First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers

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 (singlerising-dose trial evaluating safety, tolerability and pharmacokinetics (PK)); NCT03576144 (multiple-risingdose trial evaluating safety, tolerability and PK); and NCT03907280 (absolute bioavailability trial). Results: BI 1265162 single doses. <= 1200 mu g and multiple doses of 600 mu 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 drugrelated 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 similar to 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 similar to 40% of the inhaled dose reaching the systemic circulation. Accumulation was minimal. Twice-daily dosing is supported for future development.

Automated summary

BI 1265162 was well tolerated in single and multiple doses up to 6.5 days. Systemic exposure primarily represents drug absorbed through the lungs rather than renal excretion. Absolute bioavailability ranged from 0.50% to 40%.