Therapeutic Thrombin Analogs

DESCRIPTION provided by applicant Project Summary Abstract Treatment of acute ischemic stroke AIS with the thrombolytic antithrombotic agent tissue plasminogen activator tPA Activase is limited due to the potential for severe hemorrhagic side effects The first symptoms of acute ischemia to tPA treatment andquot time to needleandquot can span hours even in developed urban areas since an established diagnosis in a hospital setting is required before thrombolytic therapy Consequently there is a major unmet medical need for safe antithrombotic agents with no risk of bleeding that can be administered immediately as an emergency measure upon signs of acute cardio and cerebrovascular events To directly address this need our company has been developing a novel antithrombotic agent for the safe treatment of AIS The product candidate is a bioengineered recombinant selective protein C activator enzyme PCA that has potent antithrombotic effects without increasing hemorrhagic risks Our proprietary PCA 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 g kg are antithrombotic without systemic anticoagulation or any antihemostatic effects The first toxicity and stability batch of E WE thrombin has now been released and a pre investigational new drug pre IND meeting with the FDA is being scheduled for late All of the critical milestones for our Fast Track SBIR Phase I II grant have been reached by Demonstrating that early treatment of experimental AIS with our prototype PCA WE thrombin improves neurological outcomes without hemostatic impairment in mice Establishing a pharmaceutically acceptable dosage form of E WE thrombin Developing a serum free production process and Determining that E WE thrombin lacks demonstrable toxicity at andgt fold the expected human dosage in a preclinical acute dose escalation study at Charles River Labs We have also established the appropriate scale up methodology to produce E WE thrombin in bulk amounts sufficient to perform all preclinical and human studies Our Phase IIB aims that will support critical product development milestones are to Complete preclinical GLP toxicology studies of ProCase Manufacture a cGMP lot of ProCase for GLP stability and human clinical studies Prepare and file an IND application to test ProCase in acute ischemic stroke and Evaluate the safety tolerability pharmacokinetics and pharmacodynamics of ProCase in healthy volunteers in a phase clinical trial This SBIR Phase IIB Bridge Award matched by already secured funds will ultimately support the completion of a phase first in human safety study investigating this unique and potentially life saving antithrombotic drug candidate PUBLIC HEALTH RELEVANCE Project Narrative Ischemic stroke remains a leading cause of death and chronic disability in part because early treatment with the clot busting drug tissue plasminogen activator tPA Activase is limited by its associated risk of serious bleeding To address this problem we are developing a novel protein C activator enzyme ProCase E WE thrombin which is a first of its kind blood clot specific antithrombotic drug candidate that coul be used early in the treatment of stroke since it does not increase bleeding