A Phase 1/2 Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of HMB-001 in Participants with Glanzmann Thrombasthenia

Background & Significance: Glanzmann thrombasthenia (GT) is a rare inherited bleeding disorder characterised by severely impaired platelet aggregation. Variants in ITGA2B and ITGB3 render GPIIb/IIIa (fibrinogen) receptors absent or non-functional on platelets, hindering formation of the platelet-fibrin mesh. Consequently, the inability to form stable clots leads to frequent bleeding episodes ranging from low volume epistaxis to life- threatening gastrointestinal hemorrhages, contributing to iron deficiency anemia and negatively impacting quality of life. The current standard of care for GT is on-demand, with no approved therapies for primary prophylaxis. Limited treatment options create a sense of futility among some people with GT (PwGT), leading to underreporting of bleeding episodes to their healthcare providers and masking the true severity and prevalence of GT. Recent natural history data reveals a higher disease burden in GT than previously recognized with PwGT experiencing a high frequency of bleeds (1.54 bleeds/day), with nearly half requiring medical intervention with tranexamic acid, recombinant Factor VIIa (FVIIa), or platelet transfusions. These findings highlight GT's substantial impact on quality of life, necessitating frequent interventions and underscoring the urgent need for improved management strategies. HMB-001, an investigational bispecific antibody, is being trialed for subcutaneously administered prophylaxis in GT. HMB-001 binds to endogenous FVIIa with one arm, increasing its half-life and accumulation in the bloodstream. The other arm binds to activated platelets via TREM-like transcript 1 (TLT-1) receptor, localising FVIIa on activated platelets. HMB-001's dual mechanism concentrates thrombin generation at the site of platelet activation, fostering the development of a stable fibrin-platelet mesh essential for hemostasis. Hemab is now enrolling participants in the multiple ascending dose part of a Phase 1/2 open-label study (NCT06211634) evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), Annualized Bleed Rate (ABR), and Annualized Treated Bleeding Rate (ATBR) of HMB-001 in PwGT.

Study Design and Methods:

The study consists of 3 parts:

• Part A (completed): open-label, single ascending dose study, and evaluated the safety, tolerability, PK, and PD of HMB-001 in participants with GT. Results from Part A were presented at EAHAD 2024.

• Part B (ongoing): open-label, multiple ascending dose study evaluating the safety, tolerability, PK, PD, and preliminary effects on bleeding of repeat doses of HMB-001.

• Part C: open-label, treatment extension portion of the study. It will be open to participants who have fulfilled the requirements of Part B and are considered eligible to continue by the Investigator. Part C will evaluate longer term safety, and preliminary efficacy of repeat doses of HMB-001 for 9 months.

• Part B/C will be enrolling participants in Belgium, France, Italy, Netherlands, United Kingdom, and United States.

Study Population: Male and female participants aged 18 to 65 years with GT. Phase 2 has an inclusion criterion of approximately 2 bleeding events per week on average of any severity and type, and at least 1 spontaneous or traumatic bleed within the last 12 months requiring prescribed treatment, medical or surgical procedure.

Sivapalaratnam:Hemab Therapeutics: Consultancy, Research Funding. Austin:Hemab Therapeutics: Consultancy, Research Funding. Lorch:Hemab Therapeutics: Research Funding. Goricar:Hemab Therapeutics: Consultancy, Research Funding. Lowe:Hemab Therapeutics: Consultancy, Research Funding; Biomarin: Research Funding; CSL Behring: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Sobi: Honoraria. Gosnell:Hemab Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Gandhi:Hemab Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Vogel:Hemab Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Amin:Hemab Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Law:Hemab Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Sorensen:Hemab Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Rea:Hemab Therapeutics: Current Employment, Current holder of stock options in a privately-held company.