EClinicalMedicine · 2025
Elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis harbouring two CFTR Class I variants: real-world data from the French compassionate programme.
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Burgel Pierre-Régis, Girodon Emmanuelle, Sharma Neeraj, Raynal Caroline, Da Silva Jennifer, Sasorith Souphatta, Martin Clémence, Sermet-Gaudelus Isabelle, Raraigh Karen
Аннотация
BACKGROUND: The European Medicines Agency has recently expanded the label of elexacaftor-tezacaftor-ivacaftor (ETI) to all people with cystic fibrosis (pwCF) aged 2 years and older who have at least one non-Class I mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. No large-scale data exist on the use of ETI in pwCF harbouring two Class I CFTR variants.
METHODS: PwCF with two Class I variants who received ETI for an individual 4-6 week trial were identified within the real-world French compassionate programme and their response to ETI, as assessed by a centralized adjudication committee, was evaluated based on evolution of clinical data, lung function and sweat chloride. The lists of Class I CFTR variants were established using data from the CFTR2 and CFTR-France databases.
FINDINGS: Among 652 participants who were recruited in the French compassionate programme from May 19, 2022, to March 26, 2025, 163 had two Class I variants and received ETI. 155 (95%) were considered as non-responders and stopped ETI, whereas 8 (5%) were considered as responders and continued ETI. The six Class I variants probably responsive to ETI were: E831X and 4374+1G > A (each present in 2 participants), 1716+2T > C, 4382delA, 875+1G > A and CFTRdup1-3 (each present in 1 participant). Using CFTR2 and CFTR-France databases, a list of 955 true (i.e., shown or presumed to lead to the absence of CFTR protein) Class I variants was established. True Class I variants are predicted to be non-responsive to ETI and clinical evidence of the lack of response to ETI was confirmed in the French compassionate programme for 108 variants within this list. A second list of 78 exceptional (i.e., in which a CFTR protein may be produced) Class I variants was further established: clinical data on ETI responsiveness was available for 11 exceptional Class I variants of which six were found probably responsive and five probably non-responsive to ETI.
INTERPRETATION: Class I variants are usually not responsive to ETI and pwCF with two true Class I variants should not be treated with ETI. However, exceptional Class I CFTR variants may lead to protein production, providing a substrate for ETI. In pwCF harbouring at least one of these exceptional Class I variants, an individual trial of ETI should be granted.
FUNDING: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, Filière Maladies Rares MUCO-CFTR.
METHODS: PwCF with two Class I variants who received ETI for an individual 4-6 week trial were identified within the real-world French compassionate programme and their response to ETI, as assessed by a centralized adjudication committee, was evaluated based on evolution of clinical data, lung function and sweat chloride. The lists of Class I CFTR variants were established using data from the CFTR2 and CFTR-France databases.
FINDINGS: Among 652 participants who were recruited in the French compassionate programme from May 19, 2022, to March 26, 2025, 163 had two Class I variants and received ETI. 155 (95%) were considered as non-responders and stopped ETI, whereas 8 (5%) were considered as responders and continued ETI. The six Class I variants probably responsive to ETI were: E831X and 4374+1G > A (each present in 2 participants), 1716+2T > C, 4382delA, 875+1G > A and CFTRdup1-3 (each present in 1 participant). Using CFTR2 and CFTR-France databases, a list of 955 true (i.e., shown or presumed to lead to the absence of CFTR protein) Class I variants was established. True Class I variants are predicted to be non-responsive to ETI and clinical evidence of the lack of response to ETI was confirmed in the French compassionate programme for 108 variants within this list. A second list of 78 exceptional (i.e., in which a CFTR protein may be produced) Class I variants was further established: clinical data on ETI responsiveness was available for 11 exceptional Class I variants of which six were found probably responsive and five probably non-responsive to ETI.
INTERPRETATION: Class I variants are usually not responsive to ETI and pwCF with two true Class I variants should not be treated with ETI. However, exceptional Class I CFTR variants may lead to protein production, providing a substrate for ETI. In pwCF harbouring at least one of these exceptional Class I variants, an individual trial of ETI should be granted.
FUNDING: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, Filière Maladies Rares MUCO-CFTR.