Side versus adverse effects of elexacaftor/tezacaftor/ivacaftor therapy in people with CF

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy is highly effective for people with cystic fibrosis (pwCF) carrying at least one F508del mutation. However, clinical trials often include a limited subset of eligible patients, with inclusion rates as low as 31%. Additionally, some adverse effects linked to ETI may stem from restored CFTR function (side effects) rather than drug toxicity (adverse effects). This study evaluates the real-world efficacy and tolerability of ETI in adults with CF, while differentiating side from adverse effects. Methods: In this retrospective single-centre cohort study, 198 adults with CF (46.5% female) initiating ETI between January 2022 and April 2023 were analysed. Clinical data, laboratory results, and adverse events were collected. Subgroup-analyses were performed based on baseline ppFEV1 and genotype. Results: ETI therapy increased mean ppFEV1 by 11.2% (95% CI: 9.7%, 12.7%) and BMI by 0.7 kg/m²(95% CI: 0.5, 0.9), decreased sweat chloride by 43.7 mmol/L (95% CI: 46.7, −40.6), and reduced yearly exacerbation rate (70 vs. 12, p < 0.001). Common side effects included increased sputum, cough, and headache. Headache was more frequent in patients with ppFEV1 <40% (p < 0.001). Increased sputum and cough were most prevalent in F/F and F/MF subgroups. Frequent adverse effects were fatigue, depressed state, and mood swings. Side effects resolved spontaneously more often than adverse effects (89.3% vs. 47.9%). Conclusion: ETI demonstrates robust real-world efficacy in adults with CF. Side effects due to CFTR restoration are generally self-limiting, whereas adverse effects from drug toxicity persist longer and are more frequently cause for permanent discontinuation of ETI.