median CFTR activity in non-CF controls. This partial restoration of CFTR function is associated with residual mucus dysfunction, airway infection and inflammation. In clinical trials, ETI led to a larger reduction of sweat chloride concentration in children compared to adolescents and adults with CF. However, the degree of correction of CFTR function by ETI in children with CF is currently unknown. Therefore, the aim of this study was to quantify restoration of CFTR function in children with CF aged 2 to 11 years and one or two F508del alleles.

Methods

This prospective observational multicenter study quantified restoration of CFTR function by intestinal current measurements (ICM) before and 4 months after initiation of ETI. Additionally, we performed a combined analysis of the effects of ETI in children and our previous study in adolescents and adults with CF.

Results

A total of 26 children with CF and at least one F508del allele were enrolled in this study. ETI improved cAMP-induced chloride secretory response to a median of 89.5% (IQR, 51.4 to 125.3; p<0.001) and increased the total chloride secretory response to 99.2% (IQR, 66.3 to 144.3; p<0.001) of median CFTR activity in non-CF controls. Furthermore, we observed strong correlations of the cAMP response and the total chloride response with age (R2=0.43 and R2=0.53 respectively, both p<0.001).

Conclusions

Our results show that treatment with ETI results in near-normal CFTR function measured in freshly obtained rectal biopsies in children with CF aged 2 to 11 years and at least one F508del allele.