Novel Methods for Dissolving Blood Clots

 描述(申请人提供)：静脉血栓栓塞症(VTE)每年影响多达200万美国人和全球2400万人。静脉血栓栓塞症患者的腿部有血栓(静脉血栓形成)，可能会进入肺部(肺栓塞)。多达10%-20%的VTE患者死亡，美国每年直接的医疗成本约为100亿美元。50多年来，抗凝一直是VTE的标准治疗方法。抗凝有许多缺点：1)它不能溶解现有的血栓；2)多达50%的患者出现血栓后症状(疼痛、肿胀、慢性溃疡)；3)多达4%的患者出现慢性血栓栓塞性肺动脉高压(一种严重的心肺疾病)；4)多达30%的患者与VTE复发有关；5)它有显著的出血风险；以及，6)尚未经随机临床试验证明它能挽救生命。大剂量的组织纤溶酶原激活剂(TPA)样剂可以通过溶解血栓来预防血栓形成后的并发症，但它们：1)只有部分成功；2)导致出血；3)不能降低死亡率。的确有 需要一种更安全、更有效的治疗VTE的方法，以挽救生命、减少残疾并降低医疗保健成本。WE(翻译科学公司[TSI])，成功地完成了第一-第二阶段的STTR，在该阶段中，我们发现并开发了一种治疗性抗体(Lysimab)，它通过一种独特的机制溶解血栓。通过协同作用，Lysimab提高了TPA的效力、安全性和特异性，并避免了TPA相关的出血和神经毒性。根据FDA的建议，在第一阶段研究中，我们成功地将Lysimab开发成一种稳定的、溶解血栓的治疗药物，适合临床试验。我们的第二阶段STTR通过临床前研究推进Lysimab，通过以下方式进行人体试验：1)展示Lysimab和TPA在人源化肺栓塞模型中的安全/有效、协同、治疗剂量组合；2)在GLP条件下生产和纯化Lysimab；3)Lysimab的人体组织结合特性；4)在一种药理学相关物种的关键安全毒理学研究中展示Lysimab显著的安全性和药代动力学；5)完成FDA的一次IND前会议；6)为临床开发筹集战略投资资金；7)确保FDA Smartt监管团队对IND的竞争性选择。在这一进展的基础上，这项IIb阶段的提案旨在完成人类第一次对Lysimab的安全性、药代动力学、药效学和生物标记物功效的研究。然后，我们将利用我们的临床前/临床数据与制药合作伙伴结成战略联盟，为FDA批准Lysimab进行后期临床试验。我们预计TPA-Lysimab联合治疗每年可导致额外的17,000-36,000名患者存活，血栓形成后症状及其相关费用减少50%。在完成这个IIb阶段项目并将商业化责任移交给我们的战略合作伙伴后，TSI将研究这一平台技术对其他血栓疾病患者的潜在好处。

 DESCRIPTION (provided by applicant): Each year venous thromboembolism (VTE) affects up to 2 million Americans and 24 million people worldwide. VTE patients have blood clots in the legs (venous thrombosis) that may travel to the lungs (pulmonary embolism). Up to 10-20% of VTE patients die, and the annual direct U.S. healthcare costs are ~$10 billion. For more than 50 years anticoagulation has been the standard therapy for VTE. Anticoagulation has many drawbacks: 1) it does not dissolve existing thrombi; 2) up to 50% of patients develop post-thrombotic symptoms (pain, swelling, chronic sores); 3) up to 4% of patients develop chronic thromboembolic pulmonary hypertension (a severe cardiopulmonary disease); 4) it is linked to VTE recurrence in up to 30% of patients; 5) it has significant bleeding risk; and, 6) it has not been proven to save lives in a randomized clinical trial. High doses of tissue plasminogen activator (TPA)-like agents may prevent post-thrombotic complications by dissolving clots, but they: 1) are only partially successful; 2) cause bleeding and, 3) do not reduce mortality. There is a need for a safer, more-effective therapy for VTE that saves lives, reduces disability, and lowers health care costs. We (Translational Sciences, Inc. [TSI]), successfully completed a Phase I-II STTR in which we discovered and developed a therapeutic antibody (Lysimab) that dissolves blood clots through a unique mechanism. Through synergism, Lysimab increases the potency, safety and specificity of TPA, and it avoids TPA-related hemorrhage and neurotoxicity. Following FDA recommendations, in Phase I studies, we successfully developed Lysimab into a stable, clot-dissolving therapeutic suitable for clinical trials. Our Phase II STTR advanced Lysimab through preclinical studies toward human trials by: 1) demonstrating safe/effective, synergistic, therapeutic dose combinations of Lysimab and TPA in vivo in a humanized pulmonary embolism model; 2) producing and purifying Lysimab under GLP conditions; 3) characterizing Lysimab's human tissue binding char- acteristics; 4) demonstrating Lysimab's remarkable safety profile and pharmacokinetics in pivotal safety- toxicology studies in a pharmacologically relevant species; 5) completing a successful FDA pre-IND meeting; 6) raising strategic investment funds for clinical development and, 7) securing competitive selection by the NIH SMARTT regulatory team for FDA IND submission. Building on this progress, this Phase IIb proposal aims to complete a first-in-human, Phase I study of the safety, pharmacokinetics, pharmacodynamics and biomarker efficacy of Lysimab. Then we will leverage our pre-clinical/clinical data to form a strategic alliance with a Pharmaceutical partner to conduct later phase clinical trials for FDA approval of Lysimab. We project that combination TPA-Lysimab therapy could lead to the survival of an additional 17,000-36,000 patients per year and a >50% reduction in post-thrombotic symptoms and their associated costs. Upon completion of this Phase IIb project and transfer of commercialization responsibilities to our strategic partner, TSI will investigate the potential benefits of this platform technology to other patients with thrombotc diseases.