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.]

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/vmx-c001-is-a-reversal-agent-for-fxa-inhibiting-doacs-and-displays-a-favorable-pharmacokinetic-and-pharmacodynamic-profile/