Heart attack, or acute myocardial infarction (AMI), is a leading cause of death in the United States, with over 700,000 victims every year. The most prevalent cause of AMI is progressive thrombotic coronary artery occlusion, also known as ST-segment elevation myocardial infarction (STEMI). Early therapy to promote heart reperfusion can dramatically improve outcomes. While percutaneous coronary intervention (PCI) is preferred for early arterial recanalization, up to 70% of patients present to hospitals without this capability, and many STEMI victims must rely on thrombolytic therapy alone. However, current thrombolytics such as tissue plasminogen activator (tPA) are not fully effective, and many patients are excluded from thrombolytic therapy altogether due to bleeding concerns. Consequently, a major treatment gap exists for hemostatically safe antithrombotic and thrombolytic drugs that can be used alone or that can improve the efficacy of current treatments without increased bleeding. To directly address this need, our company has been developing a first- in-class antithrombotic agent for the safe treatment of heart attack. The product candidate is a bioengineered recombinant selective protein C activator enzyme that has potent antithrombotic effects without increasing hemorrhagic risks. Our proprietary molecule, ProCase (E-WE thrombin) has been designed to act in part by increasing the surface concentration of the anticoagulant, profibrinolytic, and cytoprotective enzyme, endogenous activated protein C (APC), at the site of developing blood clots via targeted cellular delivery. This unique mechanism of action allows E-WE thrombin to target pathological blood clots without disabling vital hemostasis. In primates, doses as low as 1 g/kg are antithrombotic without systemic anticoagulation or any antihemostatic effects. All of the critical milestones for our Fast-Track SBIR Phase I/II grant have been reached to justify progression to Phase IIB by demonstrating: 1) E-WE thrombin is effective in a mouse AMI model; 2) E-WE thrombin safely interrupts vascular graft thrombo-occlusion in primates; 3) Our sensitive blood assay can measure drug exposure levels in plasma; and 4) Limited repeat administration of E-WE thrombin does not evoke an immune response in primates. Our Phase IIB aims that will support critical product development milestones are to: 1) Determine the antithrombotic efficacy and hemostatic safety of combining E-WE thrombin plus tPA in primates; 2) Complete a bridging preclinical GLP toxicology study of E-WE thrombin combined with tPA; and 3) Transfer E-WE thrombin manufacturing to a facility capable of commercial scale production. We are currently at a critical juncture for advancing E-WE thrombin towards human trials to treat STEMI, and ultimately all acute coronary syndrome (ACS) patients. This SBIR Phase IIB Bridge Award, matched by a combination of already secured and pending funds, will lead directly to the initiation of clinical trials investigating this unique and potentially life-saving antithrombotic drug candidate.
Treating heart attack with 'clotbusters' and other antithrombotic drugs increases the risk of serious bleeding, confining their usage to the hospital and selected patients. The proposed preclinical research evaluates the therapeutic potential of a new emergency heat attack treatment that inhibits pathological blood clots by activating the endogenous antithrombotic and cytoprotective enzyme, protein C, inside blood vessels. The drug candidate to be tested, ProCase (E-WE thrombin), is not expected to produce bleeding side-effects, and may provide a safe addition to existing antithrombotic and thrombolytic treatments.
|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|