雷司替龙:一种口服小分子肝定向β选择性THR激动剂,用于治疗非酒精性脂肪性肝病和非酒精性脂肪性肝炎。

Gres Karim, Meena B Bansal
{"title":"雷司替龙:一种口服小分子肝定向β选择性THR激动剂,用于治疗非酒精性脂肪性肝病和非酒精性脂肪性肝炎。","authors":"Gres Karim,&nbsp;Meena B Bansal","doi":"10.17925/EE.2023.19.1.60","DOIUrl":null,"url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty liver disease, including non-alcoholic fatty liver (NAFL) and its more progressive form, non-alcoholic steatohepatitis (NASH). The prevalence of NAFLD/NASH along with type 2 diabetes and obesity is rising worldwide. In those who develop NASH, unlike those with bland steatosis (NAFL), lipotoxic lipids drive hepatocyte injury, inflammation and stellate cell activation leading to progressive accumulation of collagen or fibrosis, ultimately leading to cirrhosis and increased risk of hepatocellular carcinoma. Hypothyroidism is associated with NAFLD/NASH; specifically, intrahepatic hypothyroidism drives lipotoxicty in preclinical models. Agonists of thyroid hormone receptor (THR)-β, which is primarily found in the liver, can promote lipophagy, mitochondrial biogenesis and mitophagy, stimulating increased hepatic fatty acid β-oxidation, and thereby decreasing the burden of lipotoxic lipids, while promoting low-density lipoprotein (LDL) uptake and favourable effects on lipid profiles. A number of THR-β agonists are currently being investigated for NASH. This review focuses on resmetirom, an orally administered, once-daily, small-molecule, liver-directed, ß-selective THR agonist, as it is furthest along in development. Data from completed clincal studies outlined in this review demonstrate that resmetirom is effective in reducing hepatic fat content as measured by magnetic resonance imaging-derived proton density fat fraction, reduces liver enzymes, improves non-i nvasive markers of liver fibrogenesis and decreases liver stiffness, while eliciting a favourable cardiovascular profile with a reduction in serum lipids, including LDL cholesterol. Topline phase III biopsy data showed resolution of NASH and/or fibrosis improvement after 52 weeks of treatment, with more detailed peer-reviewed findings anticipated in order to certify these findings. Longer term clinical outcomes from both MAESTRO-NASH and MAESTRO-NASH OUTCOMES will be a pivotal juncture in the drug's road towards being approved as a NASH therapeutic.</p>","PeriodicalId":75231,"journal":{"name":"TouchREVIEWS in endocrinology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258622/pdf/","citationCount":"4","resultStr":"{\"title\":\"Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, β-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis.\",\"authors\":\"Gres Karim,&nbsp;Meena B Bansal\",\"doi\":\"10.17925/EE.2023.19.1.60\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty liver disease, including non-alcoholic fatty liver (NAFL) and its more progressive form, non-alcoholic steatohepatitis (NASH). The prevalence of NAFLD/NASH along with type 2 diabetes and obesity is rising worldwide. In those who develop NASH, unlike those with bland steatosis (NAFL), lipotoxic lipids drive hepatocyte injury, inflammation and stellate cell activation leading to progressive accumulation of collagen or fibrosis, ultimately leading to cirrhosis and increased risk of hepatocellular carcinoma. Hypothyroidism is associated with NAFLD/NASH; specifically, intrahepatic hypothyroidism drives lipotoxicty in preclinical models. Agonists of thyroid hormone receptor (THR)-β, which is primarily found in the liver, can promote lipophagy, mitochondrial biogenesis and mitophagy, stimulating increased hepatic fatty acid β-oxidation, and thereby decreasing the burden of lipotoxic lipids, while promoting low-density lipoprotein (LDL) uptake and favourable effects on lipid profiles. A number of THR-β agonists are currently being investigated for NASH. This review focuses on resmetirom, an orally administered, once-daily, small-molecule, liver-directed, ß-selective THR agonist, as it is furthest along in development. Data from completed clincal studies outlined in this review demonstrate that resmetirom is effective in reducing hepatic fat content as measured by magnetic resonance imaging-derived proton density fat fraction, reduces liver enzymes, improves non-i nvasive markers of liver fibrogenesis and decreases liver stiffness, while eliciting a favourable cardiovascular profile with a reduction in serum lipids, including LDL cholesterol. Topline phase III biopsy data showed resolution of NASH and/or fibrosis improvement after 52 weeks of treatment, with more detailed peer-reviewed findings anticipated in order to certify these findings. Longer term clinical outcomes from both MAESTRO-NASH and MAESTRO-NASH OUTCOMES will be a pivotal juncture in the drug's road towards being approved as a NASH therapeutic.</p>\",\"PeriodicalId\":75231,\"journal\":{\"name\":\"TouchREVIEWS in endocrinology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258622/pdf/\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"TouchREVIEWS in endocrinology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.17925/EE.2023.19.1.60\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"TouchREVIEWS in endocrinology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.17925/EE.2023.19.1.60","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 4

摘要

非酒精性脂肪性肝病(NAFLD)包括一系列脂肪性肝病,包括非酒精性脂肪性肝病(NAFL)及其更为进行性的非酒精性脂肪性肝炎(NASH)。NAFLD/NASH与2型糖尿病和肥胖症的患病率在全球范围内呈上升趋势。在NASH患者中,与轻度脂肪变性(NAFL)患者不同,脂毒性脂质驱动肝细胞损伤、炎症和星状细胞活化,导致胶原或纤维化的进行性积累,最终导致肝硬化和肝细胞癌的风险增加。甲状腺功能减退与NAFLD/NASH相关;具体来说,肝内甲状腺功能减退症在临床前模型中驱动脂肪中毒。甲状腺激素受体(THR)-β激动剂主要存在于肝脏中,可促进脂肪吞噬、线粒体生物发生和线粒体自噬,刺激肝脏脂肪酸β-氧化增加,从而减少脂毒性脂质的负担,同时促进低密度脂蛋白(LDL)的摄取,并对脂质谱产生有利影响。目前正在研究一些用于NASH的THR-β激动剂。本综述的重点是雷司替罗,这是一种口服、每日一次、小分子、肝定向、ß-选择性THR激动剂,因为它的开发进展最快。本综述中概述的已完成的临床研究数据表明,雷司替罗姆可有效降低肝脏脂肪含量(通过磁共振成像衍生的质子密度脂肪分数测量),降低肝酶,改善肝纤维化的无创标志物,降低肝脏硬度,同时通过降低血清脂质(包括LDL胆固醇)引起有利的心血管状况。Topline III期活检数据显示,治疗52周后,NASH和/或纤维化得到缓解,预计将有更详细的同行评议结果来证实这些发现。MAESTRO-NASH和MAESTRO-NASH预后的长期临床结果将是该药物被批准为NASH治疗药物的关键节点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

摘要图片

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, β-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty liver disease, including non-alcoholic fatty liver (NAFL) and its more progressive form, non-alcoholic steatohepatitis (NASH). The prevalence of NAFLD/NASH along with type 2 diabetes and obesity is rising worldwide. In those who develop NASH, unlike those with bland steatosis (NAFL), lipotoxic lipids drive hepatocyte injury, inflammation and stellate cell activation leading to progressive accumulation of collagen or fibrosis, ultimately leading to cirrhosis and increased risk of hepatocellular carcinoma. Hypothyroidism is associated with NAFLD/NASH; specifically, intrahepatic hypothyroidism drives lipotoxicty in preclinical models. Agonists of thyroid hormone receptor (THR)-β, which is primarily found in the liver, can promote lipophagy, mitochondrial biogenesis and mitophagy, stimulating increased hepatic fatty acid β-oxidation, and thereby decreasing the burden of lipotoxic lipids, while promoting low-density lipoprotein (LDL) uptake and favourable effects on lipid profiles. A number of THR-β agonists are currently being investigated for NASH. This review focuses on resmetirom, an orally administered, once-daily, small-molecule, liver-directed, ß-selective THR agonist, as it is furthest along in development. Data from completed clincal studies outlined in this review demonstrate that resmetirom is effective in reducing hepatic fat content as measured by magnetic resonance imaging-derived proton density fat fraction, reduces liver enzymes, improves non-i nvasive markers of liver fibrogenesis and decreases liver stiffness, while eliciting a favourable cardiovascular profile with a reduction in serum lipids, including LDL cholesterol. Topline phase III biopsy data showed resolution of NASH and/or fibrosis improvement after 52 weeks of treatment, with more detailed peer-reviewed findings anticipated in order to certify these findings. Longer term clinical outcomes from both MAESTRO-NASH and MAESTRO-NASH OUTCOMES will be a pivotal juncture in the drug's road towards being approved as a NASH therapeutic.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
2.40
自引率
0.00%
发文量
0
期刊最新文献
Challenges in Risk Stratification of Solid Atypical Mixed Echogenicity Thyroid Nodules. Bexagliflozin as an Adjunct Therapy to Diet and Exercise to Improve Glycaemic Control in Adults with Type 2 Diabetes. Clinical Pharmacology of Oral Octreotide Capsules for the Treatment of Acromegaly. Erratum to Correct Informed Patient Consent Statement. Insights into the Feasibility and Acceptability of a Mobile Insulin Titration Application in Clinical Practice and Its Effects on Diabetes Outcomes.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1