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

  • J Cyst Fibros. 2026 Jun 4:S1569-1993(26)01638-3. doi: 10.1016/j.jcf.2026.05.015.
Valeria Capurro  1 ,  Emanuela Pesce  1 ,  Federico Cresta  2 ,  Cristina Pastorino  1 ,  Alice Mantero  1 ,  Valeria Tomati  1 ,  Valeria Daccò  3 ,  Laura Claut  3 ,  Benedetta Fabrizzi  4 ,  Federico Zara  5 ,  Carlo Castellani  2 ,  Nicoletta Pedemonte  6
Affiliations
  • 1. UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • 2. UOSD Centro Fibrosi Cistica, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • 3. Department of Pediatrics, Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
  • 4. Department of Gastroenterology and Transplantation, Cystic Fibrosis Regional Centre, Unit of Emerging and Immunosuppressed Infectious Diseases, Azienda Ospedaliero-Universitaria 'Ospedali Riuniti', Ancona, Italy.
  • 5. UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Italy.
  • 6. UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy. Electronic address: [email protected].
PMID: 42243036 DOI: 10.1016/j.jcf.2026.05.015
Abstract

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.

Keywords
Chloride secretion; Correctors; Modulators; Nasal epithelial cells; Non-responders; Theratype.
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