Development of PAR4 Pepducins as a Novel Antithrombotic Treatment

冠状动脉疾病仍然是美国的主要死亡原因。简单地说， 在急性冠脉综合征（ACS）发病机制中的作用，如血小板活化、聚集和分泌 是动脉血栓形成的关键成分。尽管ACS的双重抗血小板治疗和 经皮冠状动脉介入治疗（PCI），许多患者维持高发病率（3年时高达20%）， 主要不良事件，如死亡、心肌梗死（MI）或卒中，并将受益于新的 干扰调节原发性血小板活化的其他重要途径的治疗剂。这些 研究结果强调了血小板活化需要多种受体， 在止血中起重要作用，同时促进病理性血栓形成。蛋白酶激活受体 (PAR)1和4被凝血酶激活并触发血小板活化/聚集。与肝素相比， 比伐卢定靶向凝血酶的出血风险较低，心脏事件减少相似，但 并伴有急性支架血栓形成率的增加。两个下游凝血酶受体 在血小板活化中具有不同的作用，并且这些中的每一个代表独立的治疗靶点。一个 靶向PAR 1的口服药物已经进入临床（由于出血风险，未批准用于急性适应症）， 然而，还没有批准用于PAR 4的药物。此外，PAR 4最近被证明是一个关键的 高血栓形成风险的促成因素，人血小板PAR 4反应性的潜在差异， 与白种人（19%）相比，非洲裔美国人（63%）更常见。PAR 4“高”的个人 反应性包括在TM 2中携带单核苷酸多态性（SNP）那些。因此，PAR 4是一个 有吸引力的抗血小板靶点，可能在预防危及生命的动脉血栓形成方面显示出额外的益处， 具有“高”PAR 4反应性的个体，同时保留PAR 1、胶原蛋白和 凝血酶Oasis Pharmaceuticals开发了一种有效的速效注射PAR 4肽蛋白抑制剂，OA- 150，以预防动脉血栓形成的急性缺血性并发症的高危PCI患者， 缓慢起效的口服PAR 4抑制剂的治疗候选物。拟议的IND赋能第一阶段的目标 STTR研究旨在为PAR 4生成FDA批准的皮下制剂（用于临床试验） 脂化肽抑制剂，其具有：i）稳定性特征，其特征在于加速和长期稳定性（>3 ii）PAR 4血小板抑制的快速起效（<30分钟），对于急性血小板减少性紫癜（AML）具有最佳的半衰期（约4-10小时）; 预防ACS患者PCI期间的缺血事件。PAR 4的最佳皮下制剂 pepducin将用于证明在啮齿动物和灵长类动物模型中的功效、有利的PK和快速递送至 非人类灵长类动物和啮齿类动物的血小板。该STTR提案的最终目标是迅速推进 将这种非常有前途的胃肠外PAR 4抑制剂临床前开发到治疗竞技场， 潜在地显著改善高风险患者的心血管疾病结局。

Coronary artery disease remains the leading cause of death in the United States. Platelets play an important role in the pathogenesis of acute coronary syndrome (ACS), as platelet activation, aggregation and secretion are key components of arterial thrombus formation. Despite dual anti-platelet therapy for ACS and percutaneous coronary interventions (PCI), many patients sustain a high incidence (up to 20% at 3 years) of major adverse events such as death, myocardial infarction (MI) or stroke, and would benefit from new therapeutics that interfere with the other important pathways that regulate primary platelet activation. These findings underscore the fact that platelet activation requires multiple receptors and that receptor interactions play an important role in hemostasis while contributing to pathological thrombosis. Protease-activated receptor (PAR) 1 and 4 are activated by thrombin and trigger platelet activation/aggregation. Compared to heparin, the bleeding risk by targeting thrombin with bivalirudin is lower with similar reductions in cardiac events, but is accompanied by an increase in the rate of acute stent thrombosis. The two downstream thrombin receptors have distinct roles in platelet activation and each of these represents an independent therapeutic target. An oral drug targeting PAR1 is already in the clinic (not approved for acute indications due to bleeding risk), however there are no drugs yet approved for PAR4. Furthermore, PAR4 was recently shown to be a critical contributing factor for high thrombotic risk with potential differences in human platelet PAR4 reactivity that are found frequently in African-Americans (63%) as compared to Caucasians (19%). Individuals with `high' PAR4 reactivity include those that carry a single nucleotide polymorphism (SNP) in TM2. Therefore, PAR4 is an attractive anti-platelet target that may show extra benefit in preventing life-threatening arterial thrombosis in individuals with `high' PAR4 reactivity, while sparing the essential hemostatic effects of PAR1, collagen and thrombin. Oasis Pharmaceuticals has developed a potent fast-acting injectable PAR4 pepducin inhibitor, OA- 150, to prevent acute ischemic complications of arterial thrombosis in high-risk PCI patients that are not treatment candidates for a slow-onset oral PAR4 inhibitor. The goal of the proposed IND-enabling Phase I STTR studies is to generate an FDA-approved subcutaneous formulation (for clinical testing) for a PAR4 lipidated peptide inhibitor with: i) stability profile characterized from accelerated and long-term stability (>3 months); ii) a rapid onset (<30 min) of PAR4 platelet inhibition with a half-life that is optimal (~4-10 h) for acute prevention of ischemic events during PCI in ACS patients. Optimal subcutaneous formulation for the PAR4 pepducin will be used to demonstrate efficacy in rodent and primate models, favorable PK and rapid delivery to platelets in non-human primates and rodents. The ultimate goal of this STTR proposal is to rapidly advance the pre-clinical development of this highly promising parenteral PAR4 inhibitor into the therapeutic arena to potentially dramatically improve cardiovascular disease outcomes in high-risk patients.