Abstract
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.
Footnotes
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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.
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- Received June 25, 2020.
- Accepted September 4, 2020.
- Copyright ©ERS 2020
This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.
