{"doi":"10.1183/23120541.00567-2023","title":"Phase I dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an inhaled recombinant human ACE2","abstract":"<jats:sec><jats:title>Background</jats:title><jats:p>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 (<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://clinicaltrials.gov/\">ClinicalTrials.gov</jats:ext-link>:<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05065645\">NCT05065645</jats:ext-link>) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted<jats:italic>via</jats:italic>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<jats:sup>−1</jats:sup>; doses in the MAD cohort were 2.5 and 5 mg·mL<jats:sup>−1</jats:sup>. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 (<jats:italic>C</jats:italic><jats:sub>max</jats:sub>) values after single and multiple doses of 5 mg·mL<jats:sup>−1</jats:sup>APN01 were 1.88 and 6.61 ng·mL<jats:sup>−1</jats:sup>, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1–5.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>","journal":"ERJ Open Research","year":2024,"id":643852,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1675501,"name":"Anselm Jorda","orcid":null,"position":1,"is_corresponding":false},{"id":1675502,"name":"Valentin al-Jalali","orcid":null,"position":2,"is_corresponding":false},{"id":1675503,"name":"Michael Wölfl-Duchek","orcid":null,"position":3,"is_corresponding":false},{"id":1675504,"name":"Felix Bergmann","orcid":null,"position":4,"is_corresponding":false},{"id":1675505,"name":"Alina Nussbaumer-Pröll","orcid":null,"position":5,"is_corresponding":false},{"id":1207563,"name":"Ariane Steindl","orcid":"0000-0002-5839-8301","position":6,"is_corresponding":false},{"id":864093,"name":"Romana Gugenberger","orcid":null,"position":7,"is_corresponding":false},{"id":1675506,"name":"Sarah Bischof","orcid":null,"position":8,"is_corresponding":false},{"id":1675507,"name":"Doris Wimmer","orcid":null,"position":9,"is_corresponding":false},{"id":458094,"name":"Marco Idzko","orcid":null,"position":10,"is_corresponding":false},{"id":1675508,"name":"Markus Zeitlinger","orcid":null,"position":11,"is_corresponding":false},{"id":999217,"name":"Martin Bauer","orcid":"0000-0001-7771-056X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Phase I dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an inhaled recombinant human ACE2","abstract":"<jats:sec><jats:title>Background</jats:title><jats:p>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 (<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://clinicaltrials.gov/\">ClinicalTrials.gov</jats:ext-link>:<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05065645\">NCT05065645</jats:ext-link>) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted<jats:italic>via</jats:italic>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<jats:sup>−1</jats:sup>; doses in the MAD cohort were 2.5 and 5 mg·mL<jats:sup>−1</jats:sup>. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 (<jats:italic>C</jats:italic><jats:sub>max</jats:sub>) values after single and multiple doses of 5 mg·mL<jats:sup>−1</jats:sup>APN01 were 1.88 and 6.61 ng·mL<jats:sup>−1</jats:sup>, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1–5.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38375429","pmcid":"PMC10875465","openalex_id":null,"authors":[],"funders":[{"funder_name":"Apeiron Biologics","grant_id":"Restricted to the Medical University of Vienna","title":null}],"total_grants":1,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://openres.ersjournals.com/content/erjor/early/2024/01/04/23120541.00567-2023.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1183/23120541.00567-2023","host_type":"publisher"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10875465/pdf/00567-2023.pdf","host_type":"repository"},{"url":"https://doaj.org/article/750610a6ecbd47c684d791e226f23204","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10875465","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10875465?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":[],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-08T19:18:44.364384Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}