094 - Biological and clinical effects of significantly corrected CFTR function in infants and young children with cystic fibrosis: The BEGIN study
Friday, April 25, 2025
5:30pm – 7:45pm HST
Publication Number: 94.3876
Lucas Hoffman, University of Washington, Seattle, WA, United States; Sonya Heltshe, University of Washington, Seattle, WA, United States; Colin O'Rourke, Seattle Children's, Seattle, WA, United States; Katie Larson Ode, University of Iowa Stead Family Children's Hospital, Iowa City, IA, United States; Edith Zemanick, University of Colorado School of Medicine, Aurora, CO, United States; Bonnie W. Ramsey, University of Washington School of Medicine, Seattle, WA, United States; Renee Russell, Seattle Children's, Seattle, WA, United States; Felix Ratjen, The Hospital for Sick Children, Toronto, ON, Canada; Rachael Buckingham, Seattle Children's Hospital, Seattle, WA, United States
Professor and Vice Chair for Research, Pediatrics University of Washington Seattle, Washington, United States
Background: The approval of elexacaftor/tezacaftor/ivacaftor (ETI) in people with CF with ≥1 F508del mutation provides an opportunity to understand pulmonary and non-pulmonary effects of highly effective modulator therapy (HEMT: ivacaftor or ETI). CF respiratory disease begins during childhood, and whether initiating HEMT early in life will prevent respiratory disease, or improve the consequences of pancreatic and gastrointestinal (GI) dysfunction, in these young children is unknown. Objective: To investigate the clinical course of CF in infants and young children before and after starting, HEMT. Design/Methods: ≤10 yo followed for up to 5 years or until the child starts HEMT. Part B will include up to 5 years of study visits after HEMT initiation. Clinical measures, specimen collection (blood, urine, stool), oropharyngeal swabs, GI and pulmonary patient/guardian symptoms are collected at each study visit. Sweat chloride (SwCl) is measured at Part B visits: baseline, 1, 6, and 24 months. Specialized procedures performed at select sites include lung clearance index (LCI) via multiple breath washout (MBW), liver transient elastography (TE) and dual-energy x-ray absorptiometry (DXA) in participants 3 years and older; continuous glucose monitoring (CGM) for 2 and older, and bronchoalveolar lavage (BAL) for 6 months and older. Mixed effects models provide mean estimation and change, 95% confidence intervals (CI). Results: Thirty-four US centers have enrolled 115 participants in Part A with an average follow-up of 1.7 years and mean±SD age at enrollment 2.9±1.4 years. Part B has enrolled 192 children who started HEMT (87/192 from Part A and 105 new participants) of which 160 have completed the 6 month visit. Age at enrollment into Part B was 4.2±1.4 years. 17 and 8 have enrolled in the CGM and BAL sub-studies, respectively. Table 1 shows results at start of HEMT, 1 and 6 months, and change (mean, 95% CI). Early and significant clinical improvements are seen in weight, percent predicted forced expiratory volume in 1 second (ppFEV1) and SwCl; there is no evidence of linear height change by six months. In a subset performing MBW at baseline and 1 month (n=27), LCI2.5 decreased by -0.58 95%CI=(-1.01, -0.15).
Conclusion(s): BEGIN is an observational study of HEMT in the youngest age group with access to ETI. Enhanced understanding of clinical impact of HEMT in this youngest CF population will provide new insights into earliest stages of disease pathogenesis and potential therapies. Most 12 month visits for those under 6 will occur summer of 2024 and future reports will present those data.
