Novel Methods for Dissolving Blood Clots

Summary

Principal Investigator: GUY LELAND REED
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2008-03-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Reversing the deleterious effects of α2-antiplasmin on tissue plasminogen activator therapy improves outcomes in experimental ischemic stroke
    Aiilyan K Houng
    Department of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
    Exp Neurol 255:56-62. 2014

Research Grants

Detail Information

Publications1

  1. pmc Reversing the deleterious effects of α2-antiplasmin on tissue plasminogen activator therapy improves outcomes in experimental ischemic stroke
    Aiilyan K Houng
    Department of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
    Exp Neurol 255:56-62. 2014
    ..Consistent with clinical observations, these data suggest that α2-antiplasmin exerts deleterious effects that reduce the efficacy and safety of TPA therapy for ischemic stroke. ..

Research Grants30

  1. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  2. Therapeutic Protein C Activator for Myocardial Ischemia
    NORAH VERBOUT; Fiscal Year: 2013
    ..Reaching our milestones will prompt the initiation of formal product development towards an IND for the emergency treatment of suspected and/or verified myocardial ischemia. ..