Novel Methods for Dissolving Blood Clots

描述（由申请人提供）：每年，多达200万美国人患上静脉血栓栓塞症（VTE）。静脉血栓是腿部的血凝块（静脉血栓），可能会转移到肺部（肺栓塞）。据估计，10-20%的静脉血栓栓塞患者死亡，每年的直接费用高达100亿美元。尽管在诊断和预防方面取得了进展，抗凝治疗，一种已有50年历史的治疗方法，仍然是静脉血栓栓塞最常用的治疗方法。抗凝的缺点包括：1)它不能溶解现有的凝块或血栓；2)高达50%的患者出现血栓形成后症状（疼痛、肿胀、慢性溃疡）；3)高达30%的患者与复发性静脉血栓栓塞有关；4)有显著出血风险；5)它从来没有被证明可以挽救生命

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. 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.