Antithrombotic Protein C Activator for Hemodialysis

用于血液透析的抗血栓蛋白 C 激活剂

• 批准号: 10616494
• 负责人: Erik Ian Tucker
• 金额: $ 99.94万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616494
• 关键词: Acute; Acute myocardial infarction; Addendum; Address; Adverse event; Animals; Anti-Inflammatory Agents; Antibodies; Anticoagulants; Anticoagulation; Authorization documentation; Biotechnology; Blood; Blood Vessels; Blood coagulation; Bolus Infusion; C-reactive protein; Cause of Death; Cells; Chemistry; Chronic; Clinical; Clinical Trials; Coagulation Process; Complication; Cytoprotection; Data; Development; Devices; Dialysis procedure; Disease; Dose; Dose Limiting; Double-Blind Method; Drug toxicity; Emergency Situation; End stage renal failure; Enzyme Activators; Enzymes; Equipment Malfunction; Evaluation; Event; Exposure to; Fibrinolytic Agents; Funding; Generations; Grant; Hemodialysis; Hemorrhage; Hemostatic Agents; Hemostatic function; Heparin; Howard Temin Award; Human; IL8 gene; Incidence; Industry; Injection product; Interleukin-6; Interruption; Ischemic Stroke; Kidney; Label; Lead; Life; Marketing; Measurable; Measures; Medical; Miniature Swine; Modeling; Morbidity - disease rate; No-Observed-Adverse-Effect Level; Outcome Measure; Papio; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Placebos; Primates; Procedures; Protein C; Publications; Pulmonary Embolism; Randomized; Recommendation; Recovery; Regimen; Risk; Safety; Secure; Serum; Site; Small Business Innovation Research Grant; Surface; TNF gene; Thrombin; Thromboembolism; Thrombolytic Therapy; Thrombosis; Thrombus; Toxic effect; Vascular Graft; activated Protein C; authority; blood vessel occlusion; cellular targeting; clinical development; clinically significant; design; disability; drug candidate; first-in-human; heparin-induced thrombocytopenia; human study; immunogenic; improved outcome; inflammatory marker; innovation; manufacture; mortality; neutralizing antibody; patient population; pilot trial; placebo controlled study; preclinical safety; preclinical study; prevent; product development; response; safety assessment; safety study; side effect; targeted treatment; thrombolysis; thrombotic; thrombotic complications; treatment duration

Project Summary Although potent antithrombotic drugs are available, all inadvertently target vital hemostatic mechanisms, resulting in dose-limiting hemorrhagic toxicity that restricts their use. Due to a lack of safe thromboprophylaxis, thrombotic/thromboembolic blood vessel occlusions and vascular device failures remain among the leading causes of death and severe chronic disability in the U.S. Consequently, there is a significant and urgent unmet medical need for safe antithrombotic drugs. The safety problem with current antithrombotics is particularly complicated in end stage renal disease (ESRD) patients on chronic hemodialysis, who are prone to both bleeding and thromboembolic complications. Moreover, some ESRD patients develop acute heparin induced thrombocytopenia (HIT), another potentially life-threatening complication of heparin use in a small but significant fraction of ESRD patients, leaving them with few if any off-label options for temporal anticoagulation during hemodialysis sessions. We are therefore continuing clinical development of our first-in-class, FDA Fast Track designated antithrombotic enzyme, AB002 (E-WE thrombin), by evaluating its safety and antithrombotic activity during hemodialysis. The product candidate is a hemostatically safe antithrombotic protein C activator enzyme that has the potential to help this desperately ill patient population. AB002 has been designed to act in part by increasing the surface concentration of the anticoagulant, profibrinolytic, and cytoprotective enzyme, endogenous activated protein C (APC), at the site of developing blood clots via targeted cellular delivery. This unique mechanism of action allows AB002 to target cell-rich pathological blood clots (thrombi) without disabling vital hemostasis. In primates, bolus doses as low as 1 µg/kg are antithrombotic without significant systemic anticoagulation or measurable antihemostatic effects. This critical Phase IIB Bridge Award grant will allow us to continue product development by providing essential support for an FDA-mandated repeat dose toxicity study and initiation of a phase 2 human clinical trial in hemodialysis patients where subjects will be repeatedly exposed to AB002. The results from this study will be used to determine if repeated exposure to AB002 has toxicity or elicits immunogenic responses. The animal toxicity study will be successful if there are no observable drug toxicities. The clinical trial will be deemed successful and support further studies in this and other indications if AB002 is not associated with clinically significant drug-related adverse events, while showing evidence of antithrombotic and/or anti-inflammatory activity. Successfully achieving our SBIR milestones will lead directly into the next product development stage: performing subsequent definitive trials in hemodialysis and other clinically important thrombotic diseases (e.g. ischemic stroke, pulmonary embolism, and acute myocardial infarction) for the benefit of patients who desperately need safer antithrombotic and thrombolytic therapies.

项目摘要 尽管有强大的抗血栓药物可用，但所有药物都无意中针对重要的止血机制， 导致剂量限制的出血毒性，限制了它们的使用。由于缺乏安全的血栓预防措施， 血栓形成/血栓栓塞性血管闭塞和血管装置故障仍然是主要的 死亡原因和严重的慢性残疾。因此，有一个重大和紧迫的未得到满足的 医疗需要安全的抗血栓药物。当前抗血栓药物的安全性问题尤其突出。 并发终末期肾病(ESRD)的慢性血液透析患者，容易同时发生 出血和血栓栓塞症并发症。此外，一些终末期肾病患者出现急性肝素诱导 血小板减少(HIT)，另一个潜在威胁生命的并发症，使用肝素在一个小的，但 很大一部分ESRD患者，使他们几乎没有标签外的临时性抗凝选择 在血液透析过程中。因此，我们正在继续进行我们一流的FDA Fast的临床开发 追踪指定的抗血栓酶AB002(E-WE凝血酶)，通过评估其安全性和抗血栓作用 血液透析过程中的活动性。候选产品是一种止血安全的抗血栓蛋白C激活剂 这种酶有可能帮助这些病入膏肓的患者。AB002被设计成在 部分通过增加抗凝剂、纤溶酶原和细胞保护酶的表面浓度， 内源性活化蛋白C(APC)，通过靶向细胞递送在形成血栓的部位。这 独特的作用机制允许AB002靶向富含细胞的病理性血栓(血栓)，而不会禁用 至关重要的止血作用。在灵长类动物中，团注剂量低至1微克/公斤就能抗血栓，而不会有明显的全身反应 抗凝或可测量的止血效果。这项关键的IIB期桥梁奖拨款将使我们能够 通过为FDA规定的重复剂量毒性研究提供必要的支持来继续产品开发 以及在血液透析患者中启动第二阶段人体临床试验，受试者将反复接受 暴露在AB002中。这项研究的结果将被用来确定反复接触AB002是否会 毒性或引起免疫原性反应。如果没有动物毒性研究，动物毒性研究就会成功。 可观察到的药物毒性。临床试验将被认为是成功的，并支持在这一领域和 AB002是否与临床上显著的药物相关不良事件无关的其他适应症，而 表现出抗血栓和/或抗炎活性的证据。成功实现我们的SBIR 里程碑将直接进入下一个产品开发阶段：在 血液透析和其他临床上重要的血栓性疾病(例如，缺血性中风、肺栓塞、 和急性心肌梗死)，以造福于迫切需要更安全的抗血栓药物和 溶栓疗法。