HTRS2025.O8C.5 Phase I Study of VGA039 in Individuals with Von Willebrand Disease Demonstrates Sustained Drug Concentrations, Increased Thrombin Generation, and Decreased Bleeding After Single Subcutaneous Injection
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Authors
Wheeler A.P.
Millar C.M.
Raheja P.
Kshirsagar S.
Schorgenhofer C.
Machin N.C.
Chowdary P.
Mason J.
Giermasz A.
Tercero A.
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2025
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Conference Proceedings
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Background: Non-factor replacement therapies have the potential to provide hemostatic balance in various bleeding disorders with less frequent dosing than factor concentrate prophylaxis. Preclinical studies of VGA039, a fully human, IgG4 monoclonal antibody targeting Protein S, have demonstrated its ability to increase thrombin generation across multiple inherited bleeding disorders, including von Willebrand disease (VWD), and prevent blood loss in vivo in a novel, non-human primate (NHP) VWD model. In healthy volunteers (HVs), single ascending doses (SADs) of subcutaneous (SC) VGA039 increase thrombin generation in a dose- and concentration-dependent manner. Objective(s): To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SC VGA039 in patients with VWD. Method(s): This is an open-label phase I study (NCT05776069) conducted in adult individuals with VWD and approved by local ethics committees. Informed consent was obtained. Key eligibility criteria included: (1) symptomatic VWD of any type or subtype, (2) baseline FVIII activity level 4 weeks following a single, SC >=4.5 mg/kg dose (Figs 1 & 2). Two evaluable 4.5 mg/kg subjects with historical annualized bleeding rates (ABRs) >50 had reductions of 75% and 88% after a single dose of VGA039; the third evaluable subject had only 1 bleed post-VGA039. Efficacy for additional 4.5 and 7.0 mg/kg subjects will become evaluable in time for presentation at the meeting. Conclusion(s): VGA039 was safe and well tolerated in this SC SAD study in VWD subjects across all types. ABR reductions at VGA039 concentrations associated with increased thrombin generation, in the absence of DLTs, have been observed. SC multi-dose VGA039 investigation is planned. Formula presented] Formula presented] Copyright © 2025
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Research and Practice in Thrombosis and Haemostasis