Preclinical Efficacy Testing of Baxter's Recombinant FVIIa

Abstract 4659

Baxter has developed a recombinant FVIIa (rFVIIa) product for the treatment of patients with hemophilia A and hemophilia B with inhibitors. The aim of the presented preclinical studies was to evaluate the efficacy of Baxter's rFVIIa. Four animal models that are considered to relevantly reflect the conditions in different patient populations were used: hemophilia A (FVIII ko) mice, hemophilia B (FIX ko) mice, factor VIII (FVIII)-inhibited rabbits and warfarin-pretreated rats.

In all studies, Baxter's rFVIIa was tested at different doses to obtain dose-effect curves. A commercially available rFVIIa served as the active control item, buffer served as the negative control item. All test and control items were administered intravenously. Mice received prophylactic treatment 5 minutes prior to start of the experiment, rabbits and rats received therapeutic treatment after the injuries were inflicted.

Twenty FVIII ko mice (B6;129S4-F8^tm1Kaz; 10m/10f) and 20 FIX ko mice (B6;129P2-F9^tm1Dws; 10m/10f) per group were used in a tail-tip bleeding model. Baxter's rFVIIa was tested at doses of 0.6, 1.2 and 2.7 mg/kg, the active control item was tested at a dose of 2.7 mg/kg.

Ten FVIII ko mice (B6;129S4-F8^tm1Kaz; 5m/5f) per group were used to assess the influence of rFVIIa on the thrombelastogram of hemophilic mice. Both items were tested at doses of 0.1, 0.6 and 1.2 mg/kg.

Six rabbits (New Zealand White; 6m) per group were used in a nail-cut model. The animals were pretreated with a goat polyclonal FVIII-antibody (34,000 BU/kg i.v., 45 minutes prior to start of the experiment), leading to deficiency of endogenous FVIII. Baxter's new rFVIIa was tested at doses of 0.1, 1.0, 2.0, 2.5 and 3.0 mg/kg, the active control item at 2.0 mg/kg.

Six rats (Sprague Dawley; 6m) per group were used in a tail-tip bleeding model. The animals were pretreated with warfarin (11 mg p.o., 1 day prior to start of the experiment), leading to a deficiency of vitamin K-dependent coagulation factors II, VII, IX and X, protein C and protein S. Baxter's new rFVIIa was tested at 0.25, 1.0 and 2.0 mg/kg, the active control item at 2.0 mg/kg.

A dose-dependent hemostatic effect of Baxter's new rFVIIa could be shown in all primary pharmacodynamic studies performed. Furthermore, statistical evaluation of the efficacy of Baxter's new rFVIIa did not reveal any statistically significant differences from the commercially available rFVIIa product after treatment at the same doses. In summary, the results of our studies show that Baxter's new rFVIIa is prophylactically and therapeutically effective in animal models of efficacy closely reflecting the conditions in hemophiliacs with inhibitors and patients suffering from FVII-deficiency.