Fig. 1: Proposed MoA of HMB-001.

a, αIIbβ3 is a receptor for fibrinogen on platelets. In the case of normal platelets, fibrinogen binding to αIIbβ3 bridges platelets and is a required step for normal platelet aggregation and subsequent formation of a hemostatic plug. In the case of GT, deficiency of αIIbβ3 results in a lack of fibrinogen-mediated bridging of platelets, leading to abnormal platelet function manifesting in a severe bleeding phenotype. Due to the autosomal pattern of inheritance, GT affects both sexes equally. b, HMB-001 is a biAb designed to restore hemostasis through a mechanism mimicking that of rFVIIa but relying exclusively on the proteolytic activity of endogenous FVIIa. One arm of HMB-001 binds to endogenous FVIIa with high affinity. The half-life of HMB-001 is much longer than that of endogenous FVIIa. Therefore, the binding of HMB-001 to circulating FVIIa confers endogenous FVIIa with an extended half-life, resulting in progressive accumulation of plasma FVIIa until a new steady-state level is reached. The second arm of HMB-001 binds to the TLT-1 receptor on activated platelets. In the case of vascular injury, the binding of the anti-TLT-1 arm of HMB-001 to the TLT-1 receptor mediates increased recruitment of FVIIa onto the surface of the activated platelet. Here, HMB-001-delivered FVIIa drives FX activation and consequently enhances local thrombin generation to support the formation of a hemostatic plug. HMB-001 has the potential to offer subcutaneous-based prophylactic treatment, with a low frequency of dosing ranging from once a week to once a month, to prevent bleeds in PwGT and those with other rare bleeding disorders for which rFVIIa has been historically effective.