Non-Thrombogenic Properties of Chimeric FVIIa

Chimera Biotechnology, Inc., San Juan Capistrano CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Chimera BioTechnology, Inc. is a privately held startup biopharmaceutical company. The co-founders have worked together for over 35 years and believe that the proposed hemostatic agent; a novel, proprietary rFVIIa analog (designated Chimera) created by replacing the tissue factor (TF) binding Gla- and EGF1-domains of human FVIIa with the corresponding domains of human factor IX, may exhibit the procoagulant activity of NovoSeven (Novo Nordisk), but with substantially reduced thrombogenic potential. NovoSeven is safe and effective in treating bleeding events in FDA/EMA approved indications primarily affecting hemophilia patients. Although NovoSeven is not FDA approved for treating bleeding events in non-hemophiliac patients, 97% of its in-hospital use in 2008 was for unapproved, off-label clinical indications where clear evidence for an increased risk of thromboembolism has been documented. To date, off-label NovoSeven use has not been found to reduce mortality rates when used to treat uncontrolled bleeding after conventional methods have failed. Guidelines are emerging, however, that provide evidence that early intervention with NovoSeven may improve secondary morbidity outcomes that could avert subsequent life-threatening or debilitating events. We believe that the TF-dependent thrombogenicity of NovoSeven is a barrier to its safe and effective use in several clinical settings. The proposed hemostatic agent is intended to address the unmet medical need for a safe and effective agent to supplement conventional methods of controlling severe bleeding in non-hemophiliac patients. The focus of the current proposal is to obtain proof of concept evidence that the Chimera is effective in a clinically relevant animal model; we have chosen a rat intracerebral hemorrhage model that mimics in many ways the human condition where hematoma size and growth are associated with neurological deterioration and death. Positive results in the rat intracerebral hemorrhage model will provide evidence that the Chimera could be effective in treating bleeding events in non-hemophiliac patients. We also propose to obtain evidence that the TF-independent procoagulant activity of the Chimera is substantially less thrombogenic than rFVIIa using well-established rabbit models of thrombosis. Positive results in well-established rabbit models of thrombosis will provide evidence that the Chimera could be a safer alternative to rFVIIa, especially in treating severe, life-threatening bleeding events in non-hemophiliac patients. Evidence of both efficacy and safety in the proposed animal studies will warrant further development of the Chimera agent within the context of a Phase II SBIR application.