@article {Mackie00447-2020, author = {Alison Mackie and Juliane Rascher and Marion Schmid and Verena Endriss and Tobias Brand and Wolfgang Seibold}, title = {First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers}, volume = {7}, number = {1}, elocation-id = {00447-2020}, year = {2021}, doi = {10.1183/23120541.00447-2020}, publisher = {European Respiratory Society}, abstract = {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); and NCT03907280 (absolute bioavailability trial).Results BI 1265162 single doses <=1200 {\textmu}g and multiple doses of 600 {\textmu}g were well tolerated. Adverse events 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 adverse event; recovered day 8). One subject experienced a serious adverse event (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{\textendash}8.7 h over the dose ranges tested. Renal excretion was not a major drug elimination route. Oral and inhaled dosing ({\textpm}activated oral charcoal) absolute bioavailability was 0.50\% and \~{}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 \~{}40\% of the inhaled dose reaching the systemic circulation. Accumulation was minimal. Twice-daily dosing is supported for future development.Cell and animal studies have demonstrated that BI 1265162 is a potent ENaC inhibitor. Three phase I trials show that single- and multiple-dose BI 1265162 is safe. BI 1265162 is being tested in phase II studies, using twice-daily dosing, in people with CF. https://bit.ly/3nPUkrO}, URL = {https://openres.ersjournals.com/content/7/1/00447-2020}, eprint = {https://openres.ersjournals.com/content/7/1/00447-2020.full.pdf}, journal = {ERJ Open Research} }