TY - JOUR T1 - Preclinical evaluation of the ENaC inhibitor BI 1265162 for treatment of cystic fibrosis JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00429-2020 SP - 00429-2020 AU - Peter Nickolaus AU - Birgit Jung AU - Juan Sabater AU - Samuel Constant AU - Abhya Gupta Y1 - 2020/01/01 UR - http://openres.ersjournals.com/content/early/2020/09/17/23120541.00429-2020.abstract N2 - Background Epithelial sodium channel (ENaC) is an important regulator of airway surface liquid volume; ENaC is hyperactivated in cystic fibrosis (CF). ENaC inhibition is a potential therapeutic target for CF. Here, we report in vitro and in vivo results of BI 1265162, an inhaled ENaC inhibitor currently in Phase II clinical development, administered via the Respimat® Soft Mist™ inhaler.Methods In vitro inhibition of sodium ion (Na+) transport by BI 1265162 was tested in mouse renal collecting duct cells (M1) and human bronchial epithelial cells (NCI-H441); inhibition of water transport was measured using M1 cells. In vivo inhibition of liquid absorption from rat airway epithelium and acceleration of mucociliary clearance (MCC) in sheep lungs were assessed. Fully differentiated normal and CF human epithelium was used to measure the effect of BI 1265162 with or without ivacaftor and lumacaftor on water transport and MCC.Results BI 1265162 dose-dependently inhibited Na+ transport and decreased water resorption in cell line models. BI 1265162 reduced liquid absorption in rat lungs and increased MCC in sheep. No effects on renal function were seen in the animal models. BI 1265162 alone and in combination with CF transmembrane conductance regulator (CFTR) modulators decreased water transport and increased MCC in both normal and CF airway human epithelial models and also increased the effects of CFTR modulators in CF epithelium to reach the effect size seen in healthy epithelium with ivacaftor/lumacaftor alone.Conclusion These results demonstrate the potential of BI 1265162 as a mutation agnostic, ENaC-inhibitor-based therapy for CF.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: P. Nickolaus is an employee of Boehringer Ingelheim International GmbH.Conflict of interest: Dr. Jung was an employee of Boehringer Ingelheim at the time of study.Conflict of interest: Dr. Sabater reports grants from Boehringer Ingelheim, during the conduct of the study;.Conflict of interest: Dr. Constant reports grants from Boehringer Ingelheim, during the conduct of the study;.Conflict of interest: A. Gupta is an employee of Boehringer Ingelheim International GmbH. ER -