Development of a 12-LOX inhibitor for heparin induced thrombocytopenia and thrombosis

The goal of this project is to develop a therapeutic capable of treating heparin induced thrombocytopeniaHITand HIT with thrombosisHITTHIT and HITT are acquired life threatening thrombocytopenic and thrombotic complications that occur in patients exposed to unfractionated heparinUFHor low molecular weight heparinLMWHthe most widely used anticoagulants in the worldApproximatelymillion patients are exposed to UFH and LMWH annually in the US alone withdeveloping HIT and HITT every yearThe syndromes are caused by autoantibody production against the complex of heparin and platelet factorwhich results in aberrant platelet activation and aggregation leading to platelet derived microparticle releaseincreased thrombin generation and can ultimately lead to catastrophic arterial and venous thrombosisvenous limb gangrenedeep venous thrombosispulmonary embolismCurrent treatment of HITT includes immediate discontinuation of all heparin products and initiation of argatrobana direct thrombin inhibitorbut this carries a significant risk of severe bleeding and both mortality and amputation rates remain unacceptably highmortality rate andamputation rateRecent evidence has established that the enzymelipoxygenaseLOXand its metabolic producthydroxyeicosatetraenoic acidHETEare key contributors to the underlying pathology of HITT including platelet reactivitythrombus formation stability as well as vessel occlusionVERALOX s lead compoundVLXselectively inhibitsLOXhalts aberrant platelet activation and thrombosis and has shown efficacy in numerous animal models including mesenteric arteriole injury and laser induced cremaster arteriole thrombosisImportantlyin animal modelsVLXdoes not impair normal clotting functionsThis profile significantly lowers the risk of potentially deadly bleeding complicationswhich are common detrimental side effects of argatrobanthe only US FDA approved treatment for HITTIn this projectwe will accomplish the following aimsAimDetermine PK parametersCmaxTmaxTFCL and AUCand dose linearity in ratsAimSingle ascending dose MTD in ratsAimday repeat dose toxicity toxicokineticTKstudies in ratsAimDetermine efficacy of VLXin a murine model of HITT and duration of therapeutic effect Project Narrative Public Health Relevance StatementThe goal of this project is to develop a novel therapeutic for patients suffering from heparininduced thrombocytopenia and thrombosisHITTThis syndrome arises from an auto immune response to heparin and can result in severe complications including deep vein thrombosislimb amputation and deathWe have identified a clinical candidate that has a promising DMPK profile and has shown good in vivo efficacy in models of HITT and we will continue development towards IND enabling studies and ultimately first in human clinical trials