Implications for cystic fibrosis therapy: Potentiator icenticaftor is superior to ivacaftor in improving function and maintaining stability of F508del CFTR

ObjectiveThe objective of this study was to compare CFTR potentiators icenticaftor versus ivacaftor (IVA) to elucidate efficacy in augmenting CFTR function while preserving CFTR protein levels.MethodsSingle-channel measurements of CFTR in the presence and absence of IVA or icenticaftor were performed with membrane vesicles from BHK-21 cells stably expressing CFTR. CFTR-expressing BHK-21 cells and non-cystic fibrosis (CF) and CF primary human bronchial epithelial cultures were treated for 48 hours with elexacaftor/tezacaftor (ELX/TEZ) plus IVA or icenticaftor and then western blot analyses were performed to assess CFTR protein maturation. Non-CF and CF primary human bronchial epithelial cultures treated with CFTR modulators were subjected to Ussing chamber analysis to evaluate CFTR functional rescue upon 48-hour treatment and acute potentiator exposure.ResultsCorrector-rescued F508del CFTR displayed increased function with icenticaftor compared to IVA by single-channel measurements. In primary F508del cultures, 48-hour treatment with ELX/TEZ plus icenticaftor led to increased CFTR function in Ussing chambers compared to treatment with ELX/TEZ plus IVA. Western blot analysis demonstrated that F508del was destabilized by IVA but not icenticaftor. Primary N1303K CFTR cultures did not exhibit enhanced rescue with icenticaftor when compared to IVA, indicating that different CFTR mutations respond differently to potentiators.ConclusionIcenticaftor is superior to IVA as a potentiator for ELX/TEZ-rescued F508del CFTR, as 48-hour treatment with icenticaftor enhanced F508del function but did not destabilize F508del. Understanding the mechanisms underlying CFTR potentiator activities may offer further benefits for people with CF who have F508del or other CFTR mutations.