Elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis harbouring two CFTR Class I variants: real-world data from the French compassionate programme
Pierre‐Régis Burgel, Emmanuelle Girodon, Neeraj Sharma, Caroline Raynal, Jennifer Da Silva, Souphatta Sasorith, Clémence Martin, Isabelle Sermet‐Gaudelus, Karen S. Raraigh
Abstract
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.