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: 10378696
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378696
• 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; 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; Recovery; Regimen; Risk; Safety; Secure; Serum; Site; Small Business Innovation Research Grant; Surface; TNF gene; Thrombin; Thromboembolism; Thrombolytic Therapy; Thrombosis; Thrombus; Time; Toxic effect; Vascular Graft; activated Protein C; base; 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; mortality; neutralizing antibody; patient population; pilot trial; placebo controlled study; preclinical safety; preclinical study; prevent; product development; response; 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 虽然有效的抗血栓药物是可用的，但所有这些药物都无意中靶向重要的止血机制， 导致限制其使用的剂量限制性出血毒性。由于缺乏安全的血栓预防措施， 血栓性/血栓栓塞性血管闭塞和血管装置失效仍然是主要的 因此，有一个重大和紧迫的未满足的 医疗需要安全的抗血栓药物。目前抗血栓药物的安全性问题尤其是 在接受长期血液透析的终末期肾病（ESRD）患者中， 出血和血栓栓塞并发症。此外，一些ESRD患者发生急性肝素诱导的 血小板减少症（HIT），另一个潜在的危及生命的并发症肝素使用在一个小，但 ESRD患者中的显著比例，使他们很少有（如果有）临时抗凝的标签外选择 在血液透析期间。因此，我们正在继续临床开发我们的一流的，FDA快速 通过评估指定抗血栓酶AB 002（E-WE凝血酶）的安全性和抗血栓性，跟踪其 血液透析期间的活动。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群绝望的病人。AB 002被设计用于 部分通过增加抗凝剂、纤维蛋白溶解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凝块的部位。这 独特的作用机制使AB 002能够靶向富含细胞的病理性血凝块（血栓）， 至关重要的止血。在灵长类动物中，低至1 µg/kg的推注剂量具有抗血栓作用，而无显著的全身性 抗凝或可测量的抗止血作用。这一关键的IIB阶段桥梁奖赠款将使我们能够 继续产品开发，为FDA规定的重复给药毒性研究提供必要支持 并在血液透析患者中启动2期人体临床试验，其中受试者将反复接受 接触AB 002。本研究的结果将用于确定重复暴露于AB 002是否 毒性或诱发免疫原性应答。动物毒性研究将是成功的， 可见的药物毒性。该临床试验将被视为成功，并支持进一步的研究， 其他适应症，如果AB 002与临床显著的药物相关不良事件无关， 显示出抗血栓形成和/或抗炎活性的证据。成功实现SBIR 里程碑将直接进入下一个产品开发阶段：进行后续的最终试验， 血液透析和其它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），以使迫切需要更安全的抗血栓药物的患者受益， 血栓溶解疗法。