Abstract
We evaluated the effectiveness and safety of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in three subjects carrying the Phe508del/unknown CFTR genotype. An ex vivo analysis on nasal epithelial cells (NEC) indicated a significant improvement of CFTR gating activity after the treatment. Three patients were enrolled in an ELX/TEZ/IVA managed-access program, including subjects with the highest percent predicted Forced Expiratory Volume in the 1st second (ppFEV1) < 40 in the preceding 3 months. Data were collected at baseline and after 8, 12 and 24 weeks of follow-up during treatment. All patients showed a considerable decrease of sweat chloride (i.e., meanly about 60 mmol/L as compared to baseline), relevant improvement of ppFEV1 (i.e., >8) and six-minute walk test, and an increase in body mass index after the first 8 weeks of treatment. No pulmonary exacerbations occurred during the 24 weeks of treatment and all domains of the CF Questionnaire-Revised improved. No safety concerns related to the treatment occurred. This study demonstrates the benefit from the ELX/TEZ/IVA treatment in patients with CF with the Phe508del and one unidentified CFTR variant. The preliminary ex vivo analysis of the drug response on NEC helps to predict the in vivo therapeutic endpoints.
Highlights
Cystic fibrosis (CF) is an autosomal recessive genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]
360 CFTR variants are known to be CF-causing. These variants are classified according to the impact they have on the synthesis, processing or function of the CFTR protein
The patients were enrolled in an ELX/TEZ/IVA managed access program (MAP), performed between October 2019 and April 2021 in Italy for patients with CF aged 12 years and older, heterozygous for the Phe508del variant and a minimal function (MF) variant and with severe lung disease, defined as either a highest predicted Forced Expiratory Volume in the 1st second (FEV1) < 40% in the preceding 3 months or being on a lung transplant waiting list
Summary
Cystic fibrosis (CF) is an autosomal recessive genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. 360 CFTR variants are known to be CF-causing (https://cftr2.org/, accessed on 6 July 2021). These variants are classified according to the impact they have on the synthesis, processing or function of the CFTR protein. Ivacaftor (Kalydeco®) is approved in the USA for children with CF aged four months or older who have at least one responsive variant in the CFTR gene, based on clinical and/or in vitro assay data. Kalydeco is approved on its own in the EU for the treatment of patients with CF aged four months and older with gating variants [2,3,4]
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