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Multicenter Study
. 2025 Aug-Sep:245:108221.
doi: 10.1016/j.rmed.2025.108221. Epub 2025 Jun 24.

Real-world effectiveness and safety of elexacaftor/tezacaftor/ivacaftor in cystic fibrosis patients with Phe508del -gating and -residual function genotypes

Donatello Salvatore  1 , Paola Iacotucci  2 , Angela Pepe  3 , Alberto Terminiello  4 , Fabio Majo  5 , Vincenzo Carnovale  6 , Pamela Vitullo  7 , Barbara Messore  8 , Giuseppe Fabio Parisi  9 , Maria Adelaide Calderazzo  10 , Giuseppina Leonetti  11 , Vito Terlizzi  4
Affiliations
Multicenter Study

Real-world effectiveness and safety of elexacaftor/tezacaftor/ivacaftor in cystic fibrosis patients with Phe508del -gating and -residual function genotypes

Donatello Salvatore et al. Respir Med. 2025 Aug-Sep.

Abstract

Background: Cystic fibrosis (CF) is a genetic disease caused by CFTR protein dysfunction. Elexacaftor/tezacaftor/ivacaftor (ETI) shows promise in improving outcomes for people with CF (pwCF) with Phe508del combined with gating (F/G) or residual function (F/RF) mutations, though real-world evidence remains scarce.

Objectives: This study evaluated the effectiveness and safety of ETI therapy in pwCF with F/G and F/RF genotypes in real-world settings.

Methods: A multicentre, retrospective study enrolled 78 pwCF (24 F/G and 54 F/RF) receiving ETI after prior CFTR modulator treatments (ivacaftor and tezacaftor/ivacaftor). Endpoints included changes in ppFEV1, sweat chloride concentration (SCC), CFQ-R respiratory domain scores, body mass index (BMI), pulmonary exacerbations (PEx), and antibiotic use over 24 weeks. Safety was assessed via self-reported adverse events.

Results: ETI improved ppFEV1 (mean increase: 3.8; 95 % CI, 1.8-5.8), SCC (mean decrease: -23.7 mmol/L; 95 % CI, -28.6 to -18.9), and CFQ-R scores (median improvement: 9.4 points; p < 0.05). BMI increased (mean change: 0.41 kg/m2; 95 % CI, 0.05-0.76), while PEx and antibiotic use decreased by 65.2 % and >50 %, respectively (p < 0.001). Subgroup analysis revealed greater ppFEV1 improvement in F/G patients (6.0 points; 95 % CI, 2.6-9.4) compared to F/RF patients (2.8 points; 95 % CI, 0.4-5.2). No serious adverse events were reported.

Conclusions: ETI therapy provides significant clinical benefits in pwCF with F/G and F/RF genotypes, including improved lung function, SCC normalization, and reduced PEx, compared with previous modulator treatments. Further research is needed to confirm long-term outcomes.

Keywords: Cystic fibrosis; Elexacaftor/tezacaftor/ivacaftor; Gating mutations; Residual function mutations.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Donatello Salvatore reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory and speaking and lecture fees. Paola Iacotucci reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory and speaking and lecture fees. Maria Adelaide Calderazzo reports a relationship with Chiesi Farmaceutici SpA that includes: consulting or advisory. Vincenzo Carnovale reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory and speaking and lecture fees. Giuseppe Fabio Parisi reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory and speaking and lecture fees. Fabio Majo reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory and speaking and lecture fees. Vito Terlizzi reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory and speaking and lecture fees. Barabara Messore reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory and speaking and lecture fees. Angela Pepe reports a relationship with Vertex Pharmaceuticals Incorporated that includes: travel reimbursement. Giuseppina Leonetti reports a relationship with Vertex Pharmaceuticals Incorporated that includes: travel reimbursement. Angela Pepe reports a relationship with DMF Pharma Foodar that includes: travel reimbursement. Giuseppina Leonetti reports a relationship with DMF Pharma Foodar that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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