Rethinking CFTR variant responsiveness: Differential responses to vanzacaftor and elexacaftor.

Cystic fibrosis (CF) care has been revolutionized by CFTR modulators, particularly the triple combination elexacaftor/tezacaftor/ivacaftor (ETI). However, a subset of people with CF (pwCF) carrying ETI-unresponsive variants still lack effective therapies. A nextgeneration modulator combination, vanzacaftor/tezacaftor/deutivacaftor (VTD), shows promise in addressing this gap. Phase 3 trials report superior efficacy of VTD in reducing sweat chloride and suggest potential benefit for 31 CFTR variants previously deemed ETI-unresponsive based on limited in vitro data. Reassessment of these variants reveals that some demonstrate residual function or borderline ETI responsiveness, challenging their unresponsive classification. Differences in molecular interactions, particularly within NBD1 and modulator-binding sites, may account for variant-specific responses. Patient-derived intestinal organoid (PDIO) assays showed significant functional improvement with VTD, but not ETI, in 2 pwCF with G458V and G85R mutations, supporting the notion of distinct mechanisms of action. These findings underscore the need to refine CFTR variant classifications and highlight the limitations of current in vitro thresholds. While PDIOs offer physiologically relevant insights, clinical outcomes remain the ultimate determinant of therapeutic benefit. Broader access to raw data and individualized in vitro-clinical correlations are essential for informed therapeutic decisions. VTD offers new hope for pwCF with rare or previously unresponsive variants, reinforcing the importance of a personalized, datadriven approach to CF care.