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Presentation Details
| First-in-Human Investigation of HMB-002: A Subcutaneous Antibody for Prophylactic Management of Von Willebrand Disease Priyanka Raheja1, Amy Knott2, Ulrike Lorch3, Henrik Ostergaard4, Catherine Rea4. 1Department of Hematology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.2Bristol Haematology Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.3Richmond Pharmacology, London, United Kingdom.4Hemab Therapeutics, Cambridge, MA, USA |
Abstract
Background: Von Willebrand disease (VWD) results from quantitative or qualitative defects in von Willebrand factor (VWF), a protein which is essential for both primary (platelet adhesion) and secondary (factor VIII stabilization) hemostasis. VWF deficiency results in recurrent hemorrhagic events across severity levels, with episodes requiring appropriate therapeutic management including intravenous replacement therapy with VWF/FVIII. HMB-002 is a monovalent antibody that aims to offer convenient subcutaneous prophylaxis for people with various subtypes of VWD by binding to and elevating levels of endogenous circulating VWF, thereby also increasing FVIII. Here, we present interim results from a first-in-human study of HMB-002 in VWD. Methods: VELORA Pioneer (NCT06754852) is an ongoing Phase 1/2, open-label, dose-escalation study evaluating HMB-002 in adults aged 18-65 years with VWD (baseline VWF activity ≤40 IU/dL, FVIII ≤70 IU/dL). The study consists of Part A (single ascending dose) and Part B (multiple dose assessment). Part A evaluates safety, tolerability, pharmacokinetics, and pharmacodynamics of HMB-002. Results: Six participants with Type 1 VWD were enrolled in cohort A1 (n=3) or cohort A2 (n=3), receiving a single 20 mg or 50 mg subcutaneous dose of HMB-002, respectively. HMB-002 demonstrated a favorable safety profile with no reported treatment-emergent adverse events, no injection site or hypersensitivity reactions, no changes in D-dimer levels or inflammatory markers, and negative antidrug antibody (ADA) testing at all timepoints. Pharmacokinetic analysis showed dose-dependent increases in HMB-002 plasma concentrations and prolonged exposure with subcutaneous dosing. Pharmacodynamic response was evident as a dose-dependent accumulation of VWF and FVIII. In cohort A2 (50 mg), >1.5-fold elevation VWF and FVIII was achieved and maintained for at least 8-10 days. In parallel, restoration of thrombin generation to the normal range and shortening of the APTT were observed. The multimer distribution remained stable in both cohorts, with updated profiling to be presented. Conclusions: This first-in-human study demonstrates that HMB-002 is well-tolerated and produces dose-dependent increases in VWF and FVIII levels with sustained duration. These preliminary results support continued dose escalation to explore increased accumulation and duration of PD response with higher doses of HMB-002. Pharmacodynamic and pharmacokinetic data confirm proof of mechanism and support infrequent dosing, validating HMB-002’s novel mechanism and potential as a subcutaneous prophylactic therapy targeting the underlying pathology of VWD rather than episodic treatment. The VELORA Pioneer study continues enrollment and dose escalation in Part A, supporting development of HMB-002 as a prophylactic therapy for VWD.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.