Chimeric FVIIa

DESCRIPTION provided by applicant In patients with hemophilia intravenous administration of blood coagulation factors e g factor VIII is a safe and effective therapeutic approach for the treatment and prevention of bleeding episodes However up to of the patients receiving factor VIII treatment develop an inhibitory immune response to the administered factor VIII such that subsequent treatment is no longer effective For those inhibitor patients whose immune response cannot be suppressed so called inhibitor by passing agents e g recombinant human factor VIIa rFVIIa are used to treat bleeding episodes To treat a severe bleeding episode with currently available by passing agents requires multiple intravenous doses Development of a by passing agent with longer duration of effect such that fewer injections are required would be a major advance in therapy The goal of the current application is to evaluate a novel bioengineered protein Chimera that consists of functionally important structural domains of blood coagulation factor IX FIX that replace the homologous domains of rFVIIa In preliminary studies the Chimera has been found to be as effective as rFVIIa in treating bleeding in an animal model of hemophilia The Chimera also displays a dramatically reduced thrombotic potential The hypothesis of this application is that the Chimera will have an extended half life of therapeutic effectiveness The FIX structural properties of the Chimera are anticipated to reduce clearance by natural inhibitors This is anticipated to increase the plasma half life Further the FIX structural properties are expected to substantially increase distribution of the protein into the extravascular space where it is anticipated to persist in an active form even after plasma levels have returned to baseline In the current application we propose to utilize readily available commercial technology to manufacture sufficient amounts of the Chimera to rigorously evaluate the structural and functional properties of the protein Well characterized protein will be advanced to in vivo evaluation of the circulating half life and prolonged hemostatic effectiveness in a well established mouse model of bleeding in hemophilia We anticipate that the proposed work will show a significant increase in the circulating half life of the Chimera relative to rFVIIa We also anticipate that hemostasis will be maintained in a bleeding model for even longer than the circulating half life Such results will suggest that it could be plausible for prophylactic dosing with the Chimera to be extended from daily to at most once every second day with the possibility of once weekly dosing while achieving breakthrough bleeding rates comparable to what has been observed with replacement therapy This significant increase in effectiveness would warrant further commercial development of the chimera product under a Phase II SBIR application wherein cell line development would begin in order to produce representative clinical product for evaluation in the dog model of hemophilia This canine model has been documented to correlate well with the clinical effectiveness of hemophilia products in humans PUBLIC HEALTH RELEVANCE The long term objective of the current project is to commercialize a safe and effective product for the treatment and prevention of bleeding episodes in hemophilia patients who have developed an inhibitory immune response to intravenously administered blood coagulation factors Specifically Chimera BioTechnology is developing a novel recombinant coagulation factor product to by pass blood coagulation factor inhibitors that is anticipated to stop bleeding with fewer doses and to persist for longer periods of time post administration than existing commercially available products thereby facilitating prophylactic treatment in children and ameliorating the joint damaging effects of chronic bleeding A more effective longer lasting inhibitor by passing agent with an increased margin of safety such as that under development by Chimera BioTechnology is expected to improve the quality of life for persons suffering from hemophilia while increasing treatment compliance by reducing dosing which will in turn reduce the overall cost of care