Background:
BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor (TFPI) developed as a bypass agent for hemophilia patients with inhibitors. It restores thrombin burst for stable clot formation in hemophilic conditions in vitro.
Aims:
The goal of this study was to elucidate the in vivo prophylactic hemostatic potency of BAY 1093884.
Methods:
The hemophilia A mouse tail vein transection model was used for this study to mimic the venous bleeding characteristics of severe hemophilia. Male hemophilia A mice (n=12/group) were treated prophylactically with escalating doses of BAY 1093884. All treatments were administered as single intravenous (IV) bolus at 4 different time courses prior to injury (1, 3, 5, and 7 days). Bleeding was induced by a 1.2-mm deep incision across the left lateral vein. Following injury, the animals were monitored hourly for moribundity for up to 9 hours and after 24 hours followed by euthanasia.
Results:
Efficacious doses of BAY 1093884 providing 50% protection for survival (ED50) for up to 6 days after IV bolus ranged from 0.6–2 mg/kg. In comparison, only 25% protection was achieved 6 days after the treatment with a very high dose of 1000 IU/kg of recombinant factor VIII (rFVIII). The effect of a single IV dose of 18 mg/kg BAY 1093884 providing 80%–90% survival was maintained over 8 days (ED50 6 mg/kg), whereas a single IV dose of rFVIII failed to provide protection over an 8-day period.
Conclusions:
These studies demonstrate that BAY1093884 prevents bleeding and increases long-term survival to a greater degree than rFVIII in hemophilia A mice and may offer a convenient prophylactic treatment option for hemophilia patients with inhibitors.