Subcutaneous, every-four-week maintenance dosing of a novel protein S antibody is well-tolerated and substantially reduces bleeding rates: Results from A phase 1/2 multidose study of VGA039 in patients with von Willebrand disease

Abstract Introduction: Patients with von Willebrand Disease (VWD) experience frequent, prolonged bleeding of variable types and severity. Recurrent and severe bleeds are often treated with therapies that are associated with side effects or require frequent intravenous infusions of factor concentrate, resulting in suboptimal bleed protection and high treatment burden. VGA039 is a fully human, IgG4 monoclonal antibody that inhibits the cofactor activity of Protein S to enhance both primary and secondary hemostasis by promoting thrombin generation. In a single-ascending-dose study, VGA039 showed marked reductions in bleeding rates associated with VGA039 concentrations ≥25 µg/mL. The aim of this study was to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of multiple administrations of subcutaneous (SC) VGA039 in patients with VWD. Materials and Methods: This open-label, phase 1/2 study (NCT05776069; VIVID-3) was conducted in adolescents and adults with VWD. Key eligibility criteria included: (1) symptomatic VWD of any type or subtype, (2) baseline FVIII activity at or below the lower limit of normal, (3) and no laboratory evidence of thrombophilia or prior history of thromboembolism. Dosage regimens for each cohort were determined in conjunction with an independent Data Monitoring Committee. Patients received scheduled doses of SC VGA039 over 120 days, followed by a follow-up period up to 42 days during which patients had the option to transition to an open-label extension study. Safety, pharmacokinetic, and pharmacodynamic parameters were collected at regular intervals, and participants recorded information on bleeding and treatments in a weekly diary. Results: As of July 31, 2025, 11 patients aged 15-53 years with various VWD types/subtypes, including types 1, 2A, 2M, or 3, participated in the study and received a treatment regimen consisting of a single SC loading dose on Day 1, followed by 5 SC maintenance doses starting on Day 8 and continuing every 4 weeks (Q4W) thereafter through Day 120. Six patients in Cohort MD-1 received a flat dose level of 225 mg SC VGA039. Five patients in Cohort MD-2 received weight-banded dose regimen of 187.5 mg (45-<60 kg), 262.5 mg (60-100 kg), or 450 mg (>100 kg) SC VGA039. As of July 31, 2025, there have been no drug-related AEs except for 2 events of headache in 1 patient, no thromboembolic events, and no injection site reactions reported. No clinically significant elevations in D-dimer levels were observed. One patient has completed the study as of July 31, 2025. This patient was on VWF-containing concentrate prophylaxis and still had a pre-study historical annualized bleeding rate of 56.8. Prior to study start, prophylaxis was discontinued and washed out. VGA039 concentrations were maintained within target concentrations and associated with a substantial (74%) reduction in bleeding over 148 days compared to prior prophylaxis, with unremarkable D-dimer levels throughout the study. During the follow-up period, the subject elected to directly transition into the open-label extension study to continue VGA039 treatment. Beyond this first patient, preliminary efficacy and safety data in other patients in this cohort show similar reductions in bleeding without meaningful changes in D-dimer levels. Updated safety, bleeding rates, and pharmacokinetics for all patients in both cohorts will be presented at the meeting. Conclusions: VGA039 was safe and well tolerated over multiple doses in Type 1, 2, and 3 VWD subjects weighing 45-160.5 kg. Preliminary findings suggest substantial reductions in bleeding rates following a single SC loading dose and every-four-week maintenance dosing schedule in patients reporting high historical bleed rates prior to entering the study. These data inform selection of a dosage regimen optimized for durable bleed control with a favorable safety profile for assessment in a Phase 3 trial of VGA039 as every-4-week subcutaneous prophylaxis for patients with VWD of all types.