非酒精性脂肪性肝炎新药研发的一些关键因素

郭朝阳; 芮法娟; 李婕

doi:10.3969/j.issn.1001-5256.2021.06.004

非酒精性脂肪性肝炎新药研发的一些关键因素

DOI: 10.3969/j.issn.1001-5256.2021.06.004

山东大学附属山东省立医院感染性疾病科，济南 250021

基金项目:

国家自然科学基金 (81970545);

山东省自然科学基金重点项目 (ZR2020KH006);

济南市科技发展计划项目 (202019079)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：李婕负责文章思路设计；郭朝阳、芮法娟负责文献数据获取分析；李婕、郭朝阳、芮法娟负责起草或修改文章关键内容。

详细信息

作者简介:
郭朝阳(1986—)，女，主治医师，主要从事非酒精性脂肪性肝病的临床与基础研究

通信作者:
李婕，lijier@sina.com

中图分类号: R575.5
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- 被引次数: 0
出版历程
- 收稿日期: 2021-05-04
- 录用日期: 2021-05-04
- 出版日期: 2021-06-20

Key factors in the research and development of new drugs for nonalcoholic steatohepatitis

Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

摘要

摘要: 非酒精性脂肪性肝病(NAFLD)已成为我国第一大慢性肝病，以及欧美发达国家肝移植的主要病因。在NAFLD的各种表型中，非酒精性脂肪性肝炎(NASH)极有可能发展为包括肝硬化、肝癌在内的终末期肝病，导致肝脏相关的死亡率增加。但目前尚无针对NASH的治疗药物，许多新药正在开展临床试验中。NASH新药的研发，需要依据抗代谢、抗炎以及抗纤维化作用方式来选择合适的目标人群和治疗终点。总结和论述了目前NASH新药研发中的一些关键因素。
- 非酒精性脂肪性肝病 /
- 药物发现 /
- 模型, 生物学
Abstract: Nonalcoholic fatty liver disease (NAFLD) has become the most important chronic liver disease in China and a major cause of liver transplantation in developed countries in Europe and America. Among the various phenotypes of NAFLD, nonalcoholic steatohepatitis (NASH) is highly likely to progress to end-stage liver disease including liver cirrhosis and liver cancer, resulting in an increase in liver-related mortality. However, there are still no therapeutic drugs for NASH at present, and many new drugs are under development in ongoing clinical trials. The research and development of new drugs for NASH require the selection of an appropriate target population and treatment outcomes depending on anti-metabolic, anti-inflammatory or anti-fibrotic effect. This article summarizes and reviews several key factors in the research and development of new drugs for NASH.
- Non-alcoholic Fatty Liver Disease /
- Drug Discovery /
- Models, Biological

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参考文献(31)

[1]	YOUNOSSI Z, ANSTEE QM, MARIETTI M, et al. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(1): 11-20. DOI: 10.1038/nrgastro.2017.109.
[2]	LI J, ZOU B, YEO YH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: A systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol, 2019, 4(5): 389-398. DOI: 10.1016/S2468-1253(19)30039-1.
[3]	YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64(1): 73-84. DOI: 10.1002/hep.28431.
[4]	YOUNOSSI ZM. Non-alcoholic fatty liver disease - A global public health perspective[J]. J Hepatol, 2019, 70(3): 531-544. DOI: 10.1016/j.jhep.2018.10.033.
[5]	RINELLA ME, TACKE F, SANYAL AJ, et al. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD[J]. J Hepatol, 2019, 71(4): 823-833. DOI: 10.1016/j.jhep.2019.04.019.
[6]	FDA. Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: Developing drugs for treatment guidance for industry[EB/OL]. [2018-11-04]. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM627376.pdf
[7]	MICHAEL M. FDA issues draft guidance on NASH drug development[EB/OL]. [2018-11-04]. https://endpts.com/fda-issues-draft-guidance-on-nash-drug-development.
[8]	China Food and Drug Administration. Guidelines for clinical trials of drugs for the treatment of nonalcoholic steatohepatitis[EB/OL]. [2019-12-30]. http://www.nmpa.gov.cn/WS04/CL2138/372284.html. 国家食品药品监督管理总局. 非酒精性脂肪性肝炎治疗药物临床试验指导原则(试行)[EB/OL]. 国家食品药品监督管理总局, 2019-12-17[2019-12-30]. http://www.nmpa.gov.cn/WS04/CL2138/372284.html.
[9]	RATZIU V. A critical review of endpoints for non-cirrhotic NASH therapeutic trials[J]. J Hepatol, 2018, 68(2): 353-361. DOI: 10.1016/j.jhep.2017.12.001.
[10]	SAYINER M, ARSHAD T, GOLABI P, et al. Extrahepatic manifestations and healthcare expenditures of non-alcoholic fatty liver disease in the Medicare population[J]. Hepatol Int, 2020, 14(4): 556-566. DOI: 10.1007/s12072-020-10038-w.
[11]	CHINNADURAI R, CHRYSOCHOU C, KALRA PA. Increased risk for cardiovascular events in patients with diabetic kidney disease and non-alcoholic fatty liver disease[J]. Nephron, 2019, 141(1): 24-30. DOI: 10.1159/000493472.
[12]	CHINNADURAI R, RITCHIE J, GREEN D, et al. Non-alcoholic fatty liver disease and clinical outcomes in chronic kidney disease[J]. Nephrol Dial Transplant, 2019, 34(3): 449-457. DOI: 10.1093/ndt/gfx381.
[13]	DAVID D, EAPEN CE. What are the current pharmacological therapies for nonalcoholic fatty liver disease?[J]. J Clin Exp Hepatol, 2021, 11(2): 232-238. DOI: 10.1016/j.jceh.2020.09.001.
[14]	FDA. Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry[EB/OL].[2019-03-06].https://www.fda.gov/media/127738/download.
[15]	SANYAL AJ, MILLER V. Regulatory science and drug approval for alcoholic and nonalcoholic steatohepatitis[J]. Gastroenterology, 2016, 150(8): 1723-1727. DOI: 10.1053/j.gastro.2016.02.044.
[16]	SIDDIQUI MS, HARRISON SA, ABDELMALEK MF, et al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science[J]. Hepatology, 2018, 67(5): 2001-2012. DOI: 10.1002/hep.29607.
[17]	PATEL YA, IMPERIAL JC, MUIR AJ, et al. Baseline parameters in clinical trials for nonalcoholic steatohepatitis: Recommendations from the liver forum[J]. Gastroenterology, 2017, 153(3): 621-625. e7. DOI: 10.1053/j.gastro.2017.07.024.
[18]	HANNAH WN Jr, TORRES DM, HARRISON SA. Nonalcoholic steatohepatitis and endpoints in clinical trials[J]. Gastroenterol Hepatol (N Y), 2016, 12(12): 756-763. http://pubmedcentralcanada.ca/pmcc/articles/PMC5193083/
[19]	MISHRA A, CASTAÑEDA TR, BADER E, et al. Triantennary GalNAc molecular imaging probes for monitoring hepatocyte function in a rat model of nonalcoholic steatohepatitis[J]. Adv Sci (Weinh), 2020, 7(24): 2002997. DOI: 10.1002/advs.202002997.
[20]	VILAR-GOMEZ E, CHALASANI N. Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers[J]. J Hepatol, 2018, 68(2): 305-315. DOI: 10.1016/j.jhep.2017.11.013.
[21]	LOOMBA R. Role of imaging-based biomarkers in NAFLD: Recent advances in clinical application and future research directions[J]. J Hepatol, 2018, 68(2): 296-304. DOI: 10.1016/j.jhep.2017.11.028.
[22]	CHEUNG A, NEUSCHWANDER-TETRI BA, KLEINER DE, et al. Defining Improvement in nonalcoholic steatohepatitis for treatment trial endpoints: Recommendations from the liver forum[J]. Hepatology, 2019, 70(5): 1841-1855. DOI: 10.1002/hep.30672.
[23]	JAYAKUMAR S, MIDDLETON MS, LAWITZ EJ, et al. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase Ⅱ trial of selonsertib[J]. J Hepatol, 2019, 70(1): 133-141. DOI: 10.1016/j.jhep.2018.09.024.
[24]	YOUNOSSI ZM, LOOMBA R, RINELLA ME, et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Hepatology, 2018, 68(1): 361-371. DOI: 10.1002/hep.29724.
[25]	TOWNSEND SA, NEWSOME PN. Review article: New treatments in non-alcoholic fatty liver disease[J]. Aliment Pharmacol Ther, 2017, 46(5): 494-507. DOI: 10.1111/apt.14210.
[26]	ROWE IA, WAI-SUN WONG V, LOOMBA R. Treatment candidacy for pharmacologic therapies for NASH[J]. Clin Gastroenterol Hepatol, 2021. DOI: 10.1016/j.cgh.2021.03.005.[Online ahead of print]
[27]	ANANIA FA, DIMICK-SANTOS L, MEHTA R, et al. Nonalcoholic steatohepatitis: Current thinking from the division of hepatology and nutrition at the food and drug administration[J]. Hepatology, 2021, 73(5): 2023-2027. DOI: 10.1002/hep.31687.
[28]	COLE BK, FEAVER RE, WAMHOFF BR, et al. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery[J]. Expert Opin Drug Discov, 2018, 13(2): 193-205. DOI: 10.1080/17460441.2018.1410135.
[29]	OZAWA Y, TAMURA T, OWADA Y, et al. Evaluation of safety for hepatectomy in a novel mouse model with nonalcoholic-steatohepatitis[J]. World J Gastroenterol, 2018, 24(15): 1622-1631. DOI: 10.3748/wjg.v24.i15.1622.
[30]	JIANG M, WU N, CHEN X, et al. Pathogenesis of and major animal models used for nonalcoholic fatty liver disease[J]. J Int Med Res, 2019, 47(4): 1453-1466. DOI: 10.1177/0300060519833527.
[31]	SANYAL AJ, FRIEDMAN SL, MCCULLOUGH AJ, et al. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: Findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop[J]. Hepatology, 2015, 61(4): 1392-1405. DOI: 10.1002/hep.27678.