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

Non-cystic fibrosis bronchiectasis (NCFB) is a disease characterized by abnormal dilatation of the airways, airflow obstruction, persistent cough, excessive sputum production and recurrent lung infections. NCFB 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 NCFB 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 NCFB, many of whom exhibit decreased CFTR function. Accordingly, we are conducting a clinical trial of ETI in subjects carrying a diagnosis of NCFB. 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 FEV 1 , sweat chloride, quality of life questionnaire, and weight. The study will evaluate response of patients with NCFB to ETI, and test usefulness of iPSC-derived airway epithelial monolayers as a novel in vitro technology for predicting clinical benefit. FUNDING SOURCE Marcus Foundation, Inc “Main Study” Summary Objectives ‘Lead in’ study: Incidence of diminished CFTR activity among patients with NCFB In order to gain information regarding numbers of individuals with NCFB who may be eligible for our ‘main’ study, patients at Emory followed with bronchiectasis (who do not have clinical criteria sufficient for a diagnosis of cystic fibrosis) will be asked to consider participating in a ‘lead in’ study that will determine the subject’s CFTR genotype and sweat chloride level. A separate consent form will be utilized for the ‘lead in’ study. Subjects who exhibit a single CF-causing mutation in CFTR and/or sweat chloride 30-59 mEq/L will be approached about their interest in reviewing the consent form for the ‘main’ study (“iPSC derivation and in vivo ETI treatment for 4 weeks”; see following section). Up to 200 subjects will be included in the ‘lead-in’ study. ‘Main’ study: iPSC derivation and in vivo ETI treatment for 4 weeks We propose a clinical trial of subjects with a diagnosis of NCFB. Participants will exhibit one disease-causing CFTR mutation and/or sweat chloride measurements of 30-59 mEq/L. Each patient will be given ETI for approximately four weeks. We will monitor clinical endpoints that include FEV 1 , sweat chloride, quality of life questionnaire, and weight. We will also collect cutaneous punch biopsy material or blood samples from subjects so iPS cells can be differentiated into airway epithelial monolayers and tested for response to ETI.