Evaluation of anti-fibrotic and anti-inflammatory semi-synthetic oxysterol, Oxy210, as a therapeutic drug candidate for non-alcoholic steatohepatitis

抗纤维化和抗炎半合成氧甾醇 Oxy210 作为非酒精性脂肪性肝炎候选治疗药物的评价

• 批准号: 10697132
• 负责人: FARHAD PARHAMI
• 金额: $ 89.7万
• 依托单位: MAX BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697132
• 关键词: Actins; Acute; Affect; Agonist; Alcoholic Fatty Liver; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Atherosclerosis; Award; CETP gene; COL1A1 gene; California; Cardiovascular Diseases; Cells; Cholesterol; Chronic; Circulation; Cirrhosis; Collagen; Deposition; Development; Diabetes Mellitus; Diet; Disease; Drug Kinetics; Endocrinology; Endogenous Factors; Erinaceidae; Esterification; Evaluation; Exposure to; FDA approved; Family; Fatty acid glycerol esters; Fibrosis; Future; Gene Expression; Genotype; Grant; Guidelines; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; Hyperlipidemia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhibition of Apoptosis; Injury; Investigation; Kidney; Lead; Ligands; Lipids; Liver; Liver Failure; Liver Fibrosis; Lung; Macrophage; Manuscripts; Mediating; Medical; Medicine; Metabolic; Metabolism; Molecular; Molecular Mechanisms of Action; Morbidity - disease rate; Mus; Myofibroblast; National Institute of Diabetes and Digestive and Kidney Diseases; Oncology; Oral; Oral Administration; Organ; Orthopedics; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phase; Phenotype; Phosphorylation; Population; Predisposition; Prevention; Primary carcinoma of the liver cells; Proliferating; Property; Protein-Lysine 6-Oxidase; Public Health; Publishing; Publishing Peer Reviews; Receptor Signaling; Reporting; Role; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle; Structure-Activity Relationship; TGFB1 gene; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Toxicokinetics; Toxicology; Transforming Growth Factor beta; Tyrosine Kinase Receptor Inhibition; Virus Diseases; alcohol exposure; analog; antagonist; apolipoprotein E-3; clinically significant; connective tissue growth factor; culture plates; cytokine; drug candidate; efficacy evaluation; fatty liver disease; humanized mouse; improved; in vivo; inhibitor; kinase inhibitor; liver injury; liver transplantation; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel drug class; pandemic disease; patient population; pre-clinical; response; safety study; small molecule; stellate cell; therapeutic development; tissue culture; transcriptome sequencing; western diet; wound healing

ABSTRACT Pathologic tissue fibrosis, impelled by uncontrolled wound healing responses to acute or chronic injury is a significant problem in many organs including kidney, lung, and liver. Liver fibrosis is a major health problem that causes morbidity and mortality in the affected patient population. Liver fibrosis occurs in various pathologies including chronic alcohol exposure, non-alcoholic fatty liver disease (NAFLD) that can lead to non- alcoholic steatohepatitis (NASH), and viral infection, and can lead to cirrhosis and hepatocellular carcinoma. A number of molecular mechanisms have been scrutinized to identify the root causes of liver fibrosis. Among these, prominent studies point to aberrant Hedgehog (Hh) and transforming growth factor-β (TGF-β) signaling as prime factors underlying the pathogenesis of liver fibrosis, and hence extensively investigated. Accumulating evidence also suggests the role of Toll-Like Receptors (TLRs) in mediating the inflammatory responses of liver cells to endogenous factors and bacterial products present in the liver in NAFLD and NASH. At MAX BioPharma, we have identified semi-synthetic oxysterols that act as Hh pathway modulators, both as agonists and antagonists. We found oxysterol Hh pathway antagonists that also have potent inhibitory effects on TGF-β signaling in fibroblastic cells and in primary human hepatic stellate cells (HSC). With support from an SBIR Phase 1 grant from NIDDK, we recently published findings about the anti-NASH properties of an oxysterol analogue, Oxy210, that has led to the present application. Oxy210 has anti-fibrotic as well as anti- inflammatory properties that are mediated through inhibition of Hh, TGF-β and TLR signaling. Oxy210 induced robust inhibitory effects in a humanized hyperlipidemic mouse model of NASH, ApoE*3-Leiden.CETP mice on a high fat Western Diet, evidenced by inhibition of hepatic lipid deposition, inflammatory cytokine expression and fibrosis, associated with reduced hepatic cell apoptosis and improved circulating ALT levels. Based on these properties of Oxy210, in addition to its favorable pharmacokinetic and safety profiles, oral availability, and scalability, in the present SBIR Phase 2 application we propose to continue the examination of the disease modifying effects of Oxy210 in ApoE*3-Leiden.CETP mice in reversing already established disease in contrast to our published report when Oxy210 was administered at the initiation of the disease. We propose to identify the molecular and cellular mechanisms of anti-NASH properties of Oxy210 by performing metabolic tests as well as RNA-sequencing studies in livers of NASH mice with or without Oxy210 treatment. We propose to perform non-GLP in vitro and in vivo safety studies that will provide essential information for future IND-enabling GLP studies required in our anticipated IND filing for Oxy210 as a first-in-class new drug candidate for targeting NASH. NASH is a huge unmet medical need since there are no FDA approved therapies, leaving a large global population susceptible to severe liver failure and the need for liver transplantation.

摘要 病理性组织纤维化是由对急性或慢性损伤的不受控制的伤口愈合反应所推动的 很多器官都有严重的问题，包括肾、肺和肝脏。肝纤维化是一个主要的健康问题。 这会在受影响的患者群体中造成发病率和死亡率。肝纤维化发生在不同的 病理包括慢性酒精暴露，非酒精性脂肪性肝病(NAFLD)，可导致非 酒精性脂肪性肝炎(NASH)和病毒感染，并可导致肝硬化和肝细胞癌。一个 许多分子机制已经被仔细研究，以确定肝纤维化的根本原因。其中， 突出的研究指出，Hedgehog(HH)和转化生长因子-β(转化生长因子-β)信号是启动信号 肝纤维化发病机制的潜在因素，因此得到了广泛的研究。积累证据 提示Toll样受体(TLRs)在介导肝细胞炎症反应中的作用 内源性因子和细菌产物存在于NAFLD和NASH的肝脏中。 在Max BioPharma，我们已经确定了作为HH途径调节剂的半合成氧固醇，两者都是 激动剂和拮抗剂。我们发现了氧固醇HH途径拮抗剂，它们也有很强的抑制作用。 成纤维细胞和原代人肝星状细胞中转化生长因子-β信号的研究。在来自 作为NIDDK提供的SBIR第一阶段拨款，我们最近发表了关于一种新的抗NASH特性的研究结果 氧甾醇类似物，Oxy210，导致了本申请。Oxy210既有抗肝纤维化作用，又有抗肝纤维化作用。 炎症特性是通过抑制HH、转化生长因子-β和转铁蛋白受体信号而介导的。Oxy210诱导 人源化高脂血症小鼠模型NASH，ApoE*3-Leden.CETP对小鼠的抑制作用 一种高脂肪的西方饮食，抑制肝脏脂肪沉积，炎性细胞因子表达 和纤维化，与减少肝细胞凋亡和改善循环ALT水平有关。基于 Oxy210的这些特性，除了其良好的药代动力学和安全性、口服利用度和 可伸缩性，在目前的SBIR第二阶段应用中，我们建议继续检查疾病 Oxy210对ApoE*3-Leden.CETP小鼠逆转已有疾病的修饰作用 我们发表的报告，当Oxy210是在疾病开始时使用的。我们建议确定 通过代谢试验研究Oxy210抗NASH的分子和细胞机制 用或不用Oxy210治疗的NASH小鼠肝脏的AS RNA测序研究。我们打算表演 非GLP的体外和体内安全性研究将为未来IND使能的GLP提供必要的信息 我们预期将Oxy210作为一流的靶向新药候选提交给IND所需的研究 纳什。NASH是一个巨大的未得到满足的医疗需求，因为FDA没有批准的治疗方法，留下了大量的 全球易患严重肝功能衰竭和需要肝移植的人群。