Pharmacologic treatment of thromboembolism

DESCRIPTION (provided by applicant): Thromboembolic disorders are major causes of morbidity and mortality in the Western societies. Anticoagulants are pivotal agents in the prevention and treatment of arterial and venous thrombosis. The limitations of currently approved anticoagulant drugs have prompted the search for new anticoagulants with better pharmacological profiles. EVAS Therapeutics, LLC has developed a series of recombinant fusion proteins, termed ANV-KPIs . These proteins possess the ability to target themselves to sites of thrombogenesis and exert powerful inhibition of coagulation enzyme/cofactor complexes on the membrane surfaces of thrombogenic cells without inducing a prolonged systemic anticoagulation, and thereby can potentially achieve a long-lasting antithrombotic effect with reduced risks for bleeding. We have selected the most potent molecule of the series, TAP-ANV, for further development. The specific aims of this phase I proposal are: 1) Production of recombinant TAP-ANV by a simplified, improved process. We will use an improved fermentation method and a streamlined purification process to achieve production of gt100 mg of high quality recombinant TAP-ANV per run; 2) Dissection of the antithrombotic effect vs. bleeding tendency of TAP-ANV in mouse in vivo. The temporal relationship among the antithrombotic effect, tail vein bleeding time, and plasma levels of TAP-ANV will be determined to demonstrate that TAP-ANV can achieve thrombogenic site- directed antithrombotic effect by bolus injection without prolonged systemic hypocoagulation and bleeding; and 3) Assess PK/PD and effects of TAP-ANV on in vivo thrombosis in rabbits. We will obtain PK/PD parameters of TAP-ANV in rabbit, and determine whether they have superior efficacies compared to conventional anticoagulants in rabbit thrombosis models that simulate acute plaque rupture or surgical trauma to arteries and veins. The phase I studies will allow us to develop a scale-up process amendable for production of GLP materials, which are needed for safety/toxicity and clinical studies in the next stages of development. In addition, the antithrombotic effect vs. bleeding tendency of TAP-ANV in mice, the PK/PD parameters of TAP- ANV, and the therapeutic effect of TAP-ANV in rabbit arterial and venous thrombosis models will be determined. Based on positive data from these Phase I studies, we will propose a series of studies to obtain a more complete preclinical data package for IND filing in our Phase II application. PUBLIC HEALTH RELEVANCE: Thromboembolic disorders are major causes of morbidity and mortality in the world. This project will conduct pre-clinical studies of a novel anticoagulant protein for the experimental treatment of arterial and venous thrombosis.