Antithrombotic Protein C Activator for Hemodialysis

Project Summary Although potent antithrombotic drugs are availableall inadvertently target vital hemostatic mechanismsresulting in dose limiting hemorrhagic toxicity that restricts their useDue to a lack of safe thromboprophylaxisthrombotic thromboembolic blood vessel occlusions and vascular device failures remain among the leading causes of death and severe chronic disability in the U SConsequentlythere is a significant and urgent unmet medical need for safe antithrombotic drugsThe safety problem with current antithrombotics is particularly complicated in end stage renal diseaseESRDpatients on chronic hemodialysiswho are prone to both bleeding and thromboembolic complicationsMoreoversome ESRD patients develop acute heparin induced thrombocytopeniaHITanother potentially life threatening complication of heparin use in a small but significant fraction of ESRD patientsleaving them with few if any options for temporal anticoagulation during hemodialysis sessionsWe will therefore continue clinical development of our first in classFDA Fast Track designated antithrombotic enzymeProCaseE WE thrombinABby beginning to explore its safety and antithrombotic activity during hemodialysisThe product candidate is a hemostatically safe antithrombotic protein C activator enzyme that has the potential to help this desperately ill patient populationE WE thrombin has been designed to act in part by increasing the surface concentration of the anticoagulantprofibrinolyticand cytoprotective enzymeendogenous activated protein CAPCat the site of developing blood clots via targeted cellular deliveryThis unique mechanism of action allows E WE thrombin to target cell rich pathological blood clotsthrombiwithout disabling vital hemostasisIn primatesdoses as low asg kg are antithrombotic without significant systemic anticoagulation or measurable antihemostatic effectsThis critical Phase I II Fast Track SBIR grant will allow us to continue product development by providing essential support for an exploratory phasea clinical study to evaluate the safety and antithrombotic effect of E WE thrombin during hemodialysis in a small group of ESRD patientsThe trial will be deemed successful and support further studies in this and other indications if E WE thrombin is not associated with an increase in clinically significant drug related adverse events versus placebowhile showing evidence of antithrombotic activity in the hemodialysis deviceSuccessfully achieving our SBIR milestone will lead directly into the next product development stageperforming subsequent definitive trials in hemodialysis and other important blood clotting diseasese gischemic strokepulmonary embolismand acute myocardial infarctionfor the benefit of patients who desperately need safer antithrombotic and thrombolytic therapies Project Narrative While anticoagulant drugsblood thinnerscan improve the outcome of blood clot related diseases and procedurestheir utilization is frequently restricted due to severe bleeding related side effectsConsequentlythere remains an urgent unmet need for safer drugs in numerous disease conditions that involve excessive blood clottingThe proposed project addresses this need by evaluating our innovative antithrombotic drug candidateProCaseE WE thrombinin end stage renal disease patients who cannot tolerate standard anticoagulation during hemodialysisE WE thrombin has been shown in preclinical studies to inhibit blood clot formation in synthetic vascular grafts and devices without increased bleedingand therefore may provide a safer clinical approach for preventing blood clot developmentwhich is a prevalent complication of hemodialysis when performed without the use of anticoagulants