Development of PAR2 Pepducins as a Novel NASH Treatment

开发 PAR2 Pepducins 作为一种新型 NASH 治疗方法

• 批准号: 9408141
• 负责人: Athan Kuliopulos
• 金额: $ 104.86万
• 依托单位: OASIS PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408141
• 关键词: Affect; Agonist; Agreement; American; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Biological Markers; Bone Marrow; Canis familiaris; Cells; Central obesity; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Collaborations; Cyclic GMP; Data; Death Rate; Development; Development Plans; Diet; Dose; Drug Exposure; Drug Kinetics; Evaluation; Exposure to; Fatty Change; Fatty Liver; Fibrosis; Funding; Future; G-Protein-Coupled Receptors; Gastroenterology; Goals; Grant; Heart; Hepatic; Hepatocyte; Human; Inborn Genetic Diseases; Inflammation; Inflammatory; Injury; Insulin Resistance; International; Investigation; Kidney; Laboratories; Lead; Ligands; Liver; Liver Cirrhosis; Liver Fibrosis; Liver neoplasms; Lobular; Lung; Mediation; Medical center; Metabolic; Metabolism; Modeling; Mouse Strains; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; No-Observed-Adverse-Effect Level; Organ; Organ Transplantation; PAR-2 Receptor; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacology and Toxicology; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Primary carcinoma of the liver cells; Procedures; Rattus; Receptor Signaling; Research Design; Resolution; Risk; Rodent; Safety; Series; Signal Transduction; Site; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Specificity; Surface; Technology; Therapeutic; Tissues; Toxic effect; Toxicology; Transplantation; Treatment Efficacy; United States; United States National Institutes of Health; Universities; Validation; Weight; Weight Gain; Work; base; commercialization; cost; design; drug candidate; drug development; effective therapy; efficacy study; extracellular; healthy volunteer; human study; in vivo; inhibitor/antagonist; liver development; liver transplantation; medical schools; meetings; mortality; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; phase 2 study; programs; reproductive organ; small molecule; stellate cell; translational study

Non-alcoholic steatohepatitis (NASH) is characterized by fatty changes in the liver with inflammation and hepatocellular injury that in advanced stages leads to fibrosis, 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 effective therapeutic approach for severe NASH or other forms of liver fibrosis with no approved drug treatments to date. Protease-activated receptor-2 (PAR2) is a signaling receptor that is highly abundant in liver stellate cells, hepatocytes and inflammatory cells which controls fibrotic, inflammatory and metabolic processes that lead towards severe NASH and liver cirrhosis. The cell-penetrating, lipidated PAR2 inhibitor OA-235i, was developed using our proprietary PepducinTM technology. PepducinTM technology offers a unique opportunity to target the intracellular surface of recalcitrant G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives, with prolonged drug exposure to the target tissue, namely liver. OA-235i is an advanced anti-fibrotic/anti- inflammatory drug candidate that blocks PAR2 signaling in hepatic stellate, inflammatory cells and hepatocytes. In the past 3 years, with Fast-Track support from the NIDDK, Oasis Pharmaceuticals successfully formulated and produced cGMP OA-235i at 97-98% purity and high stability. In in vivo efficacy studies, OA- 235i significantly reduced fatty liver steatosis/lobular inflammation/ballooning injury (NAS score) and ALT levels by 50% and gave complete suppression of AST in mouse models of diet-induced NASH to the same level of protection afforded by PAR2-deficiency. OA-235i afforded highly significant suppression of weight gain, liver weight, TGs, steatosis and development of liver tumor foci in a 6-month DEN-NASH model in mice fed a HFD. Delayed OA-235i treatment gave a significant 44-49% suppression of severe liver fibrosis induced by 8-weeks of CCl4 exposure. In 7-28 day repeat-dose safety/toxicology studies, OA-235i was safe and tolerated in dogs and in rat GLP studies with no evidence of liver, heart, kidney, lung, bone marrow, or other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic dose. The translational studies in this Phase 2b application provide a rapid clinical validation and accelerate the commercialization of OA-235i for the treatment of NASH patients in collaboration with Duke Medical Center and Tufts Medical Center. Aim 1 will complete the IND Data Package for OA-235i in year 1 of funding with submission of the IND to the FDA as the first milestone. In years 2-3, Aim 2 will conduct a Phase I-single ascending dose (SAD) study in 17 normal healthy volunteers (NHV) and NASH patients followed by multi ascending 7-day repeat dose study (MAD) in 15 NHV/NASH subjects as the second major milestone. This First-in-Human study will establish the safe dose range, tolerability and PK/PD efficacy of OA-235i using ex vivo PAR2 assays and biomarkers and will inform the design and endpoints of Phase 2 studies to be conducted in the NASH population. 1

非酒精性脂肪性肝炎（NASH）的特征在于肝脏中的脂肪变化伴炎症， 晚期肝细胞损伤导致纤维化、肝硬化和高死亡率。NASH是 经常与其他常见的代谢异常，如胰岛素抵抗和内脏 肥胖肝移植是目前治疗严重NASH或其他非酒精性肝炎的唯一有效的治疗方法。 肝纤维化的形式，迄今为止没有批准的药物治疗。蛋白酶激活受体-2（PAR 2）是一种 在肝星状细胞、肝细胞和炎性细胞中高度丰富的信号受体， 控制导致严重NASH和肝硬化的纤维化、炎症和代谢过程。的 细胞渗透性脂化PAR 2抑制剂OA-235 i是使用我们专有的PepducinTM技术开发的。 PepducinTM技术提供了一个独特的机会，靶向细胞内表面的柠檬酸G蛋白 偶联受体（GPCR），如PAR 2，具有精确的特异性、效力和长半衰期， 延长药物暴露于靶组织，即肝脏。OA-235 i是一种先进的抗纤维化/抗 阻断肝星状细胞、炎性细胞中PAR 2信号传导的炎性药物候选物， 肝细胞在过去的3年里，在NIDDK的快速通道支持下，绿洲制药成功地 配制并生产了97-98%纯度和高稳定性的cGMP OA-235 i。在体内疗效研究中，OA- 235 i显著降低脂肪肝脂肪变性/小叶炎症/气球样损伤（NAS评分）和ALT水平 50%，并在饮食诱导的NASH小鼠模型中将AST完全抑制至与 PAR 2缺陷的保护。OA-235 i对体重增加、肝脏和肝脏的生长有非常显著的抑制作用。 在喂食HFD的小鼠的6个月DEN-NASH模型中的体重、TG、脂肪变性和肝肿瘤病灶的发展。 延迟OA-235 i治疗对8周诱导的严重肝纤维化有显著的44-49%抑制作用， CCl 4暴露在7-28天重复给药安全性/毒理学研究中，OA-235 i在犬中安全且耐受 在大鼠GLP研究中，无肝、心脏、肾、肺、骨髓或其他器官毒性的证据，或 在治疗剂量的高倍数下出现任何实验室异常。本阶段的翻译研究 2b应用提供了快速的临床验证，并加速了OA-235 i的商业化， 与杜克医学中心和塔夫茨医学中心合作治疗NASH患者。目标1将 在资助第1年完成OA-235 i的IND数据包，并将IND提交给FDA， 第一个里程碑在第2-3年，Aim 2将在17名正常人中进行I期单次剂量递增（SAD）研究。 健康志愿者（NHV）和NASH患者，随后在15名受试者中进行多次递增7天重复给药研究（MAD） NHV/NASH受试者作为第二个主要里程碑。这项首次人体研究将确定安全剂量 使用离体PAR 2测定和生物标志物评估OA-235 i的范围、耐受性和PK/PD疗效，并将为 在NASH人群中进行的II期研究的设计和终点。 1