HLS Potent, novel inhibitor of fibrinolytic hemorrhage- Phase II

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This SBIR Application is responsive to NHLBI Small Business Topics of Special Interest (therapeutics) that are of high programmatic interest (HLS-17-04). Hemorrhage or bleeding is a serious or fatal complication of surgery. Antifibrinolytic agents that inhibit plasmin-mediated fibrinolysis can significantly reduce blood loss, emergency reoperation, morbidity and death in patients with severe hemorrhage. Antifibrinolytic agents have been reported to have value in cardiac surgery, orthopedic surgery, liver transplantation, vascular surgery, thoracic surgery, gynecological surgery, end-stage renal disease, peripartum bleeding, gastrointestinal bleeding, prostate surgery, neurosurgery, trauma, traumatic brain injury, intracerebral bleeding and subarachnoid hemorrhage. However, current antifibrinolytic agents have properties that limit their efficacy and may cause serious complications including: low potency, poor specificity, accumulation in renal disease and penetration of the blood brain barrier and placenta. Safer, more specific and potent antifibrinolytic agents may prevent thousands of deaths per year. To address this need, Translational Sciences, Inc. seeks to produce a safe, high-affinity, ultra- specific, antifibrinolytic monoclonal antibody as the first new agent to treat severe hemorrhage in more than 50 years. This novel antifibrinolytic acts as a non-competitive, direct inhibitor and has greater specificity and potency than any known agent. It blocks fibrinolysis in human plasma with several thousand-fold greater potency than the currently used, small molecule antifibrinolytic agents such as epsilon amino caproic acid (EACA) or tranexamic acid. As a monoclonal antibody this antifibrinolytic is unlikely to cross the blood brain barrier, which avoids the risk of seizures associated with tranexamic acid. Also unlike tranexamic acid or EACA, this agent will not significantly cross the placenta, making it a more attractive agent for use in severe, pregnancy-associated hemorrhage. In vivo, this antifibrinolytic was significantly more potent at stopping hemorrhage than clinical doses of EACA. By virtue of its exquisite potency and specificity, this antifibrinolytic agent has extraordinary potential for improving the treatment of severe and fatal bleeding. We project that, by comparison to currently available agents, this novel antifibrinolytic will significantly reduce the need for transfusions, reoperations and mortality in bleeding patients—without serious adverse events. This proposal follows a successful Phase I project, which converted this potent monoclonal antibody into a recombinant, first-in-class, antifibrinolytic agent. In this Phase II proposal, we will follow FDA guidance to develop this novel therapeutic for the treatment of severe clinical hemorrhage, by pursuing master cell bank creation, bioreactor production and testing, pivotal safety-toxicology studies, as well as pre-IND and IND submission.