Factor XII Inhibitor for Surface Initiated Thrombosis

表面引发血栓形成的因子 XII 抑制剂

• 批准号: 10170412
• 负责人: Christina U Lorentz
• 金额: $ 98.2万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170412
• 关键词: Acute; Address; Adult; Adverse effects; Antibodies; Anticoagulants; Anticoagulation; Award; Blood; Blood Vessel Prosthesis; Blood Vessels; Blood coagulation; Blood flow; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cell Line; Clinical Trials; Complement-Dependent Cytotoxicity; Cyclic GMP; Data; Development; Devices; Dose; Dose-Limiting; Double-Blind Method; Drug Kinetics; Effectiveness; Equilibrium; Equipment Malfunction; Evaluation; Extracorporeal Membrane Oxygenation; Factor XII; Factor XII Deficiency; Fibrinolytic Agents; Funding; Generations; Grant; Hemodialysis; Hemorrhage; Hemostatic Agents; Hemostatic function; Heparin; Human; Impairment; Inflammatory; Intervention; Investigational Drugs; Investigational New Drug Application; Kininogenase; Lead; Life; Link; Lung; Mammals; Medical; Membrane; Modeling; Molecular; Monoclonal Antibodies; Mus; Neurologic; No-Observed-Adverse-Effect Level; Papio; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Placebos; Primates; Procedures; Production; Protocols documentation; Publishing; Pump; Randomized; Recombinants; Registries; Reporting; Research; Risk; Rivers; Safety; Savings; Secure; Small Business Innovation Research Grant; Surface; Testing; Thrombin; Thrombosis; Tissues; Toxic effect; Toxicology; Vascular Graft; antibody-dependent cell cytotoxicity; base; blocking factor; cross reactivity; cytokine; drug candidate; experience; expiration; first-in-human; human study; humanized antibody; immunogenicity; implantation; improved; in vivo; inhibitor/antagonist; innovation; mortality; murine antibody; pharmacokinetics and pharmacodynamics; phase 1 study; preclinical development; preclinical study; prevent; product development; prototype; respiratory; safety study; side effect; success; thrombotic; thrombotic complications; ventricular assist device; volunteer

Project Summary Certain life-saving interventions such as cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), hemodialysis, or ventricular assist device (VAD) pumps require the use of heparin to maintain blood flow through the devices and/or to prevent downstream thromboembolic complications. Several other invasive vascular procedures also utilize temporal anticoagulation, such as during and after prosthetic vascular graft implantation. Unfortunately, antithrombotic agents such as heparin inadvertently target vital hemostatic molecular mechanisms and can have severe dose-limiting hemorrhagic toxicity. Consequently, the level of anticoagulation must be limited to balance the risk of bleeding with that of thrombosis. As a result, device failure and thrombotic complications can be frequent and devastating. Our recent studies suggest that coagulation factor XII (FXII) contributes to the progression of thrombosis, and thereby is a potential target for a new class of antithrombotic drugs. Since data also suggests that FXII does not contribute to hemostasis, and FXII deficiency is an asymptomatic condition in mammals, FXII inhibition is unlikely to have significant adverse effects. In this Phase IIB Small Market project, we will continue to develop our innovative anticoagulant drug candidate for use during ECMO and other thrombotic indications with a high bleeding risk. We are currently on track to reach all of our Phase I/II Fast-Track milestones by the beginning of Phase IIB and have: 1) confirmed that targeting FXII in our ECMO model is antithrombotic and improves the effectiveness of heparin without a detectable increase in hemostasis impairment, 2) humanized our lead murine anti-FXII antibody, which is now designated as AB054, and 3) completed development of a stable manufacturing cell line that is being used to produce a toxicology lot of AB054. We have also developed IND-enabling GLP toxicity protocols for studies that will commence at Charles River Labs (Reno, NV) upon release of our toxicology lot at the start of Phase IIB. This Small Market project, combined with our secured matching funds, will provide essential support for continued product development towards an IND application and clinical trials for the ECMO indication. Our specific aims are to: 1) determine the toxicity of the humanized anti-FXII antibody, AB054, 2) manufacture a cGMP lot of AB054 for human studies, and 3) initiate a phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AB054. Success of this project will propel AB054 towards a phase 2 human proof-of-concept clinical trial in our proposed initial small market entry indication: safe anticoagulation during ECMO, where heparin can cause bleeding and often fails to sustain device perfusion.

项目概要 某些挽救生命的干预措施，例如体外循环 (CPB)、体外膜 氧合 (ECMO)、血液透析或心室辅助装置 (VAD) 泵需要使用肝素 维持通过装置的血流和/或防止下游血栓栓塞并发症。一些 其他侵入性血管手术也利用颞部抗凝，例如在假体植入期间和之后 血管移植物植入。不幸的是，肝素等抗血栓药物无意中靶向了重要的靶点。 止血分子机制，并可能具有严重的剂量限制性出血毒性。因此， 必须限制抗凝水平以平衡出血与血栓形成的风险。因此， 装置故障和血栓并发症可能很频繁且具有破坏性。我们最近的研究表明 凝血因子 XII (FXII) 有助于血栓形成的进展，因此是治疗血栓形成的潜在靶点 新型抗血栓药物。由于数据还表明 FXII 不会有助于止血，并且 FXII 缺乏症在哺乳动物中是一种无症状病症，抑制 FXII 不太可能产生明显的不良反应 影响。在这个IIB期小市场项目中，我们将继续开发我们的创新抗凝药物 适用于 ECMO 和其他出血风险高的血栓适应症。我们目前正在 跟踪在第 IIB 阶段开始时达到所有第 I/II 阶段快速通道里程碑，并已： 1) 确认 我们的 ECMO 模型中的靶向 FXII 具有抗血栓作用，并且可以提高肝素的有效性，且无需 止血损伤可检测到增加，2) 将我们的主要鼠抗 FXII 抗体人源化，该抗体现已 指定为 AB054，以及 3) 完成了稳定生产细胞系的开发，该细胞系用于 生产毒理学批号 AB054。我们还开发了支持 IND 的 GLP 毒性研究方案 该项目将在阶段开始时释放我们的毒理学批次后在查尔斯河实验室（内华达州里诺）开始 IIB。这个小市场项目与我们获得的配套资金相结合，将为 继续针对 ECMO 适应症的 IND 申请和临床试验进行产品开发。我们的 具体目标是：1) 确定人源化抗 FXII 抗体 AB054 的毒性，2) 制造 AB054 的 cGMP 批次用于人体研究，以及 3) 启动 1 期临床试验以评估安全性、耐受性、 AB054的药代动力学和药效学。该项目的成功将推动 AB054 迈向 我们提议的初始小规模市场进入适应症中的第 2 阶段人体概念验证临床试验：安全 ECMO 期间的抗凝治疗，肝素会导致出血，并且通常无法维持装置灌注。