The goal of this project is to develop a therapeutic capable of treating heparin-induced thrombocytopenia (HIT) and HIT with thrombosis (HITT). HIT and HITT are acquired life-threatening thrombocytopenic and thrombotic complications that occur in patients exposed to unfractionated heparin (UFH) or low molecular weight heparin (LMWH): the most widely used anticoagulants in the world. Approximately 12 million patients are exposed to UFH and LMWH annually in the US alone with ~24,000 developing HIT and HITT every year. The syndromes are caused by autoantibody production against the complex of heparin and platelet factor 4, which results in aberrant platelet activation and aggregation leading to platelet-derived microparticle release, increased thrombin generation and can ultimately lead to catastrophic arterial and venous thrombosis: venous limb gangrene, deep venous thrombosis, pulmonary embolism. Current treatment of HITT includes immediate discontinuation of all heparin products and initiation of argatroban (a direct thrombin inhibitor), but this carries a significant risk of severe bleeding and both mortality and amputation rates remain unacceptably high (~12% mortality rate and ~10% amputation rate). Recent evidence has established that the enzyme 12-lipoxygenase (12-LOX), and its metabolic product, 12-hydroxyeicosatetraenoic acid (12-HETE) are key contributors to the underlying pathology of HITT including platelet reactivity, thrombus formation/stability as well as vessel occlusion. VERALOX?s lead compound, VLX-1005, selectively inhibits 12-LOX, halts aberrant platelet activation and thrombosis and has shown efficacy in numerous animal models including mesenteric arteriole injury and laser-induced cremaster arteriole thrombosis. Importantly, in animal models, VLX-1005 does not impair normal clotting functions. This profile significantly lowers the risk of potentially deadly bleeding complications, which are common detrimental side-effects of argatroban, the only US FDA approved treatment for HITT. In this project, we will accomplish the following aims:
Aim 1. 1: Determine PK parameters (Cmax, Tmax, T1/2, %F, CL and AUC) and dose linearity in rats.
Aim 1. 2: Single ascending dose MTD in rats.
Aim 1. 3: 7-day repeat dose toxicity/toxicokinetic (TK) studies in rats.
Aim 2 : Determine efficacy of VLX-1005 in a murine model of HITT and duration of therapeutic effect.
/Public Health Relevance Statement: The goal of this project is to develop a novel therapeutic for patients suffering from heparin- induced thrombocytopenia and thrombosis (HITT). This syndrome arises from an auto-immune response to heparin and can result in severe complications including deep vein thrombosis, limb amputation and death. We 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.
