This SBIR Application is responsive to NHLBI Small Business Topics of Special Interest (therapeutics) that are of high programmatic interest (HL-16-332). 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 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. As a monoclonal antibody this agent will not be excreted by the kidney, making it a safer agent than tranexamic acid or EACA to use in patients that have, or are at risk for, kidney disease. 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. The goal of this Phase I proposal is to follow FDA guidance to convert this potent monoclonal antibody into a humanized, first-in-class antifibrinolytic for the treatment of severe human hemorrhage.
Fibrinolysis contributes to severe and fatal hemorrhage in surgery and many other conditions. Current inhibitors of fibrinolysis are weak and lack specificity, which limits their efficacy and causes serious complications. We are developing an ultra-specific, high potency, anti-fibrinolytic agent as a more effective therapy to reduce blood loss and mortality in patients with severe hemorrhage.
| Agarwal, Manyoo A; Garg, Lohit; Lavie, Carl J et al. (2018) Impact of family history of coronary artery disease on in-hospital clinical outcomes in ST-segment myocardial infarction. Ann Transl Med 6:3 |
| Agarwal, Manyoo; Agrawal, Sahil; Garg, Lohit et al. (2018) Impact of smoking in patients undergoing transcatheter aortic valve replacement. Ann Transl Med 6:2 |
| Zambetti, Benjamin R; Thomas, Fridtjof; Hwang, Inyong et al. (2017) A web-based tool to predict acute kidney injury in patients with ST-elevation myocardial infarction: Development, internal validation and comparison. PLoS One 12:e0181658 |
| Tripathi, Ranjana; Sullivan, Ryan; Fan, Tai-Hwang M et al. (2017) Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy. PLoS One 12:e0189315 |
