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3981 A Phase Ia Study of VGA039, a Protein S-Targeting Monoclonal Antibody, in Individuals with Von Willebrand Disease Demonstrates Concentration-Dependent Increases in Thrombin Generation for Reducing Bleeding

Program: Oral and Poster Abstracts
Session: 323. Disorders of Coagulation, Bleeding, or Fibrinolysis, Excluding Congenital Hemophilias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Bleeding and Clotting, Clinical Research, Diseases, VWD
Monday, December 9, 2024, 6:00 PM-8:00 PM

Carolyn M Millar, MD, PhD1,2*, Priyanka Raheja, MBBS, MD3*, Allison P Wheeler, MD/MSCI4, Shrinath Kshirsagar, MD, MBBS5*, Christian Schoergenhofer, MD, PhD6*, Nicoletta C Machin, DO7,8, Cihan Ay9*, Almudena Tercero, PharmD10*, Hayley Lane10*, Christopher J Horvath, DVM, MS10*, Sandip Panicker, PhD10, Gary Patou, MD10*, Benjamin Kim, MD, MPhil10 and Savita Rangarajan, MD11,12

1Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
2Imperial College Healthcare NHS Trust, London, United Kingdom
3The Royal London Hospital Haemophilia Centre, Barts Health NHS Trust, London, United Kingdom
4Washington Center for Bleeding Disorders, Division of Pediatric Hematology/Oncology & Division of Hematology and Oncology, University of Washington School of Medicine, Seattle, WA
5Advanced Center for Research in Oncology, Hematology and Rare Disorders (ACOHRD), K J Somaiya Medical College and Research Centre, Mumbai, Maharashtra, India
6Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
7Hemophilia Center of Western Pennsylvania, Pittsburgh, PA
8Division of Classical Hematology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
9Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
10Star Therapeutics, Inc., South San Francisco, CA
11University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
12Hematology Laboratory, K J Somaiya Hospital and Research Centre, Mumbai, India

Introduction: 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 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 (Schörgenhofer et al., ISTH 2024).

The objective of this SAD study is to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SC VGA039 in VWD patients.

Methods: This is an open-label phase Ia 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 ≤50 IU/dL, (3) and no laboratory evidence of thrombophilia or prior history of thromboembolism. The starting SC SAD of 3.0 mg/kg was the pre-specified maximum dose tested in HVs and selected as the initial SAD to be tested in individuals with VWD. Continued dose escalations in subsequent cohorts were determined based on emerging D-dimer levels, with a dose limiting toxicity (DLT) threshold set at 4 times the upper limit of normal.

Results: As of August 1, 2024, a total of 6 subjects equally divided into 2 SAD cohorts (3.0 and 4.5 mg/kg) have been dosed: 1 with Type 1 VWD + mild hemophilia A, 1 with Type 2A VWD, 2 with Type 2M VWD, and 2 with Type 3 VWD. Related to VGA039, there were no adverse events, changes in coagulation laboratory parameters, thromboembolic events, DLTs, or injection-site reactions that have been reported. While mild increases in D-dimer levels were observed in healthy volunteers at 3.0 mg/kg, no significant D-dimer elevations have been observed in VWD subjects at either 3.0 or 4.5 mg/kg. Preliminary thrombin generation results show increased thrombin generation at similar VGA039 concentrations in VWD subjects as in HVs. Additional clinical, PK, and PD data for these and subsequent SAD cohort(s) will be presented at the meeting.

Conclusions: Clinical data suggest VGA039 is well tolerated and can increase thrombin generation in the absence of clinically significant D-dimer elevations in individuals with VWD. Drug concentration data continue to support the potential for weekly or less frequent SC prophylactic dosing. Further SAD evaluation of VGA039 in VWD patients is ongoing, and future multi-dose and surgical prophylaxis investigation is planned.

Disclosures: Millar: Vega Therapeutics, Inc.: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Grifols: Research Funding; LFB: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Leo Pharma: Speakers Bureau; Novo Nordisk: Speakers Bureau. Raheja: BioMarin: Consultancy, Honoraria; Sobi: Consultancy, Honoraria, Research Funding; Idogen: Consultancy, Honoraria; Takeda: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sigilon: Consultancy, Honoraria. Wheeler: Takeda Pharmaceuticals: Honoraria; Sanofi-Aventis: Honoraria; Pfizer Inc: Honoraria; HEMA Biologics: Honoraria; Genentech: Honoraria; CSL Behring: Honoraria; Bayer: Honoraria; Octapharma: Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria; UniQure: Honoraria; Vega Therapeutics, Inc.: Honoraria. Kshirsagar: ApcinteX Ltd: Honoraria; Vega Therapeutics, Inc.: Consultancy, Honoraria. Schoergenhofer: Vega Therapeutics, Inc.: Honoraria, Research Funding. Machin: Sanofi: Honoraria; Takeda: Research Funding. Ay: BMS, Pfizer, Daiichi-Sankyo, Bayer, Sanofi, Novo Nordisk, CSL Behring, Sobi, Roche: Honoraria, Speakers Bureau. Tercero: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Lane: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Horvath: Star Therapeutics, Inc.: Current Employment. Panicker: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Patou: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Kim: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Rangarajan: Star Therapeutics, Inc.: Consultancy; Reliance Life Sciences: Consultancy.

*signifies non-member of ASH