IMPROVED SURGICAL ANTICOAGULATION USING A HCII AGONIST

DESCRIPTION: (Investigator's abstract) Thrombin bound to fibrin, the vessel wall and/or to extracorporeal surfaces is resistant to inhibition by heparin/antithrombin Ill (HAT). Intimatan, a dermatan disulfate semi-synthetically enriched in iduronic acid-N-acetyt-O-gafactosamine 4,6-O-disulfate, mediates the sustained inhibition of surface-bound thrbmbin. Intimatan, a potent heparin cofactor II (HCII) agonist, targets HCII to the same exosite of thrombini targeted by hirudin but not by RAT. In the pig model of cardiopulmonary bypass surgery (CPB), Intimatan, relative to heparin, maintained extra-corporeal patency at a 10-fold lower anti-thrombin dose, generated a 4-fold lower activated clotting time (ACT) and reduced bleeding 2-fold without anticoagulant neutralization. Presently unknown is whether Intimatan interacts with heparin-induced thrombocytopenia (HIT) antibody or its hemorrhagic effect relative to danaparoid and hirudin. These anticoagulants, although approved for HIT, are neither optimally safe or effective in CPB and this patient population most often develops heparin antibody. The specific aims of the Phase I STTR are to determine (relative to the anticoagulants currently approved for HIT): (1) the HIT cross-reactivity of Intimatan and its potential to ameliorate heparin/heparin antibody platelet activation; (2) its antithrombotic potency and (3) its hemorrhagic effects. It is anticipated that these studies will further the development of Intimatan for CPB based on a superior therapeutic profile and mechanism of action. PROPOSED COMMERCIAL APPLICATION: The composition of matter and use claims of intimatan as an inhibitor of thrombin generation and complement activation issued in 1999 in U.S. Patent 5,922,690. The differentiated mechanism of action of Intimatan provides a competitive advantage over existing modalities for the prevention/treatment of a wide vista of thrombo-embolic disorders in terms of lower manufacturing cost, enhanced anticoagulation efficacy against pathologic thrombosis and in device/procedure settings (CPB, dialysis, angioplasty, stents, cardiac assist devices), lower dosages, less bleeding, use in HIT patients and amelioration of hypercoagulability in HIT. Its value as a radiopharmaceutical for medical imaging of vascular diseases (including treatment of cancer) having a thrombin component is also realized.