The preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis.

INTRODUCTION

Cystic Fibrosis (CF) is caused by mutations in the (CFTR) gene. The most common mutation, , induces protein misprocessing and loss of CFTR function. The discovery through studies of the CFTR correctors (i.e. lumacaftor, tezacaftor) that partially rescue the misprocessing of F508del-CFTR with the potentiator ivacaftor is promising in giving an unprecedented clinical benefit in affected patients.

AREAS COVERED

Online databases were searched using key phrases for CF and CFTR modulators. Tezacaftor-ivacaftor treatment has proved to be safer than lumacaftor-ivacaftor, although clinical efficacy is similar. Further clinical efficacy has ensued with the introduction of triple therapy, i.e. applying second-generation correctors, such as VX-569 and VX-445 (elexacaftor) to tezacaftor-ivacaftor. The triple combinations will herald the availability of etiologic therapies for patients for whom no CFTR modulators are currently applied (i.e. /minimal function mutations) and enhance CFTR modulator therapy for patients homozygous for .

EXPERT OPINION

CF patient-derived tissue models are being explored to determine donor-specific response to current approved and future novel CFTR modulators for and other rare mutations. The discovery and validation of biomarkers of CFTR modulation will complement these studies in the long term and in real-life world.