Subcutaneous Dosing of CRA-027483, a Small Molecule FVIIa Inhibitor, Prevents Arterial Thrombosis in a Baboon Model.

Vessel injury may expose tissue factor leading to the activation of FVII, initiation of coagulation, and thrombosis. A small reversible inhibitor of FVIIa (CRA-027483), dosed by subcutaneous (SC) injection, was investigated in an arterio-venous shunt thrombosis model in non-anticoagulated awake baboons. Drug pharmacokinetics (PK) and pharmacodynamics (PD) were studied in non-shunted baboons; PK and PD results were closely correlated with ~ 100% bioavailability following SC drug administration. Thrombosis was initiated by interposing within the shunt a segment of porous expanded (poly)tetrafluoroethylene vascular graft (ePTFE, 4mm ID), filled with relipidated tissue factor. Upon initiation of blood flow at 100mL/min (wall shear rate =256/sec) thrombus growth was monitored by gamma camera imaging of autologous Indium-111 labeled platelets for 1 hour. Fibrin accumulation was quantified using trace amounts of homologous fibrinogen labeled with I-125. Both bleeding time and prothrombin time (PT), the PD marker, were monitored throughout. Animals were dosed SC 90min prior to the initiation of thrombus formation, a regimen that was predicted from PK/PD to result in a fixed concentration of CRA-027483 during the thrombosis phase. Dosing of baboons with CRA 027483 at 1mg/kg, 2mg/kg and 4mg/kg SC (4–5 animals in each study group) inhibited total platelet deposition on the tissue factor surface by 13±4%, 43±30% and 67±26% respectively, vs. control results. Fibrin accumulation was reduced by 22±9%, 50±34%, and 76±19% respectively for these doses. PT values remained stable throughout the thrombosis phase and increased 1.3-, 1.6- and 2.1-fold over baseline with the escalating doses. Bleeding time measurements were slightly prolonged at the higher doses (7.3±1.6min and 7.1±2.5min for the 2mg/kg and 4mg/kg doses, respectively) as compared to the pre-drug measurement of 3.8±0.7min. We conclude that SC administration of CRA-027483, a reversible small molecule inhibitor of FVIIa, effectively reduces tissue factor-initiated thrombus formation in baboons with minimal hemostatic impairment.