Journal Article

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

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

2023

Overview

Objective: 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. Methods: 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, n = 3), 100 μg/kg (high dose, n = 5) of SY-005 or placebo ( n = 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. Results: All patients treated with SY-005 had a normal baseline estimated glomerular filtration rate (eGFR, 104–125 mL/min/1.73 m 2 ). Both low and high doses of SY-005 were cleared within 6 h after intravenous administration. Plasma maximum concentrations (C max ), 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. Conclusion: 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. Clinical trials Registration: This study was registered with ClinicalTrials.gov (NCT04748757, first posted on 10 February 2021).

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animal models / annexin A5 / Apoptosis / Clinical trials / Coronaviruses / COVID-19 / Disease transmission / Drug dosages / Enzyme-linked immunosorbent assay / Glomerular filtration rate / Health sciences / Inflammation / Intravenous administration / Patients / Pharmacokinetics / Pharmacology / Phosphatidylserine / Placebos / Plasma / Prothrombin / Renal function / Sepsis / Statistical analysis / SY-005 / Thromboplastin / Tumor necrosis factor-TNF