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、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。虽然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，并可产生严重的剂量限制性出血毒性，从而限制了它们的使用。因此，存在对安全的抗血栓治疗替代品的重大而紧迫的医疗需求。这项拟议的研究将确定抗凝血因子XI的单抗(AXIMAbs)是否有望安全地预防和治疗急性血栓形成。首先，我们将研究独特的专有抗体14E11，它针对凝血因子XI(FXI)的苹果2结构域，并防止其被凝血因子XIIa(FXIIa)激活。为了证明最终的临床开发和商业化是合理的，我们将首先在灵长类动物中建立14E11与相关适应症的市场领先者低分子肝素(依诺肝素)相比的止血安全性和抗血栓疗效。这项拟议的研究有三个具体目标。目的1：制备和表征用于临床前产品候选评价的中和剂14E11。目标1的量化里程碑是建立14E11的最低饱和剂量，该剂量至少能在狒狒身上产生有效的抗凝作用24小时。目的：比较14E11和依诺肝素对恒河猴静脉血栓形成模型的疗效。AIM 2的量化里程碑是证明14E11在饱和剂量下具有显著的抗血栓作用，可与临床相关剂量的依诺肝素相媲美。目的3：确定14E11在阿司匹林治疗的狒狒中的止血安全性。AIM 3的量化里程碑是证明14E11产生的止血损害(出血)明显少于使用依诺肝素治疗、阿司匹林止血受损的狒狒。虽然我们最初的重点将是AXIMAB 14E11，但另一种针对FXI的Apple 3结构域并防止FXIa激活FIX的AXIMAB分子1A6也将被评估为14E11的替代品。AXIMAB方法代表了一个全新的抗凝概念，因为临床和实验证据表明，用FXIIa阻断FXI激活不会产生可能限制有效剂量的副作用。因此，AXIMAbs可能代表了一种新的抗血栓策略，它是血栓特异性的，而且特别安全。在第一阶段成功完成后，该公司将通过第二阶段或通过私人融资寻求额外资金，以启动临床前开发计划，并将AXIMAB推进到针对急性血栓栓塞症适应症的正式产品开发。 公共卫生相关性：急性血栓性血管闭塞是一种非常普遍的疾病，具有严重的后果，包括死亡和慢性发病综合征。虽然抗凝剂(血液稀释剂)改善了由血栓引起的疾病的结局，但它们的有效性受到潜在的严重出血相关(出血)副作用的影响，这些副作用限制了治疗剂量的选择。因此，对更安全的抗血栓治疗仍然存在迫切的医疗需求。这项拟议的研究通过评估一种新的候选产品来满足这一需求，这种新产品是一种抗血栓抗体，它针对的是一种凝血因子，这种凝血因子有助于血管闭塞，但对止血所需的正常凝血不是至关重要的。由于抗体预计不会产生出血副作用，这种方法可以提供一种有效但更安全的替代目前市场上销售的肠外抗凝剂。1

DESCRIPTION (provided by applicant): Thrombotic cardiovascular diseases including venous thromboembolism, myocardial infarction, and ischemic stroke, remain leading causes of death and disability in the US. 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. Consequently, there is a significant and urgent unmet medical need for safe antithrombotic treatment alternatives. The proposed research will determine whether monoclonal antibodies against coagulation factor XI (AXIMABs) hold promise for the safe prevention and treatment of acute thrombosis. Initially we will study the unique proprietary antibody 14E11, which targets the apple 2 domain of coagulation factor XI (FXI) and prevents its activation by factor XIIa (FXIIa). To justify eventual clinical development and commercialization, we will first establish in primates the hemostatic safety and antithrombotic efficacy of 14E11 compared with the market leader for relevant indications, low-molecular- weight heparin (enoxaparin). The proposed research has three specific aims. Aim 1: to prepare and characterize neutralizing 14E11 for preclinical product candidate evaluation. The quantitative milestone for Aim 1 is to establish the minimum saturating dose of 14E11 that produces effective anticoagulation for at least 24 hours in baboons. Aim 2: to determine the efficacy of 14E11 compared with enoxaparin in a baboon venous thrombosis model. The quantitative milestone for Aim 2 is to document a significant antithrombotic effect of 14E11, at a saturating dose, that is comparable to that achieved by a clinically relevant dose of enoxaparin. Aim 3: to determine the hemostatic safety of 14E11 in aspirin-treated baboons. The quantitative milestone for Aim 3 is to demonstrate that 14E11 produces significantly less hemostatic impairment (bleeding) versus that seen in enoxaparin-treated baboons that are hemostatically compromised by aspirin. While our initial focus will be on the AXIMAB 14E11, an additional AXIMAB molecule, 1A6, which targets the apple 3 domain of FXI and prevents activation of FIX by FXIa, will also be evaluated as an alternative to 14E11. The AXIMAB approach represents a fundamentally new anticoagulation concept since clinical and experimental evidence suggests that blocking FXI activation by FXIIa will not produce side-effects that could limit effective dosing. Thus AXIMABs could represent a new antithrombotic strategy that is thrombus-specific and exceptionally safe. After successful completion of Phase I, the company will seek additional capital, either through Phase II or through private financing, to commence with the preclinical development program and advance AXIMAB into formal product development for acute thromboembolism indications. PUBLIC HEALTH RELEVANCE: Acute thrombotic blood vessel occlusion is a highly prevalent disorder with severe consequences, including death and chronic morbidity syndromes. While anticoagulant drugs (blood thinners) improve the outcome of diseases that are caused by blood clots, their usefulness is compromised by potentially severe bleeding- related (hemorrhagic) side-effects that restrict therapeutic dosing options. Accordingly, there remains an urgent unmet medical need for safer antithrombotic treatments. The proposed research addresses this need by evaluating a new product candidate, an antithrombotic antibody that targets a coagulation factor that contributes to blood vessel occlusion but is non-vital for normal blood coagulation necessary to arrest bleeding. Since the antibody is not expected to produce hemorrhagic side-effects, this approach could provide an effective yet safer alternative to currently marketed parenteral anticoagulants. 1