In the U.S., as many as 1.2 million Americans suffer heart attacks each year and about 40 percent will die, making heart attack the number one killer of men and women. Moreover, approximately 1.5 million procedures for the heart (angioplasty and heart surgeries) are performed in the U.S. annually. Prolonged ischemia of the heart followed by reperfusion produces myocardial reperfusion injury. A major portion of this injury is due to reperfusion and inflammation of the myocardium and may involve portions of the myocardium which can be salvaged from irreversible injury. Reperfusion injury of the heart following angioplasty procedures and coronary artery bypass graft surgery can affect the length of hospitalization, cost of hospitalization, functional capacity of the patient at discharge, and may ultimately contribute to mortality. Following reperfusion, activation of A1 adenosine receptor (AR)s causes lipid peroxidation of cell membranes, endothelial cell injury, and proinflammatory effects of neutrophils to produce myocardial injury characterized by tissue edema, hemorrhage, inflammation, and reduced contractility. Blockade of A1ARs specifically during reperfusion attenuates the inflammatory response in reperfusion injury of the heart, and thereby increases salvage of myocardium at risk of irreversible injury. Endacea, Inc. is a biopharmaceutical company in Research Triangle Park, North Carolina developing a proprietary series of A1 AR antagonists as antiinflammatory drugs for both oral and intravenous use. Endacea's lead A1 AR antagonist molecule, L-97-1, is a water-soluble small molecule with high affinity and high selectivity (versus other human ARs) for the human A1 AR.
The Specific Aims of this SBIR Phase I grant are as follows: 1) Demonstrate proof of concept and efficacy for L-97-1 as an intravenous reperfusion therapy for treatment of reperfusion injury of the heart in an acute regional myocardial infarct rabbit model and 2) Demonstrate that L-97-1 blocks reperfusion injury of the heart and reduces myocardial infarct size in the rabbit by selectively acting on rabbit A1 ARs: Pharmacology studies with L-97-1 in the rabbit: in vitro radioligand binding studies and in vitro and in vivo functional assays for A1 AR versus A2 AR responses. Effective treatment for increasing salvage of myocardium from necrosis requires a postischemic intervention at the time of reperfusion. L-97-1 will be administered during reperfusion in this regional infarct model of reperfusion injury of the heart to block A1 AR activation. With funding from this SBIR Phase I grant and successful completion of the studies described in this grant application, Endacea will apply for an SBIR Phase II grant to fund pivotal studies demonstrating sustained protection in two different animal species, additional toxicology studies and IND application to obtain FDA approval to test L-97-1 in early Phase Ia/Ib clinical trials. With successful completion of studies proposed in SBIR Phase II grant and approval of an IND application by the FDA, Endacea will apply for a continuation grant for funding to obtain proof of concept (POC) in humans for the development of L-97-1 as an intravenous reperfusion therapy for treatment of reperfusion injury of the heart. With positive POC studies in humans, Endacea is confident that it will attract a pharmaceutical strategic partner to further develop and commercialize L-97-1 as a reperfusion treatment for reperfusion injury of the heart.
