Presentation Details
| HMB-001 for Prophylactic Treatment of Glanzmann Thrombasthenia: Phase 1/2 Trial Insights Suthesh Sivapalaratnam1, 2, Gillian Lowe3, Ashley Gosnell4, Ulrike Lorch5, Jigar Amin4, Catherine Rea4. 1Queen Mary University of London, London, United Kingdom.2Barts Health NHS Trust, London, United Kingdom.3Comprehensive Care Haemophilia Centre, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom.4Hemab Therapeutics, Cambridge, MA, USA.5Richmond Pharmacology, London, United Kingdom |
Abstract
Background: Glanzmann Thrombasthenia (GT) is a rare and severe bleeding disorder caused by a deficiency of integrin αIIbβ3, a platelet receptor essential for platelet aggregation. People with GT experience debilitating and sometimes life-threatening bleeding episodes. Approximately 50% of people with GT report 1 bleed per day, and 13% report over 500 bleeds per year. The results of frequent bleeding are both psychosocial, with affected individuals frequently missing school and work, and physical because of iron deficiency and structural abnormalities as a consequence of bleeding. HMB-001 is a novel bispecific antibody being developed by Hemab Therapeutics to prevent and reduce the frequency of bleeding episodes in patients with GT. HMB-001 is designed to restore hemostasis through a mechanism mimicking that of recombinant FVIIa (rFVIIa); however, it relies exclusively on the proteolytic activity of endogenous FVIIa. One arm of HMB-001 binds to and accumulates endogenous activated coagulation factor VII (FVIIa) and its zymogen form (FVII) [collectively referred to as total FVII(a), while the second arm binds to the TREM-like transcript 1 receptor (TLT-1) on activated platelets. TLT-1 receptor is absent on the surface of resting platelets and is redistributed to the surface from alpha granules upon platelet aggregation. The combined effect of FVIIa accumulation and targeting to the surface of activated platelets via HMB-001 brings the activity of FVIIa to levels that are considered therapeutically effective based on clinical experience with rFVIIa. The Phase 1/2 clinical study aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of HMB-001 in individuals with GT. Study Design and Methods: The ongoing Phase 1/2 study is composed of three parts: Part A (single ascending dose), Part B (multiple ascending dose), and Part C (extended dosing). The study includes male and female participants aged 18 to 65 years old who have a molecular diagnosis of GT. Results: Participants included in Part A of the study received HMB-001 subcutaneously at dose levels of 0.2 mg/kg, 0.5 mg/kg, or 1.25 mg/kg, respectively. An analysis of seven participants’ screening hemoglobin (Hb) and ferritin levels revealed that all had ferritin levels that were consistently low (<30 mcg/L), indicating iron deficiency. There were no reported treatment-related adverse events at the time of the abstract submission. Pharmacodynamic data showed positive proof of mechanism with a dose-dependent accumulation of endogenous FVIIa and total FVII(a) as well as signs of coagulation activation based on a dose-dependent reduction in prothrombin time. The pharmacokinetic profile indicates a dose-dependent response and is supportive of infrequent, subcutaneous dosing. Further safety, tolerability, pharmacodynamics, and pharmacokinetics details will be summarized. Conclusions: Understanding the implications of iron deficiency anemia in GT and its potential influence on treatment outcomes is crucial for tailored patient care and the advancement of effective interventions. The initial safety, tolerability, pharmacodynamics, and pharmacokinetics results from Part A of the Phase 1/2 study are encouraging and support the further development of HMB-001 as a potential prophylactic treatment for GT.
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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.