Factor XI inhibitor for thrombosis

描述(申请人提供)：血栓性心血管疾病，包括静脉血栓栓塞症(VTE)、深静脉血栓形成(DVT)、心肌梗死和缺血性中风，在美国仍然是导致死亡和残疾的主要原因。尽管有有效的抗血栓药物可用，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失血毒性，从而限制了它们在某些患者中的使用。因此，存在着对更安全的抗血栓治疗替代方案的重大和迫切的医疗需求。这项拟议的研究将继续开发抗凝血因子XI的抗血栓抗体(AXIMAB 1A6)，以安全地预防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)建立了1A6(0.1 mg/kg，iv)的最低饱和剂量，这种药物在狒狒中具有抗血栓作用；2)显示1A6具有显著的抗血栓作用，可与高介入剂量的低分子肝素依诺肝素(Lovenox(R)，1 mg/kg，iv)相媲美；以及3)证实AXIMAB 1A6的抗血栓剂量不会产生可测量的止血损害，而依诺肝素则增加了巴布亚的出血。在第一阶段，我们还发现1A6比我们的其他原型AXIMAB抗体14E11更有效地限制了动脉切变流条件下的血栓形成和组织因子引发的静脉型血栓形成。疗效上的差异可能与这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AXIMAB 1A6作为我们安全有效的止血抗血栓候选药物进行商业化开发。我们已经成功地推进了AXIMAB产品的开发，现在准备将AXIMAB进一步推向临床试验，用于急性DVT和VTE的短期预防和治疗。为了通过研究新药(IND)应用来支持AXIMAB 1A6的开发，这一第二阶段项目的具体目标是：1)评估重组人源化AXIMAB 1A6的活性和有效性，2)表征生产的GMP级人源化AXIMAB 1A6制剂，以及3)在临床前研究中确定GMP级人源化AXIMAB 1A6的限量毒性。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方面的作用。因此，AXIMAB可能代表了一种非常安全的有效的抗血栓策略。第二阶段的成功之处 我们关键里程碑的研究和实现将直接导致产品开发的下一个阶段，包括IND准备和归档，随后启动安全预防和治疗急性静脉血栓形成和血栓栓塞症的第一阶段临床研究。 公共卫生相关性：虽然抗凝剂(血液稀释剂)改善了血栓相关疾病(心脏病发作、中风和静脉血栓形成)的结局，但它们的有效性受到潜在严重出血相关副作用的影响。因此，对更安全的抗凝剂治疗的医疗需求仍然迫切，尚未得到满足。拟议的研究通过继续开发新的抗血栓抗体候选药物AXIMAB(抗因子XI单抗)来满足这一需求，该药物已在明确的灵长类动物研究中显示，在不增加增加的情况下有效地抑制血栓血管闭塞。 因此，它为治疗和预防血栓形成提供了一种安全有效的选择。

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.