Factor XI inhibitor for thrombosis

描述（由申请方提供）：血栓性心血管疾病，包括静脉血栓栓塞、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。虽然有效的抗血栓形成药物是可用的，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，从而限制其使用。因此，对于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。这项拟议的研究将确定抗凝血因子Xi的单克隆抗体（AXIMABs）是否有望安全预防和治疗急性血栓形成。最初，我们将研究独特的专有抗体14 E11，其靶向凝血因子Xi（FXi）的apple 2结构域并防止其被因子XIIa（FXIIa）激活。为了证明最终的临床开发和商业化，我们将首先在灵长类动物中确定14 E11与相关适应症的市场领导者低分子量肝素（依诺肝素）相比的止血安全性和抗血栓形成疗效。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候选产品评价的中和14 E11。目标1的定量里程碑是确定在狒狒中产生至少24小时有效抗凝作用的14E11的最小饱和剂量。目的2：确定14 E11与依诺肝素相比在狒狒静脉血栓形成模型中的疗效。目标2的定量里程碑是记录14 E11在饱和剂量下的显著抗血栓形成作用，该作用与临床相关剂量的依诺肝素达到的作用相当。目的3：确定14 E11在阿司匹林给药狒狒中的止血安全性。目标3的定量里程碑是证明14 E11产生的止血损害（出血）显著低于阿司匹林止血损害的依诺肝素给药狒狒。虽然我们最初的重点是AXIMAB 14 E11，但也将评价靶向FXI的apple 3结构域并阻止FXIa激活FIX的另一种AXIMAB分子1A6作为14 E11的替代药物。AXIMAB方法代表了一种全新的抗凝概念，因为临床和实验证据表明，通过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可能代表一种新的抗血栓策略，具有血栓特异性和异常安全性。在第一阶段成功完成后，公司将通过第二阶段或私人融资寻求额外资金，开始临床前开发计划，并将AXIMAB推进到急性血栓栓塞适应症的正式产品开发中。 公共卫生相关性：急性血栓性血管闭塞是一种高度流行的疾病，具有严重的后果，包括死亡和慢性病综合征。虽然抗凝药物（血液稀释剂）改善了由血凝块引起的疾病的结果，但其有用性受到限制治疗剂量选择的潜在严重出血相关（出血性）副作用的损害。因此，对于更安全的抗血栓形成治疗仍然存在迫切的未满足的医疗需求。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，其靶向凝血因子，该凝血因子有助于血管闭塞，但对止血所需的正常血液凝固并不重要。由于预期抗体不会产生出血性副作用，因此这种方法可以为目前市售的胃肠外抗凝剂提供有效但更安全的替代方案。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