Preclinical Safety of Baxter's Recombinant Factor VIIa

Abstract 1417

Baxter has developed a recombinant FVIIa (rFVIIa) product for the treatment of patients with hemophilia A and hemophilia B with inhibitors. Baxter's new rFVIIa is produced by a genetically engineered Chinese hamster ovary (CHO) cell line in a cell culture medium free from any animal or human proteins. The objective of this preclinical study-program was to evaluate the safety of Baxter's rFVIIa in different species.

To assess the anaphylactoid and thrombogenic potential of rFVIIa and its effects on blood pressure, cardiac and respiratory function, and the coagulation system the preclinical program included studies in established models of safety pharmacology in telemetered cynomolgus monkeys, rabbits, normal and spontaneously hypertensive rats, and guinea pigs. Furthermore, studies on single and repeated dose toxicity (hemophilia A mouse, rat, cynomolgus monkey), local tolerance (rabbit), and comparative immunogenicity (mouse) were conducted. Commercially available licensed rFVIIa served as active reference item.

Treatment with rFVIIa did not result in any anaphylactoid reaction, and had no adverse effect on the cardiovascular or respiratory system or on hematology parameters. Thrombogenicity studies showed no greater thrombogenic potential of Baxter's rFVIIa than the commercially available rFVIIa product. Single dose toxicity studies in mice, and repeated administration of Baxter's rFVIIa in rats and cynomolgus monkeys, administered at doses of 2.7 mg/kg, confirmed the safety of the new product. As expected, due to the pharmacological action of rFVIIa, high doses of either recombinant FVIIa product resulted in exaggerated pharmacological effects leading to thrombus formation in some organs, which are well- known effects for this class of compound. Furthermore, Baxter's rFVIIa was well tolerated at the injection site after intravenous injection. Results obtained in comparative immunogenicity studies demonstrate that Baxter's new rFVIIa and the commercially available rFVIIa product have a similar immunogenicity profile.

In summary, Baxter's rFVIIa has a safety profile that supports the evidence necessary for proceeding with human trials.