Ischemic heart disease is the leading cause of death worldwide with acute myocardial infarction (MI) as the primary culprit. In the US, about 750,000 patients have heart attacks each year and of these, 116,000 patients die. Reperfusion of infarct related artery by thrombolysis or percutaneous coronary intervention (PCI) improves survival in patients with MI. However, acute restoration of blood flow paradoxically also jeopardizes the myocardium in the first minutes of reperfusion. Therapeutic interventions and pharmacological treatments during experimental MI in animal models could reduce infarct size up to 50%. Unfortunately, translation of these experimental animal results into human clinical settings has been largely unsuccessful. EVAS Therapeutics has developed a recombinant fusion protein, A6L15, that can specifically bind to anionic phospholipids expressed on the membrane surfaces of ischemic endothelial cells and myocardium, and block coagulation and inflammatory cascades by inhibiting tissue factor (TF) pathway and cell signaling via protease activated receptors (PAR-1,2,3,4) and Toll-like recetors (TLRs). In a rat MI model, A6L15 treatment was shown to reduce infarct size by up to 87%, which was the largest infarct size reduction ever reported in literature. A6L15 treatment also ameliorated hemodynamic derangement, neutrophil infiltration and cardiomyocyte apoptosis; and decreased plasma levels of cTnI, TNF-?, and sICAM-1 by 96 %, 98 % and 83 %, respectively, without significant alteration of the coagulation parameters. In this Phase I proposal, we propose to expand preclinical development of A6L15 with the following specific aims: 1. GLP production of A6L15. A non-GLP bench process will be adapted for production of GLP-grade A6L15. 2. Verify cardioprotective effect of A6L15 in a rat MI model (Huntington Medical Research Institutes). The effect of A6L15 on myocardial infarct size and no-reflow will be determined. 3. Comparison of the cardioprotective effects of A6L15 alone,[heparin+cangrelor], and [A6L15+cangrelor] in a rat MI model (U. South Alabama). The efficacy of A6L15 in salvaging ischemic myocardium will be assessed in a clinically relevant manner. Currently there are no effective therapies to reduce myocardial infarct size after myocardial infarction. Through this study we may provide a novel and simple pharmacological intervention to increase cardiomyocyte survival, reduce infarct size and improve the outcome after acute MI. Results from this study will also provide critical data for IND filing and clinical development for MI patients undergoing PCI.
No effective therapies are currently available for reduction of infarct size after myocardial infarction. This project will evaluate the efficacy of a Kuniz inhibitor-Annexin V fusion protein for promotion of cardiomyocyte survival, reduction of infarct size and no-reflow, and improvement of outcomes in rat myocardial infarction models.
