Non-Thrombogenic Properties of Chimeric FVIIa

PROJECT SUMMARY ABSTRACT Chimera BioTechnology Inc is a privately held startup biopharmaceutical company The co founders have worked together for over 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 EGF 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 of its in hospital use in 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 PROJECT NARRATIVE The long term objective of the current project is to obtain regulatory approvals for the commercialization of a safe and effective product for use in the treatment of bleeding events in non hemophiliac patients e g intracranial hemorrhage that are often times not controllable by surgical intervention or other methods intended to stop bleeding Specifically Chimera BioTechnology is developing a novel recombinant procoagulant agent that is thought to have a substantially reduced thrombogenic potential such that it can be safely administered at higher dosages and in a more timely manner than NovoSeven the current procoagulant agent that is used off label with an associated risk of causing life threatening thrombosis A procoagulant agent with an increased margin of safety such as that under development by Chimera BioTechnology is hypothesized to safely and effectively aid in the treatment of otherwise uncontrollable bleeding events in certain non hemophiliac patient populations for which the company will conduct randomized clinical trials in order to obtain approved market indications for the product