Bauer Martin, Jorda Anselm, Al-Jalali Valentin, Wölfl-Duchek Michael, Bergmann Felix, Nussbaumer-Pröll Alina, Steindl Ariane, Gugenberger Romana, Bischof Sarah, Wimmer Doris, Idzko Marco, Zeitlinger Markus
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
M. Bauer and M. Zeitlinger contributed equally to this article as lead authors and supervised the work.
ERJ Open Res. 2024 Feb 19;10(1). doi: 10.1183/23120541.00567-2023. eCollection 2024 Jan.
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.
This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted 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; doses in the MAD cohort were 2.5 and 5 mg·mL. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed.
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 () values after single and multiple doses of 5 mg·mL APN01 were 1.88 and 6.61 ng·mL, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1-5.
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.
APN01是一种可溶性重组人血管紧张素转换酶2（rhACE2），是肾素-醛固酮-血管紧张素系统（RAAS）中的关键因子。在临床研究中，迄今为止，APN01仅通过静脉给药。本研究（ClinicalTrials.gov：NCT05065645）的目的是评估吸入性APN01的安全性、耐受性、药代动力学（PK）和药效学（PD）。
这是一项I期、双盲、安慰剂对照、剂量递增研究。在三个单剂量递增（SAD）队列（n = 24）和两个多剂量递增（MAD）队列（n = 16：每12小时一次，共7天）中，使用雾化器在15分钟内进行吸入。SAD队列中的剂量为1.25、2.5和5 mg·mL；MAD队列中的剂量为2.5和5 mg·mL。评估安全性（包括不良事件（AE）、实验室检查结果和肺功能结果）、PK和PD数据。
在SAD和MAD队列中，活性治疗组与治疗相关的AE比安慰剂组略多。AE为轻度至中度，无剂量限制性毒性。未观察到肺功能和实验室检查结果有临床相关变化。单剂量和多剂量5 mg·mL APN01后的平均最大观察血浆浓度（）值分别为1.88和6.61 ng·mL。在PD变量中，发现ACE2和血管紧张素1-5有显著意义。
雾化APN01单次和多次给药后应用安全且耐受性良好。通过在肺部实现高局部浓度和低全身生物利用度，吸入性rhACE2可能为与ACE2相关的疾病提供一种治疗选择。
