Presentation Details
| Prophylactic Treatment of Acquired Von Willebrand Disease in Non-Human Primates with VGA039, An Anti-Protein S Monoclonal Antibody Benjamin Kim, Ian Huck, Lilley Leong, Tony Byun, Aline He, Abel Silva, Joanne Chan, Young Cho, Stephen J.Moore, Graham Parry, Sandip Panicker. Vega Therapeutics, Inc., South San Francisco, CA, USA |
Abstract
Background: VGA039, a pro-hemostatic monoclonal antibody targeting Protein S (PS), is being evaluated to treat von Willebrand Disease (VWD). VWD is the most common inherited blood disorder and can be associated with significant disease burden. Current VWD treatments have limitations in effectiveness and are burdensome; thus, there is a need for new therapeutic options. VGA039 attenuates PS cofactor activity for Tissue Factor Pathway Inhibitor alpha (TFPIα) and activated Protein C (aPC) and augments and restores thrombin generation (TG) during the initiation and propagation of coagulation. VGA039 binds only human and non-human primate (NHP) PS, limiting its assessment in existing animal models of VWD. Objectives: The present study aimed to develop a NHP model of acquired VWD to evaluate the efficacy of VGA039. Methods: An acquired VWD model in healthy NHPs (cynomolgus macaques) was developed through coadministration of an anti‑von Willebrand Factor (VWF) nanobody that binds the A1 domain of VWF, inhibiting its interactions with platelet GpIb/IX/V while depleting it from the circulation (subcutaneous 5 mg/kg daily; Days -4 to 3), and a neutralizing anti-Factor VIII (FVIII) monoclonal antibody (mAb) (intravenous 0.1 mg/kg; Day 1). Bleed time was measured for up to 20 minutes following Surgicutt puncture of the labial mucosa. Blood and plasma samples were used to monitor FVIII activity, VWF activity, ex vivo TG, and hematology and coagulation parameters. VGA039 efficacy was evaluated starting 3.5 hours post coadministration of anti‑VWF and anti‑FVIII. Results: Administration of anti‑VWF or anti‑FVIII alone produced minimal and/or inconsistent decreases in hemoglobin and prolongation of bleed time. In contrast, coadministration produced a severe VWD‑like phenotype characterized by VWF and FVIII deficiency, decreased ex vivo TG, prolonged aPTT, D-dimer abrogation, markedly decreased hemoglobin (Figure 1A), and prolonged bleed times (Figure 1B), demonstrating establishment of the model. Prophylactic VGA039 administration reduced the hemoglobin decrease (Figure 2A) and prevented bleed time prolongation (Figure 2B). Conclusions: Efficacy of VGA039 was demonstrated in a novel NHP model of acquired VWD. This proof-of-concept study supports clinical evaluation of VGA039 for the treatment of VWD.
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