Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis

开发用于治疗非酒精性脂肪性肝炎的 PAR2 抑制剂

基本信息

批准号：
8648560
负责人：
Athan Kuliopulos
金额：
$ 30.42万
依托单位：
OASIS PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-25 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648560
关键词：
Affect Alanine Transaminase American Anti-Inflammatory Agents Anti-inflammatory Back Biodistribution Biological Availability Body Weight Boston Canis familiaris Cells Central obesity Cirrhosis Clinical Clinical Trials Collaborations Communities Cyclic GMP Data Death Rate Development Diet Disease Progression Dose Drug Exposure Drug Formulations Enzymes Evaluation Exposure to Family suidae Fatty Change Fatty Liver Fatty acid glycerol esters Fibrosis Future G-Protein-Coupled Receptors Gastroenterology Hematology Hepatic Hepatocyte Histologic Homing Human Hypertriglyceridemia Inflammation Inflammatory Injection of therapeutic agent Injury Insulin Resistance Lead Liver Liver Cirrhosis Liver Fibrosis Lobular Magnetic Resonance Imaging Medical center Metabolic Modeling Mouse Strains Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Organ Organ Transplantation PAR-2 Receptor Pancreatitis Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Procedures Process Production Property Rattus Receptor Signaling Risk Rodent Safety Signal Transduction Site Small Business Technology Transfer Research Specificity Staging Surface Technology Testing Therapeutic Time Tissues Toxic effect Toxicology Transplantation United States United States National Institutes of Health Validation commercialization cost design drug candidate drug development feeding inhibitor/antagonist interest liver transplantation mortality mouse model nonalcoholic steatohepatitis novel therapeutics pre-clinical preclinical efficacy public health relevance

项目摘要

DESCRIPTION (provided by applicant): Non-alcoholic steatohepatitis (NASH) is characterized by fatty changes in the liver with inflammation and hepatocellular injury that in advanced stages leads to fibrosis and cirrhosis and high mortality rates. NASH is frequently associated with other common metabolic abnormalities, such as insulin resistance and visceral obesity. Liver transplantation is currently the only therapeutic approach for severe NASH or other forms of liver fibrosis with no approved drug treatments. Organ transplantation is a difficult, risky and costly procedure with scarce organ availability and increased risk of developing cirrhosis in the transplanted liver from the original, highlighting the major unmet need for new therapeutic options. Protease-activated receptor-2 (PAR2) is a signaling receptor that is highly abundant in liver cells and inflammatory cells which controls inflammatory and fibrotic processes that lead towards severe NASH and liver cirrhosis. The cell-penetrating, lipidated PAR2 inhibitor PZ-235 was developed using pepducin technology and offers a unique opportunity to target the intracellular surface of G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives. PZ-235 is an advanced anti-inflammatory/anti-fibrotic drug candidate that targets PAR2 and blocks PAR2 signaling in hepatic stellate and inflammatory cells. PZ-235 reduces fatty liver steatosis and hypertriglyceridemia by up to 50%, and suppresses lobular inflammation and systemic alanine aminotransferase (ALT) levels in mouse models of diet-induced NASH similar to effects in a PAR2-deficient mouse strain. PZ-235 treatment gave a major improvement in NASH activity scores (NAS) in mice, which corresponded to suppression of histologic disease-progression. PZ-235 also significantly protected against severe pancreatitis, a common sequela seen with several of the newly approved type-II diabetes drugs. Together, these preclinical data identify PZ-235 as a potent and potentially effective drug candidate for NASH treatment. In Aim 1, we will test the pharmacologic properties of PZ-235 with the milestones of showing significant delivery into liver and efficacy data to demonstrate blockade of the late 2nd fibrotic hit in liver/NASH mouse models, and provide pilot safety/tox data (systemic parameters, liver enzymes, body weight, injection site tolerability, hematology) in 60 day repeat dose daily administration in rodents. Aim 2 will conduct GLP safety-toxicology and PK/PD studies of cGMP-produced PZ-235 in 2 species, with design of upcoming first-in- human phase I and II clinical trials in NASH patients with our gastroenterology and MR imaging clinical collaborators.

描述（由申请人提供）：非酒精性脂肪性肝炎（NASH）的特点是肝脏脂肪变化，伴有炎症和肝细胞损伤，晚期会导致纤维化和肝硬化以及高死亡率。 NASH 通常与其他常见的代谢异常相关，例如胰岛素抵抗和内脏肥胖。肝移植是目前治疗严重 NASH 或其他形式肝纤维化的唯一方法，尚无批准的药物治疗方法。器官移植是一项困难、危险且昂贵的手术，器官可用性稀缺，移植肝脏发生肝硬化的风险增加，这凸显了对新治疗方案的主要未满足需求。蛋白酶激活受体 2 (PAR2) 是一种信号受体，在肝细胞和炎症细胞中含量丰富，可控制导致严重 NASH 和肝硬化的炎症和纤维化过程。细胞穿透性脂质化 PAR2 抑制剂 PZ-235 采用 pepducin 技术开发，提供了独特的机会靶向 G 蛋白偶联受体 (GPCR)（例如 PAR2）的细胞内表面，具有精致的特异性、效力和长半衰期。 PZ-235 是一种先进的抗炎/抗纤维化候选药物，以 PAR2 为靶点并阻断肝星状细胞和炎症细胞中的 PAR2 信号传导。在饮食诱导的 NASH 小鼠模型中，PZ-235 可将脂肪肝脂肪变性和高甘油三酯血症降低高达 50%，并抑制小叶炎症和全身丙氨酸转氨酶 (ALT) 水平，与 PAR2 缺陷小鼠品系中的效果相似。 PZ-235 治疗使小鼠 NASH 活动评分 (NAS) 显着改善，这与组织学疾病进展的抑制相对应。 PZ-235 还可以显着预防严重胰腺炎，这是几种新批准的 II 型糖尿病药物中常见的后遗症。总之，这些临床前数据表明 PZ-235 是治疗 NASH 的有效且潜在有效的候选药物。在目标 1 中，我们将测试 PZ-235 的药理学特性，并通过显示显着进入肝脏的里程碑和功效数据来证明对肝脏/NASH 小鼠模型中的晚期第二次纤维化打击的阻断，并提供试点安全/毒性数据（啮齿类动物每日重复给药 60 天时的全身参数、肝酶、体重、注射部位耐受性、血液学）。目的 2 将在 2 个物种中对 cGMP 生产的 PZ-235 进行 GLP 安全毒理学和 PK/PD 研究，并与我们的胃肠病学和 MR 成像临床合作者一起设计即将在 NASH 患者中进行的首次人体 I 期和 II 期临床试验。