Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) in People with Cystic Fibrosis in the United States

Abstract Rationale Limited data exist on whether the benefits of elexacaftor/tezacaftor/ivacaftor (ETI) seen in randomized controlled trials are sustained in clinical practice in people with cystic fibrosis (PwCF) taking ETI. Objectives This study evaluated the longitudinal effect of ETI on lung function and nutritional outcomes in clinical practice and analyzed the heterogeneity of response. Methods PwCF ≥ 12 years with at least one copy of F508del who were enrolled in the CF Foundation Patient Registry (CFFPR) between 2018 and 2022 with documented ETI prescription were included. Mean percent predicted forced expiratory volume in 1 second (ppFEV1) and body mass index (BMI) were examined for 1 year preceding and 3 years following ETI initiation. We used linear regression with generalized estimating equations (GEE) to evaluate longitudinal changes. We compared characteristics of participants who had a clinically meaningful response for both ppFEV1 and BMI to participants with neither a ppFEV1 nor BMI response. We used a negative binomial model to evaluate pulmonary exacerbation (PEx) rates and accounted for effects of viral respiratory trends. Measurements and main results Among 11,151 PwCF included in the ppFEV1 analysis, we found a mean ppFEV1 increase of 9.9 (95% CI 9.6-10.2) between the pre- and post-ETI initiation periods over three years. Mean BMI increased by 1.03 kg/m2 (95% CI 0.98—1.07) in the 3 years post-ETI initiation among 12,119 PwCF in the BMI analysis. Among participants with both ppFEV1 and BMI data, 3,594 (32.8%) experienced significant improvement in both ppFEV1 and BMI. Participants with both ppFEV1 and BMI improvement were more likely to have had a PEx prior to ETI initiation, history of Pseudomonas aeruginosa infection, pancreatic insufficiency, CF-related diabetes, and lower BMI pre-ETI. PEx rates were significantly reduced post-ETI initiation, even after adjusting for peak respiratory virus periods (unadjusted incidence rate ratio (IRR) (95% CI) 0.26 (0.25—0.27), adjusted IRR 0.62 (0.57—0.66)). Conclusions This effectiveness analysis of observational data from the CFFPR found sustained improvements in lung function and nutritional status for three years following ETI initiation. Only 32% had an improvement in both FEV1 and BMI, indicating that not all PwCF respond uniformly to ETI therapy.