Vanzacaftor-Tezacaftor as an alternative therapeutic resource for the ETI-Resistant L467F-F508del Allele: Ex vivo prediction and exploratory clinical assessment.

BACKGROUND

The triple combination of Elexacaftor/Tezacaftor/Ivacaftor (ETI) has revolutionized cystic fibrosis (CF) treatment; however, a subset of patients with eligible genotypes remains unresponsive. We previously identified the L467F-F508del complex allele as a cause of therapeutic failure, conferring a severe processing defect that renders the CFTR protein refractory to ETI.

METHODS

To address this unmet need, we evaluated the efficacy of the next-generation combination comprising Vanzacaftor/Tezacaftor (Vnz/Tez). We utilized primary human nasal epithelial (HNE) cells derived from six patients carrying the L467F-F508del complex allele and a minimal function mutation and monitored the clinical response of a patient treated with Vanzacaftor/Tezacaftor/Deutivacaftor (VTD) via compassionate use. Mechanistic validation was performed in CFBE41o- cells.

RESULTS

In patient-derived HNE models, treatment with Vnz/Tez resulted in a consistent and significant rescue of CFTR activity, overcoming the block previously observed with ETI. Of note, we report a patient treated with VTD who experienced a partial improvement in pulmonary function (FEV1 +220 mL) and exercise tolerance and a decrease of sweat Chloride concentration from 100 to 87 mmol/L. In heterologous expression systems, Vnz/Tez, but not Elx/Tez, successfully restored the processing of the L467F-F508del mutant, promoting the formation of the mature, complex-glycosylated CFTR form.

CONCLUSIONS

Our findings demonstrate that the Vanzacaftor/Tezacaftor combination possesses superior corrective potency capable of rescuing the severe trafficking defect of the L467F-F508del complex allele. This study identifies a promising therapeutic solution for patients currently orphaned by standard-of-care modulators and highlights the utility of integrating ex vivo screening with clinical monitoring in defining precision medicine strategies.