Pharmacologic treatment of thromboembolism

描述（由申请人提供）：血栓栓塞性疾病是西方社会发病率和死亡率的主要原因。抗凝剂是预防和治疗动脉和静脉血栓形成的关键药物。目前批准的抗凝药物的局限性促使人们寻找具有更好药理学特征的新抗凝药物。EVAS Therapeutics， LLC开发了一系列重组融合蛋白，称为“anv - kpi”。这些蛋白具有靶向血栓形成部位的能力，并对血栓形成细胞膜表面的凝血酶/辅助因子复合物施加强大的抑制作用，而不会诱导长时间的全身抗凝，因此可以潜在地实现持久的抗血栓作用，降低出血风险。我们选择了该系列中最有效的分子TAP-ANV进行进一步开发。该第一阶段提案的具体目标是：1)通过简化、改进的工艺生产重组TAP-ANV。我们将采用改进的发酵方法和简化的纯化工艺，实现每次生产100毫克高质量重组TAP-ANV；2) TAP-ANV在小鼠体内抗血栓作用与出血倾向的解剖。将测定TAP-ANV抗血栓作用、尾静脉出血时间和血浆水平之间的时间关系，以证明TAP-ANV可以通过静脉注射达到血栓形成部位定向的抗血栓作用，而不会延长全身低凝和出血；3)评价TAP-ANV对兔体内血栓形成的影响及PK/PD值。我们将获得TAP-ANV在兔体内的PK/PD参数，并在模拟急性斑块破裂或动静脉外科创伤的兔血栓形成模型中，确定它们是否比传统抗凝剂具有更好的疗效。第一阶段的研究将使我们能够开发出可用于生产GLP材料的规模化工艺，这是下一阶段开发的安全性/毒性和临床研究所需要的。此外，还将测定TAP-ANV在小鼠体内的抗血栓作用与出血倾向、TAP-ANV的PK/PD参数以及TAP-ANV在兔动脉和静脉血栓模型中的治疗效果。基于这些I期研究的积极数据，我们将提出一系列研究，以获得更完整的临床前数据包，以便在我们的II期申请中提交IND申请。公共卫生相关性：血栓栓塞性疾病是世界上发病率和死亡率的主要原因。本项目将开展一种新型抗凝蛋白的临床前研究，用于实验性治疗动脉和静脉血栓形成。

DESCRIPTION (provided by applicant): Thromboembolic disorders are major causes of morbidity and mortality in the Western societies. Anticoagulants are pivotal agents in the prevention and treatment of arterial and venous thrombosis. The limitations of currently approved anticoagulant drugs have prompted the search for new anticoagulants with better pharmacological profiles. EVAS Therapeutics, LLC has developed a series of recombinant fusion proteins, termed "ANV-KPIs". These proteins possess the ability to target themselves to sites of thrombogenesis and exert powerful inhibition of coagulation enzyme/cofactor complexes on the membrane surfaces of thrombogenic cells without inducing a prolonged systemic anticoagulation, and thereby can potentially achieve a long-lasting antithrombotic effect with reduced risks for bleeding. We have selected the most potent molecule of the series, TAP-ANV, for further development. The specific aims of this phase I proposal are: 1) Production of recombinant TAP-ANV by a simplified, improved process. We will use an improved fermentation method and a streamlined purification process to achieve production of >100 mg of high quality recombinant TAP-ANV per run; 2) Dissection of the antithrombotic effect vs. bleeding tendency of TAP-ANV in mouse in vivo. The temporal relationship among the antithrombotic effect, tail vein bleeding time, and plasma levels of TAP-ANV will be determined to demonstrate that TAP-ANV can achieve thrombogenic site- directed antithrombotic effect by bolus injection without prolonged systemic hypocoagulation and bleeding; and 3) Assess PK/PD and effects of TAP-ANV on in vivo thrombosis in rabbits. We will obtain PK/PD parameters of TAP-ANV in rabbit, and determine whether they have superior efficacies compared to conventional anticoagulants in rabbit thrombosis models that simulate acute plaque rupture or surgical trauma to arteries and veins. The phase I studies will allow us to develop a scale-up process amendable for production of GLP materials, which are needed for safety/toxicity and clinical studies in the next stages of development. In addition, the antithrombotic effect vs. bleeding tendency of TAP-ANV in mice, the PK/PD parameters of TAP- ANV, and the therapeutic effect of TAP-ANV in rabbit arterial and venous thrombosis models will be determined. Based on positive data from these Phase I studies, we will propose a series of studies to obtain a more complete preclinical data package for IND filing in our Phase II application. PUBLIC HEALTH RELEVANCE: Thromboembolic disorders are major causes of morbidity and mortality in the world. This project will conduct pre-clinical studies of a novel anticoagulant protein for the experimental treatment of arterial and venous thrombosis.