Multisystemic Effects of Elexacaftor–Tezacaftor–Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease

Rationale: Limited data exist on safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. Objective: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. Methods: A prospective observational study, including all adults, aged 18 years and older, with a percent predicted FEV1 (ppFEV1)≤ 40 who initiated ETI from December 2019 to June 2021 in France was conducted. PwCF were followed until August 8th, 2022. Results: ETI was initiated in 434 pwCF with a median interquartile range, IQR ppFEV1=30 25; 35, including 27 with severe CF liver disease and 183 with diabetes. PwCF were followed for a median IQR 587 396; 728 days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was mostly due to lung transplantation (n=5) or death (n=4). Absolute increase in ppFEV1 by a mean +14.2% (95% CI, 13.1-15.4) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the younger age quartile was almost twice that of the oldest quartile (P<0.001); body mass index <18.5 kg/m2 was found in 38.6% at initiation vs. 11.3% at 12 months (P=0.0001). Increase in serum concentrations of vitamin A and E, but not 25OHD3, was observed. Significant reduction in the % of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of diabetics. Conclusion: ETI is safe in pwCF and advanced lung disease with multisystem pulmonary and extrapulmonary benefits.