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VMX-C001 Is a Reversal Agent for FXa-inhibiting DOACs and Displays a Favorable Pharmacokinetic and Pharmacodynamic Profile

D. Verhoef1,2, M. Schreuder2, K.L. Cheung2, M.H.A. Bos2, P.H. Reitsma1,2

1VarmX, Leiden, the Netherlands, 2Leiden University Medical Center, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden, the Netherlands

Abstract Number: PB0313

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Critical Care and Perioperative

Background: Reversal of anticoagulation is important for safe usage of oral factor (F)Xa-inhibiting anticoagulants (DOACs), including rivaroxaban and apixaban. VMX-C001 is a modified human FX zymogen that is insensitive to DOACs. VMX-C001 may therefore prevent and stop bleeding associated with FXa-inhibiting DOACs.

Aims: To assess the pharmacokinetics, pharmacodynamics, and safety of zymogen VMX-C001 and potency of activated VMX-C001 in cynomolgus monkeys and rats.

Methods: Zymogen VMX-C001 was administered intravenously to male and female cynomolgus monkeys and male Sprague Dawley rats at 0.3, 1.0, or 3.0 mg/kg/day for 7-8 consecutive days. Blood was drawn at regular intervals to evaluate VMX-C001 levels and determine pharmacokinetics. Pharmacodynamics were examined employing the plasma endogenous thrombin potential (ETP). For safety assessment the plasma thrombin-antithrombin complexes (TAT) and D-dimer levels were determined.

Results: VMX-C001 was successfully manufactured in suspension CHO cells and purified in a scalable process. Analysis of pharmacokinetics revealed linear and dose-proportional kinetics of VMX-C001 and a plasma half-life of 7-9 hours in monkeys (Table 1) and 6 hours in rats. The distribution volume of VMX-C001 was approximately 90 mL/kg, which equals the estimated blood volume. Period or gender effects were not observed upon repeated dosing. Robust ex vivo and in vivo reversal of the effect of apixaban/rivaroxaban on the ETP was observed at the mid-dose level. Reversal was not impaired upon repeated VMX-C001 dosing. No dose-dependent increase in TAT and D-dimer was detected upon administration of zymogen VMX-C001, indicating that VMX-C001 does not have a procoagulant effect. In contrast, a rapid and dose-dependent increase in TAT and D-dimer levels was observed upon administration of 2 µg/kg activated VMX-C001, demonstrating its in vivo potency. Adverse events, drug related toxicity, or macroscopic deviations were not observed following administration of zymogen or activated VMX-C001.

Conclusions: VMX-C001 is a potentially safe and broad anti-FXa DOAC reversal agent with favorable pharmacokinetics and pharmacodynamics.


[Table 1. Pharmacokinetic parameters of VMX-C001 in cynomolgus monkeys.]

To cite this abstract in AMA style:

Verhoef D, Schreuder M, Cheung KL, Bos MHA, Reitsma PH. VMX-C001 Is a Reversal Agent for FXa-inhibiting DOACs and Displays a Favorable Pharmacokinetic and Pharmacodynamic Profile [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/vmx-c001-is-a-reversal-agent-for-fxa-inhibiting-doacs-and-displays-a-favorable-pharmacokinetic-and-pharmacodynamic-profile/. Accessed May 16, 2022.

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