Antithrombotic Protein C Activator for Hemodialysis

用于血液透析的抗血栓蛋白 C 激活剂

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要尽管可以使用潜在的抗血栓形成药物，但所有这些都无意中针对重要的止血机制，但导致限制其使用的剂量限制出血性毒性。由于缺乏安全的血栓预防血栓形成/血栓血管闭塞和血管装置失败仍然是领先的因此，美国的死亡原因和严重的慢性残疾，因此有一个重大而紧急的未经对安全抗血栓药物的医疗需求。当前抗血栓形成的安全问题尤其是慢性血液透析的末期肾脏疾病（ESRD）患者的复杂出血和血栓并发症。此外，一些ESRD患者会诱导急性肝素血小板减少症（命中），这是肝素使用的另一种潜在威胁生命的并发症 ESRD患者的很大一部分，使他们几乎没有标签的临时抗凝选择。在血液透析期间。因此，我们正在持续对第一类FDA快速发展的临床开发通过评估其安全性和抗血栓形式血液透析期间的活性。候选产品是止血性抗血栓形成蛋白C活化剂酶有可能帮助这个剧烈生病的患者人群。 AB002已设计为行动通过增加抗凝剂，纤维蛋白水解和细胞保护酶的表面浓度的一部分内源性激活的蛋白C（APC），通过靶向细胞递送发育的部位。这独特的作用机制允许AB002靶向富含细胞的病理血凝块（血栓）而无需禁用重要止血。在初级，推注剂量低至1 µg/kg是抗血栓形成的，没有明显的全身性抗凝或可测量的抗抑制作用。这个关键阶段IIB桥奖的赠款将使我们能够通过为FDA规定的重复剂量毒性研究提供基本支持来继续产品开发以及在血液透析患者中的2期人类临床试验的主动性。暴露于AB002。这项研究的结果将用于确定反复接触AB002是否有毒性或引起免疫原性反应。如果没有，动物毒性研究将成功可观察的药物毒性。临床试验将被视为成功，并支持进一步的研究，并其他指示如果AB002与临床上与药物相关的不良事件无关，而显示抗血栓和/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：执行随后的权威试验血液透析和其他临床上重要的血栓性疾病（例如缺血性卒中，肺栓塞，和急性心肌梗塞），因为迫切需要更安全的抗血栓形成和溶栓疗法。