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

ABSTRACT: 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. 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). 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. 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.

SUBMITTER: Mackie A

PROVIDER: S-EPMC7861022 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Mackie Alison A Rascher Juliane J Schmid Marion M Endriss Verena V Brand Tobias T Seibold Wolfgang W

ERJ open research 20210101 1

<h4>Background</h4>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.<h4>Methods</h4>Three phase I trials of BI 1265162 in healthy male subjects are presented: NCT03349723 (single-rising-dose trial evaluating safety, tolerability and pharmacokinetics (PK)); NCT0357 ...[more]

PMID: 33569494

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

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

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