Rapidly progressing occlusion of the coronary artery and the subsequent acute myocardial ischemia is the most prevalent primary cause of acute myocardial infarction (AMI) and death in the United States. Early recanalization and antithrombotic therapy promotes reperfusion and improves outcomes when administered before completion of the infarct. However, most heart attack victims do not receive causal treatments to support reperfusion or inhibit progression before they reach the hospital, because current treatments, although effective, are difficult to deliver and carry a risk of severe or fatal hemorrhage. Less severe cases reach the hospital alive, sometimes within an hour from onset, and results from the causal outcomes in these patients are reasonably good;nevertheless, many victims are left without causal treatment in the most critical initial minutes to hours. Despite medical advances, more than a third of AMI victims die of their disease, with acute mortality that surpasses all other causes of death. Since time is of the essence in halting the rapid development of terminal muscle infarction and delayed treatment costs many lives, there is a major unmet medical need for a safe treatment. A safe emergency measure is needed that could be used in any patient, without limitation, as early as at the time of presentation, before the patient reaches the hospital. Our product candidate, a recombinant selective protein C activator (PCA) enzyme, ProCaseTM, is intended to address this unmet need. PCAs are recombinant thrombin analogs. ProCase is a first-in-class, unique drug candidate that currently stands without comparison or competition. Injected ProCase binds to cellular receptors and acts locally by multiple mechanisms, including induction of a potent defense mechanism by generation of endogenous activated protein C (APC) on intravascular surfaces and competitive inhibition of the platelet receptor GPIb. Endogenous protein C activation is a natural and essential defense mechanism that normally acts through cytoprotective (antiapoptotic) signaling, and through inactivation of plasma factors Va and VIIIa. Exploiting this natural mechanism, ProCase generates endogenous APC that protects cells from apoptosis, and inhibits blood vessel occlusions without systemic anticoagulation and hemostasis impairment. We have previously demonstrated the safety and efficacy of several PCAs in preclinical models of thrombosis and stroke prevention in primates and mice, respectively. We now hypothesize that, when administered during acute myocardial ischemia, ProCase may have significant cardioprotective potential and can interrupt progressive coronary artery occlusions that cause rapidly developing irreversible heart muscle necrosis. Our initial research objective is to evaluate the therapeutic potential of ProCase in an animal model of reversible myocardial ischemia.
The Specific Aims for this Fast-track Phase I/II SBIR grant application are to: 1) Evaluate the therapeutic potential of ProCase treatment in a mouse model of AMI;2) Determine the antithrombotic potential of ProCase treatment during experimental vaso-occlusive thrombosis in primates;3) Define the pharmacokinetics of ProCase;and 4) Evaluate the immunogenicity of ProCase in primates. If successful, this research will support the hypothesis that selective intravascular protein C activation is a promising early treatment strategy to interrupt the progression of acute myocardial ischemia before its evolution into acute cardiac dysfunction or terminal AMI. Reaching our milestones will prompt the initiation of formal product development towards an IND for the emergency treatment of suspected and/or verified myocardial ischemia.
The causal treatment of heart attack is intended to prevent disease progression and restore blood flow to the ischemic heart muscle, but such treatments are currently confined to the emergency and coronary care units of hospitals, and delivered to selected patients only under careful monitoring. A significant percentage of the most severe heart attack victims never receive causal treatment, and many die due to rapid disease progression before reaching the hospital. The proposed research evaluates the therapeutic potential of a novel emergency drug treatment that delivers immediate cytoprotection and also inhibits the propagation of pathological blood clots by activation of the endogenous antithrombotic enzyme, protein C, inside blood vessels. The drug candidate to be tested in the treatment of verified or suspected acute myocardial ischemia and/or infarction is a selective protein C activator (PCA) enzyme, ProCaseTM, that could be administered on site or before hospitalization, without concerns about bleeding or other side effects.
|Healy, Laura D; Puy, Cristina; Fernández, José A et al. (2017) Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem 292:8616-8629|
|Verbout, Norah G; Yu, Xiaolin; Healy, Laura D et al. (2015) Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in experimental autoimmune encephalomyelitis. Metab Brain Dis 30:57-65|