PB1311 - Prophylactic Efficacy Of VGA039, An Anti-Protein S Monoclonal Antibody, In A Novel Non-Human Primate Model Of Acquired Von Willebrand Disease

Tuesday, June 27, 2023

18:30 – 19:30 ET

Room: Exhibition

Co-Author(s)

IH

Ian Huck

Senior Scientist
Vega Therapeutics
South San Francisco, California, United States

Co-Author(s)

LL

Lilley Leong

Principal Scientist
Vega Therapeutics
South San Francisco, California, United States
TB

Tony Byun

Director
Vega Therapeutics
South San Francisco, California, United States

Presenting Author(s)

Benjamin Kim, MD, MPhil

VP, Clinical Development
Vega Therapeutics
South San Francisco, California, United States

Co-Author(s)

AH

Alina He

Associate Scientist
Vega Therapeutics
South San Francisco, California, United States
JC

Joanne Chan

Associate Scientist
Vega Therapeutics
South San Francisco, California, United States
YC

Young Choe

Senior Scientist
Vega Therapeutics
South San Francisco, California, United States
CH

Christopher J. Horvath

SVP, Preclinical Development
Vega Therapeutics
South San Francisco, California, United States
SM

Stephen J. Moore

Senior Director
Vega Therapeutics
South San Francisco, California, United States

Co-Author(s)

Sandip Panicker, PhD (he/him/his)

Chief Scientific Officer
Vega Therapeutics
South San Francisco, California, United States

Co-Author(s)

GP

Graham Parry

Background: VGA039 is a pro-hemostatic monoclonal antibody targeting Protein S (PS) being evaluated to potentially treat von Willebrand Disease (VWD). VGA039 attenuates PS cofactor activity directed towards Tissue Factor Pathway Inhibitor alpha (TFPIα) and activated Protein C (aPC) and augments and restores thrombin generation (TG) during initiation and propagation of coagulation. VGA039 binds only human and non-human primate (NHP) PS. Therefore, its efficacy cannot be assessed in any existing animal models of VWD.

Aims: The present study aimed to develop a NHP model of acquired VWD and use this model 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 depletes and binds the A1 domain of VWF, inhibiting its interactions with platelet GPIb/IX/V (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, TG, and hematology and coagulation parameters. VGA039 efficacy was evaluated 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 TG, prolonged aPTT, 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).

Conclusion(s): 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.