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

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.