TY - JOUR T1 - First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00447-2020 VL - 7 IS - 1 SP - 00447-2020 AU - Alison Mackie AU - Juliane Rascher AU - Marion Schmid AU - Verena Endriss AU - Tobias Brand AU - Wolfgang Seibold Y1 - 2021/01/01 UR - http://openres.ersjournals.com/content/7/1/00447-2020.abstract N2 - 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 µg and multiple doses of 600 µg 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 3.6–8.7 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 ∼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 ER -