Factor XI inhibitor for thrombosis

描述（由申请人提供）：血栓性心血管疾病，包括静脉血栓栓塞、心肌梗死和缺血性中风，仍然是美国死亡和残疾的主要原因。虽然有有效的抗血栓药物，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性毒性，从而限制了它们的使用。因此，对于安全的抗血栓治疗替代方案，存在着重大而紧迫的未满足的医疗需求。拟议的研究将确定抗凝血因子XI单克隆抗体（AXIMABs）是否有希望安全预防和治疗急性血栓。首先，我们将研究独特的专有抗体14E11，该抗体靶向凝血因子XI （FXI）的apple 2结构域，并阻止其被因子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身上建立14E11的止血安全性和抗血栓疗效，并将其与相关适应症的市场领导者低分子肝素（依诺肝素）进行比较。拟议的研究有三个具体目标。目的1：制备和表征中和14E11用于临床前候选产品评估。Aim 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：比较14E11与依诺肝素在狒狒静脉血栓模型中的疗效。Aim 2的定量里程碑是记录14E11在饱和剂量下的显著抗血栓作用，与临床相关剂量的依诺肝素所达到的效果相当。目的3：确定14E11在阿司匹林治疗狒狒中的止血安全性。Aim 3的定量里程碑是证明14E11产生的止血损伤（出血）明显少于用依诺肝素治疗的、因阿司匹林止血受损的狒狒。虽然我们最初的重点将放在AXIMAB 14E11上，但另一个AXIMAB分子1A6也将作为14E11的替代品进行评估，该分子靶向FXI的apple 3结构域并阻止FXIa激活FIX。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，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可以代表一种新的抗血栓策略，是血栓特异性和非常安全的。在I期成功完成后，公司将通过II期或私人融资寻求额外资金，开始临床前开发项目，并推进AXIMAB进入急性血栓栓塞适应症的正式产品开发。

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