Background:
BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor developed as a bypass agent for hemophilia patients with inhibitors. It restores thrombin burst, leading to stable clot formation in hemophilic conditions in vitro and effectively stops bleeding in vivo.
Aims:
Efficacy and thrombogenic potential of BAY 1093884 were evaluated in bleeding models in acquired hemophilia A rabbits and the Wessler venous stasis model, respectively.
Methods:
The efficacy of BAY 1093884 was tested in rabbit bleeding models. Anti-factor VIII antibodies rendered rabbits hemophilic, increasing bleeding time by ~3-fold (median 120–390 seconds) in an ear bleeding model and >7-fold (median 240–1800 seconds) in a saphenous vein bleeding model. In the Wessler model, thrombosis was induced by complete ligation of the jugular vein after administration of BAY 1093884, recombinant FVIIa (rFVIIa), or activated prothrombin complex concentrate (aPCC) to measure in vivo hypercoagulability.
Results:
In both bleeding models, BAY 1093884 corrected bleeding time close to normal in a dose-dependent manner. A statistically significant reduction in saphenous vein bleeding was reached at 1 and 3 mg/kg BAY 1093884, reducing bleeding time to 330 and 240 seconds, respectively. In contrast, 1 mg/kg rFVIIa only slightly reduced bleeding time to a median of 1200 seconds. In the Wessler model, 1 mg/kg rFVIIa and 40 IU/kg aPCC resulted in thrombus formation, reaching full occlusion in rabbits with normal coagulation system. In contrast, BAY 1093884 up to 100 mg/kg did not fully occlude, and only showed a slight increase in localized clot formation over baseline, which could be completely prevented by an anticoagulant. In addition, no stasis-triggered thrombi were seen in hemophilia A rabbits treated with BAY 1093884, indicating reduced thrombogenicity risk for BAY 1093884 in patients with hemophilia.
Conclusions:
These studies showed that BAY 1093884 potently controls bleeding in hemophilic rabbits while showing reduced thrombogenic risk compared with the current standard of care.