Strategies for the identification of people with cystic fibrosis responsive to CFTR modulator triple combinations

The triple combinations of CFTR modulators, elexacaftor-tezacaftor-ivacaftor and more recently vanzacaftor-tezacaftor-deutivacaftor, have transformed the clinical course of cystic fibrosis (CF). These drug combinations were identified for their ability to restore CFTR function in F508del epithelial cells, and their efficacy has been shown in large randomized clinical trials involving people with CF with at least one F508del variant. Approximately 20 % of pwCF worldwide have no F508del variant however. Recent data show that CFTR modulator triple combinations may be effective in a large subset of pwCF with non-F508del, often rare, CFTR variants. The purpose of this review is to explore the various strategies that may contribute to the identification of all patients with modulator-responsive CFTR variants in order to expand access to these transformative therapies.