AUTHOR=Olivier Margarete , Kavvalou Alexandra , Welsner Matthias , Hirtz Raphael , Straßburg Svenja , Sutharsan Sivagurunathan , Stehling Florian , Steindor Mathis 

TITLE=Real-life impact of highly effective CFTR modulator therapy in children with cystic fibrosis

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1176815

DOI=10.3389/fphar.2023.1176815

ISSN=1663-9812

ABSTRACT=,Introduction: Recently, CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has become available for children with cystic fibrosis (CF) carrying at least one F508del mutation. 
Objective: To assess the intermediate term effects of ETI in children with CF in a real-world setting.
Methods: We performed a retrospective analysis of records of children with CF, who started ETI between 8/2020 and 10/2022. Pulmonary function tests, nutritional status, sweat chloride and laboratory data were assessed before, 3 and 6 months after the start of ETI respectively.
Results: ETI was started in 22 children 6-11 years and in 24 children 12-17 years. N=27 (59%) were homozygous for F508del (F/F) and 23 (50%) patients were transitioned from ivacaftor/lumacaftor (IVA/LUM) or tezacaftor/ivacaftor (TEZ/IVA) to ETI. Overall, mean sweat chloride concentration decreased by 59.3 mmol/L (95% confidence interval [CI]: -65.0 to -53.7 mmol/L, p<0.0001) under ETI. Sweat chloride concentration also decreased significantly after transition from IVA/LUM or TEZ/IVA to ETI (-47.8 mmol/l; 95% CI: -57.6 to -37.8 mmol/l, n=14, p <0.0001). 
Sweat chloride reduction was more marked in children with the F/F than in those with the F/MF genotype (69.4 vs. 45.9 mmol/L, p<0.0001). At 3 months follow-up, body-mass-index-z-score increased by 0.31 (95% CI, 0.2 to 0.42, p <0.0001) with no further increase at 6 months. BMI-for-age-z-score was more markedly improved in the older group. Overall pulmonary function (percent predicted FEV1 %) at 3 months increased by 11.4% (95% CI: 8.0 to 14.9, p <0.0001) with no further significant change at 6 months. No significant differences were noted between the age groups. Children with the F/MF genotype had a greater benefit regarding nutritional status and pulmonary function tests than those with the F/F genotype. Adverse events led to ETI dose reduction in three cases and a temporary interruption of therapy in four cases.
Conclusion: In a real-world setting, ETI therapy had beneficial clinical effects and a good safety profile in eligible children with CF comparable to previously published data from controlled clinical trials. The positive impact on pulmonary function tests and nutritional status seen after 3 months of ETI therapy was sustained at 6 months follow-up.