SBIR-STTR Award

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.

Public Health Relevance Statement:
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.

Project Terms:
Acids; Active Sites; Address; Affinity; antibody engineering; Antifibrinolytic Agents; Aprotinin; Binding; Biology; Blood - brain barrier anatomy; Blood coagulation; Blood Platelets; Blood Vessels; Businesses; Cardiac Surgery procedures; Cardiovascular system; Cattle; Cessation of life; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Coagulation Process; Complication; cross reactivity; Development; drug candidate; Drug Kinetics; effective therapy; Emergency Situation; End stage renal failure; Evaluation; FDA approved; Fibrin; Fibrinolysis; Fibrinolytic Agents; Gastrointestinal Hemorrhage; Goals; Gynecologic Surgical Procedures; Health Care Costs; Hemorrhage; hexanoic acid; Human; humanized antibody; improved; in vivo; in vivo Model; inhibitor/antagonist; Injury; interest; Ischemic Stroke; Kidney; Kidney Diseases; Lead; Life; liver transplantation; lysine analog; Mediating; Modeling; Molecular Weight; Monoclonal Antibodies; Morbidity - disease rate; mortality; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; neurosurgery; New Agents; novel; novel therapeutics; operation; Operative Surgical Procedures; Orthopedic Surgery procedures; Pancreas; Parents; Patients; Penetration; Pharmacodynamics; Pharmacologic Substance; Phase; phase I trial; Placebos; Placenta; Plasma; Plasmin; Plasmin Inhibitor; Plasminogen; Pre-Clinical Model; preclinical development; preclinical study; Pregnancy; Preparation; prevent; Production; Property; prostate surgery; Repeat Surgery; Reporting; Risk; Role; Safety; Seizures; Serine Protease; Serious Adverse Event; Small Business Innovation Research Grant; small molecule; Specificity; Subarachnoid Hemorrhage; Talents; Techniques; Therapeutic; Thoracic Surgical Procedures; Thromboembolism; Thrombosis; Tissues; Tranexamic Acid; Transfusion; Translational Research; Trauma; Traumatic Brain Injury; Trypsin; Venous; Work

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.

Thesaurus Terms:
Active Sites; Acute; Address; Adverse Event; Affinity; Antibody Engineering; Antifibrinolytic Agents; Behavior; Biology; Bioreactors; Blood - Brain Barrier Anatomy; Blood Coagulation; Blood Platelets; Blood Vessels; Businesses; Cardiac Surgery Procedures; Cardiovascular System; Cell Bank; Cessation Of Life; Chinese Hamster Ovary Cell; Clinical; Clinical Data; Clinical Trials; Coagulation Process; Complication; Cross Reactivity; Cyclic Gmp; Data; Development; Dose; Drug Kinetics; Effective Therapy; Emergency Situation; End Stage Renal Failure; Evaluation; Fibrin; Fibrinolysis; Gastrointestinal Hemorrhage; Goals; Growth; Gynecologic Surgical Procedures; Health Care Costs; Hemorrhage; Hexanoic Acid; Human; Human Tissue; Immunoglobulin G; Improved; In Vivo; In Vivo Model; Inhibitor/Antagonist; Injury; Interest; Ischemic Stroke; Kidney Diseases; Kidney Failure; Life; Liver Transplantation; Manufacturing Process; Mediating; Meetings; Modeling; Monoclonal Antibodies; Morbidity - Disease Rate; Mortality; Mus; National Heart, Lung, And Blood Institute; National Institute Of Neurological Disorders And Stroke; Neurosurgery; New Agents; Nonhuman Primate; Novel; Novel Therapeutics; Operative Surgical Procedures; Orthopedic Surgery Procedures; Parents; Patients; Penetration; Perinatal; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I Trial; Pilot Projects; Placenta; Plasma; Plasmin; Plasmin Inhibitor; Plasminogen Activator; Pre-Clinical; Pre-Clinical Model; Preclinical Safety; Pregnancy; Prevent; Production; Property; Prostate Surgery; Recombinants; Recovery; Repeat Surgery; Reporting; Research; Risk; Role; Safety; Seizures; Serine Protease; Serious Adverse Event; Small Business Innovation Research Grant; Small Molecule; Specificity; Structure; Subarachnoid Hemorrhage; Talents; Targeted Treatment; Testing; Therapeutic; Therapeutic Studies; Thoracic Surgical Procedures; Thromboembolism; Thrombosis; Time; Tissues; Toxicology; Tranexamic Acid; Transfusion; Translational Research; Trauma; Traumatic Brain Injury; Venous;