Novel Methods for Dissolving Blood Clots

 描述（由申请人提供）：静脉血栓栓塞（VTE）每年影响多达200万美国人和2400万人。静脉血栓栓塞症患者腿部有血块（静脉血栓形成），可能会转移到肺部（肺栓塞）。高达10-20%的VTE患者死亡，美国每年的直接医疗费用约为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）高达50%的患者出现血栓后症状（疼痛、肿胀、慢性溃疡）; 3）高达4%的患者发生慢性血栓栓塞性肺动脉高压（一种严重的心肺疾病）; 4）它与高达30%的患者的VTE复发有关; 5）它具有显著的出血风险; 6）在随机临床试验中，它还没有被证明可以挽救生命。高剂量的组织型纤溶酶原激活剂（TPA）样药物可通过溶解凝块预防血栓形成后并发症，但它们：1）仅部分成功; 2）导致出血; 3）不降低死亡率。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。 我们（Translational Sciences，Inc.）[TSI]），成功完成了I-II期STTR，其中我们发现并开发了一种通过独特机制溶解血栓的治疗性抗体（Lysiumab）。通过协同作用，Lysiumab增加了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I期研究中，我们成功地将Lysiumab开发成适合临床试验的稳定的凝块溶解治疗药物。我们的II期STTR通过临床前研究向人体试验推进了Lysiumab：1）在人源化肺栓塞模型中体内证明Lysiumab和TPA的安全/有效、协同、治疗剂量组合; 2）在GLP条件下生产和纯化Lysiumab; 3）表征Lysiumab的人体组织结合特性; 4）在与药物相关的物种中的关键安全性毒理学研究中证明Lysiumab的显著安全性特征和药代动力学; 6）为临床开发筹集战略投资资金，7）确保NIH SMARTT监管团队对FDA IND提交的竞争性选择。在此进展的基础上，该IIb期提案旨在完成Lysiumab安全性、药代动力学、药效学和生物标志物疗效的首次人体I期研究。然后，我们将利用我们的临床前/临床数据，与制药合作伙伴建立战略联盟，进行后期临床试验，以获得FDA对Lysiumab的批准。我们预计，TPA-Lysiumab联合治疗每年可使另外17，000 - 36，000名患者存活，血栓后症状及其相关费用减少>50%。在完成IIb期项目并将商业化责任移交给我们的战略合作伙伴后，TSI将研究该平台技术对其他血栓性疾病患者的潜在益处。

 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.