Factor XI inhibitor for thrombosis

血栓形成因子 XI 抑制剂

• 批准号: 8693005
• 负责人: Erik Ian Tucker
• 金额: $ 99.22万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693005
• 关键词: Achievement; Acute; Address; Adverse effects; Animals; Antibodies; Anticoagulants; Anticoagulation; Aspirin; Binding; 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; public health relevance; 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.

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 (DVT)、心肌梗塞和缺血性中风，仍然是美国死亡和残疾的主要原因。尽管可以使用有效的抗血栓药物，但这些药物无意中针对重要的止血分子机制，并可能产生严重的剂量限制性出血 毒性，从而限制了它们在某些患者中的使用。因此，对更安全的抗血栓治疗替代方案存在重大而紧迫的未满足的医疗需求。拟议的研究将继续开发抗凝血因子 XI 的抗血栓抗体（AXIMAB 1A6），用于安全预防和治​​疗急性静脉血栓形成。我们已达到 I 期里程碑：1) 确定狒狒抗血栓的最低饱和剂量 1A6（0.1mg/kg，静脉注射），2) 表明 1A6 具有显着的抗血栓作用，可与低分子量肝素依诺肝素（Lovenox(R)，1mg/kg，静脉注射）的高介入剂量相媲美，3) 验证 AXIMAB 1A6 的抗血栓剂量不会产生可测量的止血损伤，而依诺肝素会增加狒狒的出血量。在第一阶段，我们还发现，在动脉剪切流条件下和组织因子引发的静脉型血栓形成过程中，1A6 比我们的其他原型 AXIMAB 抗体 14E11 更有效地限制血栓形成。功效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 AXIMAB 1A6 作为我们的止血安全有效的抗血栓候选药物的商业开发。我们已经成功推进了 AXIMAB 产品开发，现在准备进一步将 AXIMAB 推向短期预防和治疗急性 DVT 和 VTE 的临床试验。通过研究性新药 (IND) 申请支持 AXIMAB 1A6 开发所需的第二阶段项目的具体目标是：1) 评估重组人源化 AXIMAB 1A6 的活性和功效，2) 表征制造的 GMP 级人源化 AXIMAB 1A6 制剂，以及 3) 确定 GMP 级人源化 AXIMAB 1A6 在临床前的剂量限制毒性研究。 AXIMAB 方法代表了一种全新的抗凝概念，因为 FXI 对病理性凝血的贡献似乎远远超过其在正常止血中的作用。因此，AXIMAB 可以代表一种非常安全的有效抗血栓策略。第二阶段的成功 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阶段，包括 IND 准备和备案，然后启动安全预防和治​​疗急性静脉血栓形成和血栓栓塞的 1 期临床研究。