SBIR-STTR Award

Novel Methods for Dissolving Blood Clots
Award last edited on: 4/14/19

Sponsored Program
STTR
Awarding Agency
NIH : NHLBI
Total Award Amount
$2,692,125
Award Phase
2
Solicitation Topic Code
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Principal Investigator
Guy L Reed

Company Information

Translational Sciences Inc

1840 Overton Park Avenue
Memphis, TN 38112
   (901) 274-4506
   N/A
   www.translationalsciences.com

Research Institution

University of Tennessee - Memphis

Phase I

Contract Number: 1R41HL092750-01A2
Start Date: 5/1/10    Completed: 4/30/11
Phase I year
2010
Phase I Amount
$167,685
Cardiovascular disease is the leading cause of death worldwide. Current therapies for cardiovascular disease are associated with partial success, restricted access, delays, possible neurotoxicity and other important limitations. Our goal is to develop a novel therapeutic agent that is safer and more effective at dissolving the blood clots (thrombi) that cause heart attacks and strokes. Studies of humans and mice with lifelong deficiency of a2-antiplasmin (a2AP) have shown that it is the major regulator of blood clot dissolution. We have produced high affinity monoclonal antibodies that induce functional a2AP deficiency. We have shown that these monoclonal antibodies cause venous thrombi and pulmonary emboli to dissolve in vivo. They also accelerate the dissolution of cerebral arterial thrombi-thereby reducing stroke size without increasing bleeding. In this Phase I application, we will modify these promising antibodies by molecular engineering techniques to convert them into potential therapeutics suitable for human trials. In Aim 1 we will engineer and express a chimerized antibody and antibody fragment (Fab). In Aim 2 we will evaluate the relative abilities of the antibody and antibody fragment to bind and inhibit a2AP and enhance blood clot dissolution. With successful completion of these aims we will pursue a Phase II application to optimize the production of these molecules in order to examine their safety and efficacy in suitable pre-clinical models.

Public Health Relevance:
Cardiovascular disease is the leading cause of death worldwide. Each year ~ 1.6 million Americans suffer a heart attack or stroke. The resulting death and disability costs the U.S. a staggering $316 billion a year. Current therapies are associated with partial success, restricted access, delays, possible neurotoxicity and other important limitations. This project seeks to develop a novel therapy for heart attacks and strokes that could markedly reduce death, disability and costs.

Thesaurus Terms:
Acute; Affinity; American; Animal Model; Animal Models And Related Studies; Antibodies; Antibody Fragments; Antiplasmin; Apoplexy; Arteries; Binding; Binding (Molecular Function); Bleeding; Blood Clot; Blood Clotting; Blood Vessels; Blood Coagulation; Blood Flow; Cho Cells; Cardiac Infarction; Cardiovascular; Cardiovascular Body System; Cardiovascular Diseases; Cardiovascular System; Cardiovascular System (All Sites); Cause Of Death; Cells; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular Accident; Cerebrum; Cessation Of Life; Chinese Hamster Ovary Cell; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Clotting; Coagulation; Coagulation Process; Death; Development; Disease; Disorder; Early Treatment; Early-Stage Clinical Trials; Embolism; Embolus; Engineering; Engineerings; Ensure; Evaluation; Event; Fda Approved; Goals; Guidelines; Half-Life; Half-Lifes; Health Care Costs; Health Costs; Healthcare Costs; Hemorrhage; Human; Human, General; Immune; Immunoglobulin Fragments; Legal Patent; Life; Lung; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Methods; Methods And Techniques; Methods, Other; Mice; Moab, Clinical Treatment; Molecular; Molecular Interaction; Monoclonal Antibodies; Murine; Mus; Myocardial Infarct; Myocardial Infarction; Organ System, Cardiovascular; Parents; Patents; Patients; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Plasmin Antiactivator; Plasminogen Activator; Pre-Clinical Model; Preclinical Models; Preparation; Process; Production; Qualifying; Reaction; Recommendation; Relative; Relative (Related Person); Respiratory System, Lung; Risk; Role; Sttr; Safety; Small Business Technology Transfer Research; Specificity; Stroke; Techniques; Therapeutic; Therapeutic Agents; Thrombosis; Thrombus; Vascular Accident, Brain; Vascular, Heart; Veins; Venous; Viral; Alpha 2-Plasmin Inhibitor; Alpha-2-Antiplasmin; Blood Loss; Brain Attack; Cardiac Infarct; Cardiovascular Disease Therapy; Cardiovascular Disorder; Cardiovascular Disorder Therapy; Cerebral Vascular Accident; Chimeric Antibody; Circulatory System; Clinical Investigation; Coronary Attack; Coronary Infarct; Coronary Infarction; Cost; Disability; Disease/Disorder; Effective Therapy; Established Cell Line; Heart Attack; Heart Infarct; Heart Infarction; In Vivo; Inhibitor; Inhibitor/Antagonist; Model Organism; Neuron Toxicity; Neuronal Toxicity; Neurotoxicity; New Therapeutics; Next Generation Therapeutics; Novel; Novel Therapeutics; Phase 1 Study; Phase 1 Trial; Phase I Trial; Pre-Clinical Research; Preclinical Research; Preclinical Study; Protocol, Phase I; Public Health Relevance; Pulmonary; Restoration; Social Role; Stroke; Success; Vascular

Phase II

Contract Number: 2R42HL092750-02
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
2012
(last award dollars: 2015)
Phase II Amount
$2,524,440

Each year, as many as 2 million Americans develop venous thromboembolism (VTE). VTEs are blood clots in the legs (venous thrombosis) that may travel to the lungs (pulmonary embolism). It is estimated that 10-20% of VTE patients die, and the annual direct costs are up to $10 billion. Despite advances in diagnosis and prophylaxis, anticoagulation, a 50-year-old therapy, remains the most commonly used treatment for venous thromboembolism. The drawbacks of anticoagulation include the following: 1) it does not dissolve existing clots or thrombi;2) up to 50% of patients develop post-thrombotic symptoms (pain, swelling, chronic sores);3) it is linked to recurrent venous thromboembolism in up to 30% of patients;4) it has significant bleeding risk;and 5) it has never been shown to save lives in a randomized clinical trial. Tissue plasminogen activator (TPA) and other blood clot-dissolving drugs are better at preventing post-thrombotic symptoms, but the high doses used are: 1) only partially successful at dissolving blood clots;2) significantly increase bleeding risks and, 3) do not reduce mortality. It is clear that there is a need for a safer, more-effective therapy that savs lives, reduces disability, and lowers health care costs associated with venous thromboembolism. Through our successful completion of the Phase I portion of this multi-phase STTR study, we (Translational Sciences, Inc. [TSI]) have discovered a molecule that dissolves blood clots through a unique mechanism-inactivating the major inhibitor of plasmin. Through synergism, this molecule increases the potency and specificity of TPA, and it avoids TPA-related hemorrhage and neurotoxicity. TSI's extensive pre- clinical studies indicate that this novel approach could substantially reduce the morbidity, mortality and costs associated with VTE. In our Phase I STTR feasibility studies, we successfully converted this molecule, following FDA guidance, into a clot-dissolving biologic therapeutic (Lysimab) suitable for investigation in clinical trials. The Phase II STTR goal is to significantly advance Lysimab toward human trials by: 1) determining optimal (safe/effective) therapeutic dose combinations of Lysimab and TPA in vivo in a humanized model of pulmonary embolism;2) producing and purifying 10 g of Lysimab under GMP conditions, 3) investigating the tissue binding, safety, pharmacokinetics and pharmacodynamics of Lysimab, and 4) submitting an IND to the FDA. This work will be carried out with TSI's Phase II STTR partner, the University of Wisconsin. We will leverage our substantial pre-clinical data to form a strategic alliance with a big pharma partner with the clinical, regulatory and financial resources needed to conduct clinical trials for FDA approval of Lysimab. We project that a combination TPA/a2AP-I therapy could lead to the survival of an additional 17,000-36,000 patients per year and >50% reduction in post-thrombotic symptoms and their associated costs. Upon completion of this Phase II project and transfer of commercialization responsibilities to our strategic partner, TSI will investigate the potential benefits of this platform technology to heart and stroke victims.

Public Health Relevance:
Each year, as many as 2 million Americans develop venous thromboembolism (VTE), and the annual direct costs are up to $10 billion. Yet, despite advances in diagnosis and prophylaxis, anticoagulation, a 50-year-old therapy, remains widely used for VTE treatment despite the fact that it does not dissolve clots, it is associated with serious side-effects and, it has never been shown to save lives in a randomized clinical trial. This multi- phase STTR project seeks to develop a novel VTE therapy that could markedly reduce death, disability, and billions of dollars in direct and indirect VTE-related costs.