Research Project
10213549
Project Summary Although potent antithrombotic drugs are available, all inadvertently target vital hemostatic mechanisms, resulting in dose-limiting hemorrhagic toxicity that restricts their use. Due to a lack of safe thromboprophylaxis, thrombotic/thromboembolic blood vessel occlusions and vascular device failures remain among the leading causes of death and severe chronic disability in the U.S. Consequently, there is a significant and urgent unmet medical need for safe antithrombotic drugs. The safety problem with current antithrombotics is particularly complicated in end stage renal disease (ESRD) patients on chronic hemodialysis, who are prone to both bleeding and thromboembolic complications. Moreover, some ESRD patients develop acute heparin induced thrombocytopenia (HIT), another potentially life-threatening complication of heparin use in a small but significant fraction of ESRD patients, leaving them with few if any off-label options for temporal anticoagulation during hemodialysis sessions. We are therefore continuing clinical development of our first-in-class, FDA Fast Track designated antithrombotic enzyme, AB002 (E-WE thrombin), by evaluating its safety and antithrombotic activity during hemodialysis. The product candidate is a hemostatically safe antithrombotic protein C activator enzyme that has the potential to help this desperately ill patient population. AB002 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 AB002 to target cell-rich pathological blood clots (thrombi) without disabling vital hemostasis. In primates, bolus doses as low as 1 µg/kg are antithrombotic without significant systemic anticoagulation or measurable antihemostatic effects. This critical Phase IIB Bridge Award grant will allow us to continue product development by providing essential support for an FDA-mandated repeat dose toxicity study and initiation of a phase 2 human clinical trial in hemodialysis patients where subjects will be repeatedly exposed to AB002. The results from this study will be used to determine if repeated exposure to AB002 has toxicity or elicits immunogenic responses. The animal toxicity study will be successful if there are no observable drug toxicities. The clinical trial will be deemed successful and support further studies in this and other indications if AB002 is not associated with clinically significant drug-related adverse events, while showing evidence of antithrombotic and/or anti-inflammatory activity. Successfully achieving our SBIR milestones will lead directly into the next product development stage: performing subsequent definitive trials in hemodialysis and other clinically important thrombotic diseases (e.g. ischemic stroke, pulmonary embolism, and acute myocardial infarction) for the benefit of patients who desperately need safer antithrombotic and thrombolytic therapies.
