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. Met...
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doaj-9a8f48e57c8d4add9324a18993bc74b02021-04-06T10:24:08ZengEuropean Respiratory SocietyERJ Open Research2312-05412021-02-017110.1183/23120541.00447-202000447-2020First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteersAlison Mackie0Juliane Rascher1Marion Schmid2Verena Endriss3Tobias Brand4Wolfgang Seibold5 Boehringer Ingelheim, Biberach an der Riss, Germany SocraMetrics GmbH, Erfurt, Germany, on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany Boehringer Ingelheim, Biberach an der Riss, Germany Boehringer Ingelheim, Biberach an der Riss, Germany Boehringer Ingelheim, Biberach an der Riss, Germany Boehringer Ingelheim, Biberach an der Riss, Germany 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.http://openres.ersjournals.com/content/7/1/00447-2020.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alison Mackie Juliane Rascher Marion Schmid Verena Endriss Tobias Brand Wolfgang Seibold |
spellingShingle |
Alison Mackie Juliane Rascher Marion Schmid Verena Endriss Tobias Brand Wolfgang Seibold First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers ERJ Open Research |
author_facet |
Alison Mackie Juliane Rascher Marion Schmid Verena Endriss Tobias Brand Wolfgang Seibold |
author_sort |
Alison Mackie |
title |
First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers |
title_short |
First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers |
title_full |
First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers |
title_fullStr |
First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers |
title_full_unstemmed |
First clinical trials of the inhaled epithelial sodium channel inhibitor BI 1265162 in healthy volunteers |
title_sort |
first clinical trials of the inhaled epithelial sodium channel inhibitor bi 1265162 in healthy volunteers |
publisher |
European Respiratory Society |
series |
ERJ Open Research |
issn |
2312-0541 |
publishDate |
2021-02-01 |
description |
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. |
url |
http://openres.ersjournals.com/content/7/1/00447-2020.full |
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