PT - JOURNAL ARTICLE AU - Alison Mackie AU - Juliane Rascher AU - Marion Schmid AU - Verena Endriss AU - Tobias Brand AU - Wolfgang Seibold TI - First clinical trials of the inhaled ENaC inhibitor BI 1265162 in healthy volunteers AID - 10.1183/23120541.00447-2020 DP - 2020 Jan 01 TA - ERJ Open Research PG - 00447-2020 4099 - http://openres.ersjournals.com/content/early/2020/11/19/23120541.00447-2020.short 4100 - http://openres.ersjournals.com/content/early/2020/11/19/23120541.00447-2020.full AB - Background Inhibition of the epithelial sodium channel (ENaC) represents a mutation-agnostic therapeutic approach to restore airway surface liquid hydration and mucociliary clearance in patients with cystic fibrosis. BI 1265162 is an inhaled ENaC inhibitor with demonstrated preclinical efficacy.Methods Three Phase I trials of BI 1265162 in healthy male subjects are presented: NCT03349723 (single-rising-dose trial evaluating safety, tolerability and pharmacokinetics [PK]); NCT03576144 (multiple-rising-dose trial evaluating safety, tolerability and PK); NCT03907280 (absolute bioavailability trial).Results BI 1265162 single doses ≤1200 µg and multiple doses of 600 µg were well tolerated. Adverse events (AEs) were balanced across treatment groups, were of mainly mild or moderate intensity, and resolved by trial-end. One subject discontinued from trial medication on Day 7 (asymptomatic hyperkalaemia AE; recovered Day 8). One subject experienced a serious AE (neuropathia vestibularis) leading to hospitalisation and missed one of the four dosing periods. Both events were not considered to be drug-related and subjects recovered. BI 1265162 displayed dose-proportional, time-independent PK; maximum accumulation was 1.6-fold; calculated effective elimination half-life was 3.6–8.7 h over the dose ranges tested. Renal excretion was not a major drug elimination route. Oral and inhaled dosing (± activated oral charcoal) absolute bioavailability was 0.50% and approximately 40%, respectively.Conclusion BI 1265162 single or multiple doses up to 6.5 days were well tolerated. Systemic exposures mainly represent drug absorbed through the lungs and not the gastrointestinal tract, with approximately 40% of the inhaled dose reaching the systemic circulation. Accumulation was minimal. Twice-daily dosing is supported for future development.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: Dr. Mackie is an employee of Boehringer Ingelheim.Conflict of interest: Dr. Rascher has nothing to disclose.Conflict of interest: Dr. Schmid is an employee of Boehringer Ingelheim.Conflict of interest: Dr. Endriss is an employee of Boehringer Ingelheim.Conflict of interest: Dr. Brand is an employee of Boehringer Ingelheim.Conflict of interest: Dr. Seibold is an employee of Boehringer Ingelheim.