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（VTE）、深静脉血栓形成（DVT）、心肌梗死和缺血性卒中，仍然是美国死亡和残疾的主要原因。尽管有效的抗血栓形成药物是可用的，但这些药物无意中靶向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，对于更安全的抗血栓治疗替代方案存在显著且迫切的未满足的医疗需求。拟定研究将继续开发抗凝血因子Xi的抗血栓抗体（AXIMAB 1A 6），用于安全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）确定1A 6的最小饱和剂量（0.1mg/kg，iv），其在狒狒中具有抗血栓形成作用，2）表明1A 6具有与高干预剂量的低分子量肝素依诺肝素相当的显著抗血栓形成作用（Lovenox（R），1 mg/kg，iv），和3）证实抗血栓剂量的AXIMAB 1A 6不会产生可测量的止血损害，与依诺肝素相反，依诺肝素会增加狒狒的出血。在I期期间，我们还发现1A 6在动脉剪切流条件下和组织因子引发的静脉型血栓形成期间限制血栓形成方面比我们的其他原型AXIMAB抗体14 E11更有效。疗效差异可能与两种抗体靶向的不同FXI分子途径有关。因此，我们建议继续将AXIMAB 1A 6作为止血安全有效的抗血栓候选药物进行商业开发。我们已经成功推进了AXIMAB产品开发，现在准备进一步将AXIMAB推向临床试验，用于急性DVT和VTE的短期预防和治疗。通过研究性新药（IND）申请支持AXIMAB 1A 6开发所必需的该II期项目的具体目的是：1）评价重组人源化AXIMAB 1A 6的活性和疗效，2）表征生产的GMP级人源化AXIMAB 1A 6制剂，3）在临床前研究中测定GMP级人源化AXIMAB 1A 6的剂量限制性毒性。AXIMAB方法代表了一种全新的抗凝概念，因为FXI对病理性凝血的作用似乎远远超过其在正常止血中的作用。因此，AXIMAB可能是一种非常安全的有效抗血栓形成策略。第二阶段的成功 我们的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，随后启动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：虽然抗凝药物（血液稀释剂）改善了血凝块相关疾病（心脏病发作，中风和静脉血栓形成）的结果，但其有效性受到潜在严重出血相关副作用的影响。因此，仍然存在对更安全的抗凝治疗的迫切未满足的医疗需求。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单克隆抗体）来满足这一需求，该药物已在确定的灵长类动物研究中显示出有效抑制血栓性血管闭塞，而不增加血栓形成的风险。 出血，并因此提供了治疗和预防血栓形成的安全有效的替代方案。

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.