Factor XI inhibitor for thrombosis

血栓形成因子 XI 抑制剂

• 批准号: 8393253
• 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: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393253
• 关键词: Achievement; Acute; Address; Adverse effects; Animals; Antibodies; Anticoagulants; Anticoagulation; Aspirin; Binding; Blood Clot; Blood Coagulation Factor VII; Blood coagulation; Bolus Infusion; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Chemistry; Clinical; Clinical Data; Clinical Research; Clinical Trials; Coagulation Process; Cyclic GMP; Data; Deep Vein Thrombosis; Development; Disease; Dose; Dose-Limiting; Drug Compounding; Drug Formulations; Drug Kinetics; Enoxaparin; Factor IX; Factor XI; Feedback; Fibrinolytic Agents; Generations; Guidelines; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; Hybridomas; Impairment; Injectable; Intravenous; Investigational Drugs; Investigational New Drug Application; Ischemic Stroke; Lead; Life; Link; Low-Molecular-Weight Heparin; Manufacturer Name; Measurable; Medical; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myocardial Infarction; No-Observed-Adverse-Effect Level; Outcome; Papio; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Preparation; Prevention; Primates; Process; Production; Publishing; Quality Control; Recombinants; Research; Research Contracts; Role; Solid; Staging; Sterility; Stroke; Testing; Therapeutic; Therapeutic Index; Therapeutic antibodies; Thrombin; Thromboembolism; Thromboplastin; Thrombosis; Thrombus; Time; Toxic effect; Vascular Graft; Venous; Venous Thrombosis; Work; alternative treatment; base; blood vessel occlusion; disability; drug candidate; experience; high risk; immunogenicity; improved; in vitro activity; in vitro testing; inhibitor/antagonist; meetings; mortality; pre-clinical; preclinical study; preclinical toxicity; prevent; product development; prospective; prototype; safety study; safety testing; scale up; success

DESCRIPTION (provided by applicant): Thrombotic cardiovascular diseases including venous thromboembolism (VTE), deep vein thrombosis (DVT), myocardial infarction, and ischemic stroke, remain leading causes of death and disability in the U.S. Although effective antithrombotic agents are available, these drugs inadvertently target vital hemostatic molecular mechanisms and can produce severe dose-limiting hemorrhagic toxicity, thereby limiting their use in some patients. Consequently, there is a significant and urgent unmet medical need for safer antithrombotic treatment alternatives. The proposed research will continue the development of an antithrombotic antibody against coagulation factor XI (AXIMAB 1A6) for the safe prevention and treatment of acute venous thrombosis. We have reached our Phase I milestones: 1) Establishing a minimum saturating dose of 1A6 (0.1mg/kg, iv) that is antithrombotic in baboons, 2) Showing that 1A6 has significant antithrombotic effects that are comparable to a high interventional dose of the low-molecular-weight heparin enoxaparin (Lovenox(R), 1mg/kg, iv), and 3) Verifying that the antithrombotic dose of AXIMAB 1A6 produces no measurable hemostatic impairment, in contrast to enoxaparin, which increases bleeding in the baboons. During Phase I we also discovered that 1A6 is more effective than our other prototype AXIMAB antibody 14E11 at limiting thrombus development under arterial shear flow conditions and during tissue factor initiated venous-type thrombosis. The difference in efficacy is likely related to distinct FXI molecular pathways that are targeted by the two antibodies. We therefore propose to continue the commercial development of AXIMAB 1A6 as our hemostatically safe and effective antithrombotic drug candidate. We have successfully advanced AXIMAB product development and are now prepared to further move AXIMAB towards clinical trials for the short-term prevention and treatment of acute DVT and VTE. The Specific Aims for this Phase II project that will be necessary to support the development of AXIMAB 1A6 through an investigational new drug (IND) application are to: 1) Evaluate the activity and efficacy of recombinant humanized AXIMAB 1A6, 2) Characterize manufactured GMP-grade humanized AXIMAB 1A6 formulations, and 3) Determine the dose-limiting toxicity of GMP-grade humanized AXIMAB 1A6 in preclinical studies. The AXIMAB approach represents a fundamentally new anticoagulation concept since the contribution of FXI to pathological coagulation appears to far outweigh its role in normal hemostasis. Thus, AXIMAB could represent an effective antithrombotic strategy that is exceptionally safe. Success of this Phase II research and achievement of our critical milestones will lead directly into the next stage of product development that will consist of IND preparation and filing, followed by the initiation of phase 1 clinical studies to safely prevent and treat acute venous thrombosis and thromboembolism. PUBLIC HEALTH RELEVANCE: While anticoagulant drugs (blood thinners) improve the outcome of blood clot related diseases (heart attack, stroke, and venous thrombosis), their usefulness is compromised by potentially severe bleeding-related side effects. Consequently, there remains an urgent unmet medical need for safer anticoagulant treatments. The proposed research addresses this need by continuing the development of a new antithrombotic antibody drug candidate AXIMAB (Anti-Factor XI Monoclonal Antibody), which has been shown in definitive primate studies to potently inhibit thrombotic blood vessel occlusion without increasing bleeding, and thus provides a safe and effective alternative for treating and preventing thrombosis.

描述（由申请人提供）：血栓性心血管疾病，包括静脉血栓栓塞（VTE），深静脉血栓形成（DVT），心肌梗死和缺血性中风，仍然是美国死亡和残疾的主要原因，尽管有效的抗脑抑制剂可降低，但这些药物可用，这些药物不受限制地降低了降低的高度抑制作用，但可产生这些药物，但仍可抑制过时的高度抑制作用。毒性，从而限制了他们在某些患者中的使用。因此，对于更安全的抗血栓治疗替代方案存在巨大而紧迫的医疗需求。拟议的研究将继续开发针对凝血因子XI（Aximab 1A6）的抗血栓形成抗体，以防止和治疗急性静脉血栓形成。我们已经达到了第一阶段的里程碑：1）建立最小饱和剂量为1A6（0.1mg/kg，iv），在狒狒中是抗肉毒杆菌的，2）表明1A6具有显着的抗抗栓性作用，可与低介入的低分子肝素（lo）（lo）（lo）（lo）（lo）（lo）（lo）（lo）（lo）（lo）（lo）（lo）（lo）（lo）（3）与依诺沙司蛋白相比，轴突1a6的抗溶栓剂量不会产生可测量的止血损伤，而依诺沙司蛋白会增加狒狒的出血。在第一阶段，我们还发现，在动脉剪切流条件下，在限制血栓发育和组织因子期间启动静脉型血栓形成时，1A6比我们的其他原型aximab抗体14E11更有效。功效的差异可能与两种抗体靶向的不同FXI分子途径有关。因此，我们建议继续将阿昔单抗1a6的商业发展作为我们的血液稳态安全有效的抗血栓药物候选者。我们已经成功地采用了阿昔莫布产品的开发，现在准备进一步将阿acimab转移到临床试验中，以预防和治疗急性DVT和VTE。 The Specific Aims for this Phase II project that will be necessary to support the development of AXIMAB 1A6 through an investigational new drug (IND) application are to: 1) Evaluate the activity and efficacy of recombinant humanized AXIMAB 1A6, 2) Characterize manufactured GMP-grade humanized AXIMAB 1A6 formulations, and 3) Determine the dose-limiting toxicity of GMP-grade humanized AXIMAB 1A6 in preclinical studies. Aximab方法是一种从根本上开始的抗凝概念，因为FXI对病理凝血的贡献似乎远远超过其在正常止血中的作用。因此，阿昔单抗可以代表一个非常安全的有效抗血栓形成策略。这一阶段的成功 我们关键里程碑的研究和实现将直接进入产品开发的下一个阶段，该阶段将包括IND制备和提交，然后开始1期临床研究，以安全地预防和治疗急性静脉血栓形成和血栓栓塞。 公共卫生相关性：虽然抗凝药（血液稀释剂）改善了血凝块相关疾病的结果（心脏病发作，中风和静脉血栓形成），但其有用性受到了潜在严重的与出血相关的副作用的损害。因此，对更安全的抗凝治疗的紧急医疗需求仍未得到满足。拟议的研究通过继续开发新的抗血栓形成抗体候选药物（抗因子XI单克隆抗体）来满足这一需求，该抗体已在确定的灵长类动物研究中表明，该抗体已在不增加的血栓性血管闭塞中迅速抑制抑制性血管的闭塞 出血，因此为治疗和预防血栓形成提供了一种安全有效的替代方法。