Evaluating elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) for treatment of patients with non-cystic fibrosis bronchiectasis (NCFBE): A clinical study protocol

• Published in: PloS one Vol. 20; no. 2; p. e0316721
• Main Authors: Swenson, Colin E, Hunt, William R, Manfredi, Candela, Beltran, Diana J, Hong, Jeong S, Davis, Brian R, Suzuki, Shingo, Barillá, Cristina, Rab, Andras, Chico, Cynthia, Dangerfield, Joy, Streby, Ashleigh, Barton, Erin, Cox, Elizabeth M, Stecenko, Arlene A, Westbrook, Adrianna, Kapolka, Rebecca, Sorscher, Eric J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2025; Public Library of Science (PLoS)
• Subjects: Adult; Air flow; Aminophenols - administration & dosage; Aminophenols - therapeutic use; Benzodioxoles - therapeutic use; Biopsy; Bronchiectasis; Bronchiectasis - drug therapy; Bronchiectasis - genetics; Cell differentiation; Chloride; Chloride Channel Agonists - therapeutic use; Chloride conductance; Chlorides; Consent; Cough; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Diagnosis; Differentiation (biology); Drug Combinations; Female; Health services; Humans; In vitro methods and tests; Indoles - administration & dosage; Indoles - therapeutic use; Infections; Inflammation; Ion transport; Laboratories; Lung diseases; Male; Middle Aged; Monolayers; Mutation; Pathogenesis; Patients; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Pyrrolidines - therapeutic use; Quality of life; Quinolines; Quinolones - therapeutic use; Respiratory tract infection; Sputum; Sweat; Toxins; Treatment Outcome; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0316721

Non-cystic fibrosis bronchiectasis (NCFBE) is a disease that exhibits dilatation of airways, airflow obstruction, persistent cough, excessive sputum production, and refractory respiratory infections. NCFBE exhibits clinical and pathological manifestations similar to key features of cystic fibrosis (CF) lung disease. In CF, pathogenesis results from dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), and diagnosis is made by demonstrating elevated sweat chloride concentrations (typically ≥60 mEq/L), two CFTR mutations known to be causal, multi-organ tissue injury, or combination(s) of these findings. Based on a considerable body of evidence, we believe many patients with NCFBE have disease likely to benefit from drugs such as elexacaftor/tezacaftor/ivacaftor (ETI) that activate CFTR-dependent ion transport. ETI is currently prescribed solely for treatment of CF and has not been adequately tested or proposed for patients with NCFBE, many of whom exhibit decreased CFTR function. Accordingly, we are conducting a clinical trial of ETI in subjects carrying a diagnosis of NCFBE. Participants will exhibit one disease-causing CFTR mutation and/or sweat chloride measurements of 30-59 mEq/L. Cutaneous punch biopsy or blood samples will be obtained for iPS cell differentiation into airway epithelial monolayers-which will then be tested for response to ETI. Each patient will be given CFTR modulator treatment for approximately four weeks, with monitoring of clinical endpoints that include FEV1 (forced expiratory volume in one second), sweat chloride, quality of life questionnaire, and weight. The study will evaluate response of patients with NCFBE to ETI, and test usefulness of iPSC-derived airway epithelial monolayers as a novel in vitro technology for predicting clinical benefit. This trial is registered at clinicaltrials.gov (Identifier: NCT05743946. Date: 02/23/2023).