Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR

Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by similar to 24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+ VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants. (C) 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Automated summary

The study found that the combination therapy of VX-445 and VX-770 has significant therapeutic effects on CF patients with the F508del mutation, improving CFTR channel currents. VX-445 has a unique potentiator activity that can enhance the effect of VX-770, especially beneficial for CF patients with G551D and other dual potentiator responsive mutations.