The Lancet. Respiratory medicine · 2025
Sweat chloride and lung function responses to elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with two versus one responsive CFTR variants: an analysis of two real-world observational studies.
СтатьяНаблюдательное исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Burgel Pierre-Régis, Da Silva Jennifer, Girodon Emmanuelle, Durieu Isabelle, Reynaud-Gaubert Martine, Murris-Espin Marlene, Chiron Raphael, Grenet Dominique, Ramel Sophie, Mely Laurent, Hamidfar Rebecca, Douvry Benoit, Houdouin Véronique, Audousset Camille, Macey Julie, Mittaine Marie, Weiss Laurence, Cosson Laure, Danner-Boucher Isabelle, Reix Philippe, Baravalle Mélisande, Burnet Espérie, Sermet-Gaudelus Isabelle, Martin Clémence, Paillasseur Jean-Louis, French Cystic Fibrosis Reference Network study group
Аннотация
BACKGROUND: Among people with cystic fibrosis, sweat chloride and lung function response to elexacaftor-tezacaftor-ivacaftor (ETI) is variable. We hypothesised that the presence of two versus one ETI-responsive CFTR variant could predict response variability.
METHODS: In this analysis of two real-world observational studies, data from a French national cohort of adults (aged ≥18 years) with cystic fibrosis and at least one F508del variant treated with ETI and the French compassionate programme for ETI in people (aged ≥6 years) with cystic fibrosis without F508del were used to examine sweat chloride concentrations (SCCs) after ETI initiation, and the absolute change in SCC and percentage of predicted forced expiratory volume in 1 s (ppFEV1) following ETI initiation. The ETI responsiveness of CFTR variants was determined following the French compassionate programme's classification.
FINDINGS: Among 1266 participants, 834 had two ETI-responsive variants and 432 had only one. Median SCC after ETI initiation was 36 mmol/L (IQR 24-50) in participants with two ETI-responsive variants and 53 mmol/L (26-72) in those with only one (p<0·0001). The proportion of participants with SCC of less than 30 mmol/L was 298 (36%) of 834 among those with two ETI-responsive variants and 65 (15%) of 432 in those with one ETI-responsive variant (χ2 p<0·00001). Multivariable analyses showed that the number of ETI-responsive variants was a determinant of SCC after ETI initiation (p<0·0001) but not of the absolute change in ppFEV1 (p=0·80).
INTERPRETATION: People with cystic fibrosis with two responsive CFTR variants had a better correction of CFTR function in sweat glands after ETI initiation than those with only one responsive variant, but the response in terms of ppFEV1 was similar. These findings suggest that maximal improvement in lung function could be reached with current CFTR modulators and that no further increase in lung function would be expected from more potent restoration of CFTR function. Reaching normal lung function in people with cystic fibrosis and established lung disease might be limited by irreversible lung damage, suggesting that new therapeutic strategies aimed at improving lung function should be developed.
FUNDING: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.
METHODS: In this analysis of two real-world observational studies, data from a French national cohort of adults (aged ≥18 years) with cystic fibrosis and at least one F508del variant treated with ETI and the French compassionate programme for ETI in people (aged ≥6 years) with cystic fibrosis without F508del were used to examine sweat chloride concentrations (SCCs) after ETI initiation, and the absolute change in SCC and percentage of predicted forced expiratory volume in 1 s (ppFEV1) following ETI initiation. The ETI responsiveness of CFTR variants was determined following the French compassionate programme's classification.
FINDINGS: Among 1266 participants, 834 had two ETI-responsive variants and 432 had only one. Median SCC after ETI initiation was 36 mmol/L (IQR 24-50) in participants with two ETI-responsive variants and 53 mmol/L (26-72) in those with only one (p<0·0001). The proportion of participants with SCC of less than 30 mmol/L was 298 (36%) of 834 among those with two ETI-responsive variants and 65 (15%) of 432 in those with one ETI-responsive variant (χ2 p<0·00001). Multivariable analyses showed that the number of ETI-responsive variants was a determinant of SCC after ETI initiation (p<0·0001) but not of the absolute change in ppFEV1 (p=0·80).
INTERPRETATION: People with cystic fibrosis with two responsive CFTR variants had a better correction of CFTR function in sweat glands after ETI initiation than those with only one responsive variant, but the response in terms of ppFEV1 was similar. These findings suggest that maximal improvement in lung function could be reached with current CFTR modulators and that no further increase in lung function would be expected from more potent restoration of CFTR function. Reaching normal lung function in people with cystic fibrosis and established lung disease might be limited by irreversible lung damage, suggesting that new therapeutic strategies aimed at improving lung function should be developed.
FUNDING: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.
Предметные рубрики MeSH
AdolescentAdultFemaleHumansMaleMiddle AgedYoung AdultAminophenolsBenzodioxolesChloride Channel AgonistsChloridesCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDrug CombinationsForced Expiratory VolumeFranceIndolesLungPyrazolesPyridinesPyrrolidinesRespiratory Function TestsSweatQuinolines