Development of PAR4 Pepducins as a Novel Antithrombotic Treatment

开发 PAR4 Pepducins 作为新型抗血栓治疗方法

基本信息

批准号：
9254228
负责人：
Athan Kuliopulos
金额：
$ 36.65万
依托单位：
OASIS PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9254228
关键词：
Acute Address Adverse event Affect African American American American Heart Association Animal Model Animals Antihypertensive Agents Aspirin Biological Availability Blood Platelets Blood coagulation Boston Cardiac Cardiovascular Diseases Cardiovascular system Caucasians Cause of Death Cells Cessation of life Chronic Clinic Clinical Trials Coagulation Process Collaborations Collagen Coronary Arteriosclerosis Coronary artery Death Rate Development Disease Disease Outcome Dose Drug Kinetics Drug Targeting Event F2R gene FDA approved Formulation Funding G-substrate GTP-Binding Proteins Goals Half-Life Hemorrhage Hemostatic Agents Hemostatic function Heparin High Prevalence Human Incidence Individual Injectable Interruption Intravenous Life Lipid Bilayers Lipids Mediating Medical center Modeling Mus Myocardial Myocardial Infarction Oral Oregon PAR-1 Receptor PAWR gene Papio Pathogenesis Pathologic Pathway interactions Patient risk Patients Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase II Clinical Trials Platelet Activation Platelet aggregation Play Population Prevention Primary Prevention Primates Procedures Production Proteinase-Activated Receptors Recurrence Reperfusion Injury Research Personnel Risk Rodent Role Safety Secondary Prevention Signal Transduction Single Nucleotide Polymorphism Small Business Technology Transfer Research Stents Stroke Surface Technology Testing Therapeutic Therapeutic Intervention Thrombin Thrombin Receptor Thrombosis Thrombus Toxic effect Toxicology United States Unstable angina Update acute coronary syndrome bivalirudin coronary angioplasty efficacy testing experience hazard high risk high risk population improved in vivo inhibitor/antagonist interest mouse model nonhuman primate novel novel therapeutics percutaneous coronary intervention preclinical development prevent programs receptor stent thrombosis subcutaneous therapeutic candidate therapeutic target

项目摘要

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.

冠状动脉疾病仍然是美国的首要死因。血小板发挥重要作用血小板活化、聚集和分泌在急性冠脉综合征 (ACS) 发病机制中的作用是动脉血栓形成的关键成分。尽管针对 ACS 进行了双重抗血小板治疗，经皮冠状动脉介入治疗 (PCI) 后，许多患者的并发症发生率很高（3 年时高达 20%）死亡、心肌梗塞 (MI) 或中风等重大不良事件，并将受益于新的干扰调节初级血小板活化的其他重要途径的治疗方法。这些研究结果强调了血小板活化需要多个受体并且受体相互作用的事实在止血中发挥重要作用，同时有助于病理性血栓形成。蛋白酶激活受体 (PAR) 1 和 4 被凝血酶激活并触发血小板激活/聚集。与肝素相比，使用比伐卢定靶向凝血酶的出血风险较低，心脏事件也有类似的减少，但伴随着急性支架内血栓形成率的增加。两个下游凝血酶受体在血小板活化中具有不同的作用，并且每一个都代表一个独立的治疗靶点。一个靶向 PAR1 的口服药物已进入临床（由于出血风险，未批准用于急性适应症），然而，目前还没有批准用于 PAR4 的药物。此外，PAR4 最近被证明是一个关键的人血小板 PAR4 反应性的潜在差异是导致血栓形成高风险的因素与白人 (19%) 相比，非洲裔美国人 (63%) 更常见。 PAR4“高”的个人反应性包括那些在 TM2 中携带单核苷酸多态性 (SNP) 的反应性。因此，PAR4 是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”PAR4 反应性的个体，同时保留 PAR1、胶原蛋白和凝血酶。 Oasis Pharmaceuticals 开发了一种有效的速效注射用 PAR4 pepducin 抑制剂 OA- 150、预防非PCI高危患者发生动脉血栓形成的急性缺血性并发症慢效口服 PAR4 抑制剂的候选治疗方案。拟议的 IND 启用第一阶段的目标 STTR 研究旨在为 PAR4 生成 FDA 批准的皮下制剂（用于临床测试）脂化肽抑制剂具有： i) 稳定性特征，以加速和长期稳定性为特征 (>3 月）； ii) PAR4 血小板抑制快速起效（<30 分钟），其半衰期对于急性发作来说是最佳的（~4-10 小时）预防 ACS 患者 PCI 期间的缺血事件。 PAR4 的最佳皮下配方 pepducin 将用于证明在啮齿动物和灵长类动物模型中的功效、良好的 PK 和快速递送非人类灵长类动物和啮齿类动物的血小板。该 STTR 提案的最终目标是快速推进这种极具前景的肠外 PAR4 抑制剂进入治疗领域的临床前开发可能显着改善高危患者的心血管疾病结局。