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. 2025 Nov;24(6):1017-1026.
doi: 10.1016/j.jcf.2025.10.007. Epub 2025 Oct 17.

Global prevalence of CFTR variants with respect to their responsiveness to elexacaftor-tezacaftor-ivacaftor

P-R Burgel  1 , A Orenti  2 , E Cromwell  3 , M Macek  4 , H H Gutierrez  5 , B Karadag  6 , A Faro  3 , J G van Rens  7 , L Naehrlich  8 , E Bakkeheim  9 , S B Carr  10 , A Lindblad  11 , A Zolin  2 , E Lammertyn  12 , R Ruseckaite  13 , M Zampoli  14 , C A Byrnes  15 , Lvrf da Silva-Filho  16 , A Elbert  3 , S Y Cheng  17 , A L Stephenson  18 ; on the behalf of the ECFSPR scientific committee and the Global CF Registry Collaboration
Affiliations
Free article

Global prevalence of CFTR variants with respect to their responsiveness to elexacaftor-tezacaftor-ivacaftor

P-R Burgel et al. J Cyst Fibros. 2025 Nov.
Free article

Abstract

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is mostly approved in people with cystic fibrosis (pwCF) with a p.Phe508del CFTR variant. The US Food and Drug Administration (FDA) approved ETI for an additional 177 rare CFTR variants and studies identified 7 non-FDA approved variants also responsive to ETI. The global impact of expanding the ETI label to rare responsive CFTR variants on the number of eligible pwCF is unknown.

Methods: Data were obtained from CF registries and individual CF clinics in countries without registries. Individuals were classified according to five mutually-exclusive categories (1) at least one p.Phe508del variant (2) at least one of the 177 FDA-approved variants (3) at least one non-FDA-approved variant responsive to ETI (4) two variants resulting in no CFTR protein (5) all other variants. The first 3 groups were considered responsive to ETI, group 4 was nonresponsive and group 5 of undetermined responsiveness.

Results: Data were obtained from 95,838 pwCF living in 69 countries: 78,566 (82.0 %) had at least one p.Phe508del, 6175 (6.4 %) at least one FDA-approved variants, and 2981 (3.1 %) at least one non-FDA-approved responsive variants. Two variants resulting in no CFTR protein were found in 3574 (3.7 %) and other variant combinations in 4490 (4.7 %). The prevalence of p.Phe508del ranged from 7 % to 98 % in individual countries and expanding the eligibility to responsive non-p.Phe508del variants resulted in greatest eligibility increase in countries with low p.Phe508del prevalence.

Conclusion: Expanding the label of ETI to rare responsive CFTR variants will make at least 91.5 % of pwCF eligible to this disease-modifying therapy.

Keywords: CFTR; CFTR modulators; Cystic fibrosis; Elexacaftor-tezacaftor-ivacaftor; Rare variants.

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Conflict of interest statement

Declaration of competing interest The authors report no conflict of interest for completion of this work. PRB has received grants from GSK and Vertex, consulting fees from Astra-Zeneca, Chiesi, GSK, Insmed, MSD, Vertex, Viatris and Zambon, and support for travelling from Astra-Zeneca and Chiesi, all outside of this work. EC, AE and AF are employees of the US Cystic Fibrosis Foundation. MM has received grants and honoraria from Vertex pharmaceutical outside of this work. HG has received grants and support for travelling from the US Cystic Fibrosis Foundation, all outside of this work. LN has received institutional fees from the German Center for Lung Research, Vertex Pharmaceuticals and the Mukoviszidose Institute, all outside of this work; LN has participated to a data monitoring safety board for the CF STORM study, and act as the medical lead of the German CF-registry and pharmacovigilance study manager of the European Cystic Fibrosis Society Patient Registry (ECFSPR); he has received support for medical writing from Articulate Science, all outside of this work. EB acts as director of the ECFSPR. SBC has received grants from CF Trust research and NIHR, honoraria from Chiesi and Vertex, support for attending meeting from Chiesi, and participated to advisory boards with Chiesi and Vertex, all outside of this work. SBC acts as Chair of UK CF Registry steering Committee. EL has received consulting fees paid to her institution from Patient Centrics and Roche Belux, all outside of this work. EL is a member of the ECFSPR Scientific Committee. LVRFDSF had received grants from Vertex Pharmaceuticals, TimPel, and Fundación Infant; consulting fees from Vertex Pharmaceuticals Omron, Astra Zeneca, Sanofi, Omron and participated to advisory boards with Vertex, all outside of this work. AS has received honoraria from Vertex outside of this work and acts as the Medical Director of Canadian CF Registry. AO, AL, AZ, BK, CAB, JGVR, MZ, RR and SC have nothing to disclose.

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