DEVELOPMENT OF A FIRST-IN-CLASS TARGETED FIBRINOLYTIC FOR POST-SURGICAL THROMBOPR

Summary

Principal Investigator: Ronald Carnemolla
Abstract: DESCRIPTION (provided by applicant): Targeted Therapeutic Solutions (TTS, a small business) is developing a first-in-class thromboprophylactic agent (TTS01) for use in the hospital setting having a rapid onset of action to dissolve clots and prevent the formation of new clots with a reduced risk of bleeding. Two thirds of venous thromboembolism (VTE) cases and deaths are hospital-acquired and is the most common preventable cause of hospital death and disability. Despite prophylaxis with low molecular weights heparins (LMWHs) or warfarin, 15%-30% patients still develop DVT. We envision that TTS101 will be a unique drug for use (1) post-surgically in knee or hip replacement patients and (2) in patients with acute thrombosis (TIA, AMI) at high-risk of bleeding presenting to the emergency room, medical intensive care units (MICUs) and other hospital-associated settings, needing rapid protection against or reversal of thrombosis. We believe TTS 101 is a new type of thromboprophylactic drug that can be used in patients in the first hours after elective surgery for prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE). Our technology is based on a novel zymogen fusion protein scFv/uPA-T (consisting of lmw-scuPA-T and anti- glycophorin A (GPA)). Data to date demonstrate this construct has suitable pharmacological characteristics for our intended therapeutic use in thromboprophylaxis. Two additional features of our novel molecule that remain to be established in detail are its (1) therapeutic window and (2) safety (bleeding complications). We are proposing to work with murine models of thrombosis and bleeding that are often used to address these questions and these models are in place at our collaborator's laboratory. The mouse version of our potential scFv/uPA-T product (TTS101m) and its non-targeted analog are produced in our laboratory where we also have well established mouse models of thrombosis and bleeding. Our proposal focuses on establishing: (1) the minimum effective dose (MED) of TTS101m;(2) its safety (no bleeding predisposition) at MED in a post- operative model;(3) the duration of antithrombotic effect at 1/2 max dose. Successful completion of the AIMS provides the justification for the development of the human form of TTS101 as our lead product development candidate. The critical activities in this development program would be: (1) Creation of a humanized fusion protein capable of binding to human red blood cells;(2) Manufacture of TTS101h under good manufacturing practices (GMP);(3) IND-directed preclinical safety assessment;(4) Formation of a medical advisory board;(5) Phase 1 dose-escalation, safety and tolerability studies. Funding for further development will be pursued through grants, such as SBIR/STTR &advocacy groups (National Blood Clot Alliance, AHA), and solicitation of equity investments.
Funding Period: 2013-09-20 - 2014-08-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. Factor XI in Thrombosis
    David Gailani; Fiscal Year: 2013
    ..abstract_text> ..
  2. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  3. PET Imaging of Thrombus
    PETER D CARAVAN; Fiscal Year: 2013
    ..Dosimetry estimates will be performed on optimized probes and the most promising will be evaluated for acute toxicity. The output of this research will be a novel thrombus imaging probe that may be subsequently developed for human use. ..
  4. Prognostic Risk Score for Post-Discharge VTE in Surgical Oncology Patients
    Sara S Cheng; Fiscal Year: 2013
    ..This has important implications for rationale selection of prophylactic medications in these patients. ..
  5. GENETICS-InFORMATICS TRIAL (GIFT) OF WARFARIN TO PREVENT DVT
    Brian F Gage; Fiscal Year: 2013
    ..Although the American College of Chest Physician (ACCP) recommends a target INR of 2.5, the AAOS recommends <2.0 and these conflicting goals have never been compared in a trial of primary VTE prevention. ..
  6. Prevention and management of perioperative pulmonary embolism
    Vladimir R Muzykantov; Fiscal Year: 2013
    ....
  7. Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism
    Jeffrey A Kline; Fiscal Year: 2013
    ..if NO+O2 corrects defective platelet oxidative metabolism associated with PE, and reduces release of CF DNA/RNA coincident with reduced clotting time and strength on thromboelastography. ..
  8. Microvesicle production after trauma &its Clinical Impact on Venothromboembolism
    Myung S Park; Fiscal Year: 2013
    ..Almost a third of the patients with this clotting abnormality die as a result of this. More research needs to be done to better diagnose and prevent this complication. ..
  9. 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. ..
  10. Chemistry and Biology of Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013
    ..This program seeks to develop new information by which key reactions of blood clotting are regulated. This information will lead to new concepts and strategies for the treatment of blood clotting-related human disease. ..
  11. 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. ..
  12. Novel Methods for Dissolving Blood Clots
    GUY LELAND REED; Fiscal Year: 2013
    ..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. ..
  13. Biological Variation in Hemophilia
    JOHN S LOLLAR; Fiscal Year: 2013
    ..The program represents a fertile environment for training the next generation of physician-scientists, clinical, and basic researcher in the management and research of hemostatic disorders ..
  14. Hypoxic Adenosine Responses
    Michael R Blackburn; Fiscal Year: 2013
    ..Three Component Projects, Two Scientific Cores and an Administrative Core are planned to facilitate the research goals and interactions of this PPG. ..
  15. Predictive optimal anticlotting treatment for segmented patient populations
    Peter J Tonellato; Fiscal Year: 2013
    ..Such predictive evidence can then be used to guide clinical trial designs, and suggest improvements to hospital-wide anticlotting treatment plans. ..