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
Authors: Millar Carolyn M , Raheja Priyanka , Wheeler Allison P , Kshirsagar Shrinath , Schoergenhofer Christian , Machin Nicoletta C , Ay Cihan , Tercero Almudena , Lane Hayley , Horvath Christopher J , Panicker Sandip , Patou Gary , Kim Benjamin , Rangarajan Savita 
Published: December 2024

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.