Hermann Bihler, Andrey Sivachenko, Priyanka Bhatt, Ashley Baldwin, Jan Harrington, Violaine Bailey, Alexi Panagiotou, Divesh Patel, Michael J Mulligan, Rachel Valdez Misiolek, Kylie Arnold, Yi Cheng, Kevin Coote, Normand E Allaire, Joshua Conte, Karen S Raraigh, Garry R Cutting, Martin Mense
We evaluated 417 CFTR variants for VTI responsiveness, including 272 tested for the first time and 145 previously categorized as non-responsive (NR) or borderline-responsive (BR) to ETI. Overall, ∼76% of variants achieved ≥10% of WT improvement, the threshold for responsiveness. This included 87% of newly tested variants and 55% of ETI NR/BR variants. Notably, 50 variants classified as NR/BR to ETI reached the responsive threshold with VTI using empirical Bayes criteria. Compared with ETI, VTI demonstrated broader efficacy across this dataset. These results expand the number of CFTR variants likely to benefit from highly effective modulator therapy and highlight remaining variants that may require alternative therapeutic strategies.
BACKGROUND: This study sought to identify additional rare CFTR variants that show improved chloride (Cl⁻) transport in response to the modulator combination vanzacaftor/tezacaftor/ivacaftor (VNZ/TEZ/IVA; VTI). It builds on prior work evaluating 655 variants treated with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA; ETI). The findings may inform people with cystic fibrosis (pwCF) and caregivers pursuing off-label access to modulator therapies when genotype-based eligibility is limited.
METHODS: Fischer Rat Thyroid (FRT) cells, which do not express endogenous CFTR, were transfected with plasmids encoding wildtype (WT) CFTR or specific CFTR variants. After 24 h under control conditions or treatment with VNZ and TEZ, cells received an acute addition of IVA. CFTR activity was quantified using transepithelial current clamp conductance assays. For each variant, we measured basal forskolin (Fsk)/cAMP-stimulated Cl⁻ transport, potentiation by IVA, and responsiveness to the full VTI combination. CFTR maturation was assessed via Western blot.
RESULTS AND CONCLUSIONS: We evaluated 417 CFTR variants for VTI responsiveness, including 272 tested for the first time and 145 previously categorized as non-responsive (NR) or borderline-responsive (BR) to ETI. Overall, ∼76% of variants achieved ≥10% of WT improvement, the threshold for responsiveness. This included 87% of newly tested variants and 55% of ETI NR/BR variants. Notably, 50 variants classified as NR/BR to ETI reached the responsive threshold with VTI using empirical Bayes criteria. Compared with ETI, VTI demonstrated broader efficacy across this dataset. These results expand the number of CFTR variants likely to benefit from highly effective modulator therapy and highlight remaining variants that may require alternative therapeutic strategies.