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Phase I dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an inhaled recombinant human ACE2

Authors :
Martin Bauer
Anselm Jorda
Valentin al-Jalali
Michael Wölfl-Duchek
Felix Bergmann
Alina Nussbaumer-Pröll
Ariane Steindl
Romana Gugenberger
Sarah Bischof
Doris Wimmer
Marco Idzko
Markus Zeitlinger
Source :
ERJ Open Research, Vol 10, Iss 1 (2024)
Publication Year :
2024
Publisher :
European Respiratory Society, 2024.

Abstract

Background APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin–aldosterone–angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01. Methods This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL−1; doses in the MAD cohort were 2.5 and 5 mg·mL−1. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed. Results In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration (Cmax) values after single and multiple doses of 5 mg·mL−1 APN01 were 1.88 and 6.61 ng·mL−1, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1–5. Conclusions The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases.

Subjects

Subjects :
Medicine

Details

Language :
English
ISSN :
23120541
Volume :
10
Issue :
1
Database :
Directory of Open Access Journals
Journal :
ERJ Open Research
Publication Type :
Academic Journal
Accession number :
edsdoj.750610a6ecbd47c684d791e226f23204
Document Type :
article
Full Text :
https://doi.org/10.1183/23120541.00567-2023