Safety Pharmacology, Toxicokinetics and Pharmacodynamics of VMX-C001, an Intravenous Bypassing Agent for Factor Xa Inhibitors, in Animal Models

Background: Anticoagulation therapy confers increased risk of potentially life-threatening bleeding events. Limited options exist for anticoagulation reversal in patients treated with direct oral factor Xa (FXa) anticoagulants (aka FXa inhibitors). Clinical development of reltodecacog alfa (VMX-C001), a modified form of human zymogen FX, as an FXa inhibitor-bypassing agent is ongoing. We report non-clinical pharmacology, toxicokinetic and pharmacodynamic studies of VMX-C001. Methods: Dose-ranging and 2-week toxicity studies were conducted in which Sprague–Dawley rats and cynomolgus monkeys received VMX-C001 at various doses for ≤2 weeks. Safety, pharmacologic, toxicokinetic and pharmacodynamic parameters were assessed. The anticoagulation-bypassing ability of VMX-C001 against edoxaban (ex vivo spiking) and rivaroxaban (in vivo) in monkeys was also evaluated. Results: No safety concerns were noted in either species at VMX-C001 doses up to 10 mg/kg; no VMX-C001-related adverse clinical signs were observed. VMX-C001 exhibited approximately dose-proportional kinetics, with no accumulation after repeat dosing. Changes in thrombin-generation parameters in both species were mild and non-adverse. VMX-C001 restored rivaroxaban-induced decreases in thrombin generation toward pre-rivaroxaban levels. In blood samples spiked ex vivo with edoxaban, the ability of VMX-C001 to support thrombin generation was maintained, even after repeat dosing. Conclusions: Treatment with VMX-C001 for 2 weeks was well tolerated at all tested doses. VMX-C001 had an approximately dose-proportional toxicokinetic profile, and accumulation was not observed upon repeat dosing. VMX-C001 also displayed a favourable pharmacodynamic profile and supported thrombin generation in the presence of FXa inhibitors.