AUTHOR=Tschirhart Brent J. , Lu Xiangru , Mokale Kognou Aristide Laurel , Martin Claudio M. , Slessarev Marat , Fraser Douglas D. , Leligdowicz Aleksandra , Urquhart Bradley , Feng Qingping 

TITLE=Pharmacokinetics of recombinant human annexin A5 (SY-005) in patients with severe COVID-19

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1299613

DOI=10.3389/fphar.2023.1299613

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> Annexin A5 is a phosphatidylserine binding protein with anti-inflammatory, anticoagulant and anti-apoptotic properties. Preclinical studies have shown that annexin A5 inhibits pro-inflammatory responses and improves organ function and survival in rodent models of sepsis. This clinical trial aimed to evaluate the pharmacokinetic (PK) properties of the recombinant human annexin A5 (SY-005) in severe COVID-19.</p><p><bold>Methods:</bold> This was a pilot randomized, double-blind, placebo-controlled trial. Severe COVID-19 patients were randomly assigned to receive intravenous 50 μg/kg (low dose, <italic>n</italic> = 3), 100 μg/kg (high dose, <italic>n</italic> = 5) of SY-005 or placebo (<italic>n</italic> = 5) every 12 h for 7 days. Plasma SY-005 levels were assessed using enzyme-linked immunosorbent assay (ELISA) and the PK parameters were determined using non-compartmental analysis.</p><p><bold>Results:</bold> All patients treated with SY-005 had a normal baseline estimated glomerular filtration rate (eGFR, 104–125 mL/min/1.73 m<sup>2</sup>). Both low and high doses of SY-005 were cleared within 6 h after intravenous administration. Plasma maximum concentrations (C<sub>max</sub>), half-life, clearance and volume distribution of low and high doses of SY-005 were 402.4 and 848.9 ng/mL, 0.92 and 0.96 h, 7.52 and 15.19 L/h, and 9.98 and 20.79 L, respectively. Daily pre-dose circulating annexin A5 levels were not significantly different when SY-005 was administered at the low or the high dose 12-h intervals. There was no significant effect on activated partial thromboplastin time (aPTT) or INR (international normalized ratio of prothrombin time) during 7 days of SY-005 treatment.</p><p><bold>Conclusion:</bold> SY-005 doses of 50 and 100 μg/kg were detectable and subsequently cleared from the plasma in severe COVID-19 patients with normal baseline renal function. There was no significant plasma SY-005 accumulation 6 h after drug administration and coagulation was not altered during 7 days of treatment.</p><p><bold>Clinical trials Registration:</bold> This study was registered with <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link> (NCT04748757, first posted on 10 February 2021).</p>