Response to elexacaftor/tezacaftor/ivacaftor in intestinal organoids derived from people with cystic fibrosis

Superior efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) over tezacaftor/ivacaftor (TEZ/IVA) in people with cystic fibrosis (CF) and Phe508del/Phe508del genotype was shown in clinical trials. We utilized intestinal organoid approach to compare in vitro responses to these 2 CFTR modulator drug combinations and to check potential inter-individual variability in therapeutic response to the triple combination. Organoids from 17 subjects with Phe508del/Phe508del were screened with forskolin induced swelling assay. Significantly larger swelling, when exposed to ELX/TEZ/IVA as compared to TEZ/IVA, was observed in 16 of them. However, 1 sample showed no additional effect of ELX. The finding of unique CFTR variants in this sample indicates that genetic traits other than CF-causing CFTR mutation are worth exploring as they may have an impact on the definitive modulator drug response. (C) 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Automated summary

This study compared the in vitro responses of two CFTR modulator drug combinations and explored potential inter-individual variability in therapeutic response to the triple combination. The findings showed that elexacaftor/tezacaftor/ivacaftor was more effective than tezacaftor/ivacaftor in cystic fibrosis patients with a specific genotype. The presence of unique CFTR variants in one sample suggests that genetic traits beyond the CF-causing CFTR mutation may influence the response to modulator drugs.