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

Alison Mackie, Juliane Rascher, Marion Schmid, Verena Endriss, Tobias Brand, Wolfgang Seibold, Alison Mackie, Juliane Rascher, Marion Schmid, Verena Endriss, Tobias Brand, Wolfgang Seibold

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 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.

Conflict of interest statement

Conflict of interest: A. Mackie is an employee of Boehringer Ingelheim. Conflict of interest: J. Rascher has nothing to disclose. Conflict of interest: M. Schmid is an employee of Boehringer Ingelheim. Conflict of interest: V. Endriss is an employee of Boehringer Ingelheim. Conflict of interest: T. Brand is an employee of Boehringer Ingelheim. Conflict of interest: W. Seibold is an employee of Boehringer Ingelheim.

Copyright ©ERS 2021.

Figures

FIGURE 1
FIGURE 1
Trial design of a) the single-rising-dose trial, b) the multiple-rising-dose trial and c) the bioavailability trial. T: treatment; R: reference.
FIGURE 2
FIGURE 2
Geometric mean plasma concentration–time profiles of BI 1265162 in a) the single-rising-dose trial and b) the multiple-rising-dose trial (doses given twice daily). gMean: geometric mean.
FIGURE 3
FIGURE 3
Comparison of geometric mean (gMean) plasma concentration–time profiles of BI 1265162 after single administration of BI 1265162 following oral administration (1.25 mg), inhalation with and without charcoal (200 µg) and intravenous infusion (50 µg) (semi-logarithmic scale). LLOQ: lower limit of quantification.

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