Enhancing Coagulation: The Development and Efficacy of VGA039, a Universal Hemostatic Agent

A monoclonal antibody, identified as VGA039, was developed through immunization targeting human Protein S (ProS). It was chosen based on its cross-reactivity with human and non-human primate (NHP) ProS and its ability to counteract the anticoagulant effects of activated protein C (aPC) and tissue factor pathway inhibitor alpha (TFPIα). VGA039 was found to bind specifically to human and NHP ProS, excluding other species such as porcine, canine, or rodent ProS. In vitro studies using thrombin generation assays (TGA) showed that VGA039 significantly boosted thrombin generation in aPC-treated normal human and NHP plasma, with an effective concentration (EC50) of approximately 10 μg/mL. This enhancement was also observed in human plasma with added recombinant human TFPIα (rTFPIα), where VGA039 increased thrombin generation in a concentration-dependent manner.
The compound's efficacy in restoring thrombin generation and clot formation in various bleeding disorders was tested using TGA and microfluidics assays with either congenital factor-deficient patient plasma or normal blood treated to simulate specific factor deficiencies. VGA039 increased thrombin generation in a concentration-dependent manner in plasma deficient in von Willebrand factor (vWF), factor VII, VIII, IX, XI, and XIII, but not in deficiencies of factors X or V. Additionally, it promoted fibrin deposition in a microfluidics chamber with normal blood and a neutralizing anti-FVIII antibody. These findings suggest that VGA039 could compensate for missing coagulation factors, improving coagulation.
In vivo studies revealed that VGA039, when administered intravenously or subcutaneously, demonstrated dose-proportional exposure without target-mediated drug disposition. The compound had a relatively long half-life of 21 days when given intravenously and 12 days when administered subcutaneously at a dose of 1 mg/kg, with dose-dependent accumulation observed upon repeated dosing. Ex vivo pharmacodynamic assessments indicated a concentration-dependent increase in thrombin generation within the range of 10 μg/mL to 100 μg/mL plasma concentration of VGA039. Consistent with these findings, VGA039 also increased plasma D-dimer concentrations in a dose- and concentration-dependent manner. After single-dose administration of VGA039, plasma D-dimer levels were higher than control values when plasma concentrations reached or exceeded 10 μg/mL, with peak levels averaging around 2 μg/mL before returning to pre-dose levels following clearance of VGA039. This indicates that VGA039 is bioavailable when administered subcutaneously and can stimulate thrombin generation in vivo.
In conclusion, VGA039 is a novel pro-hemostatic monoclonal antibody that inhibits the cofactor activity of ProS. Given its mechanism of action, subcutaneous bioavailability, and extended half-life, VGA039 holds promise as a universal pro-hemostatic agent that could simplify the treatment regimen for patients undergoing factor replacement therapy. The study also highlighted that ProS, a critical negative regulator in the coagulation cascade, can be targeted to treat bleeding disorders. VGA039, by inhibiting ProS's cofactor activity for TFPIα and aPC, enhances thrombin generation at both the initiation and propagation phases of coagulation. Current treatments for congenital factor deficiencies are limited by the need for frequent factor replacement, which is burdensome and compliance is often low. VGA039, as a universally applicable hemostatic agent with subcutaneous bioavailability, could offer a significant reduction in treatment burden for conditions like von Willebrand Disease (vWD). The study's objectives were to delineate the molecular pharmacology of VGA039 and to assess its pharmacokinetic and pharmacodynamic profile in non-human primates.