非酒精性脂肪性肝病的药物治疗进展

靳睿; 王晓晓; 刘峰; 饶慧瑛

doi:10.3969/j.issn.1001-5256.2022.07.033

非酒精性脂肪性肝病的药物治疗进展

DOI: 10.3969/j.issn.1001-5256.2022.07.033

北京大学人民医院，北京大学肝病研究所，丙型肝炎和肝病免疫治疗北京市重点实验室，非酒精性脂肪性肝病诊断北京市国际科技合作基地，北京 100044

基金项目:

国家自然科学基金项目 (81870406)

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：饶慧瑛、靳睿负责课题设计，撰写论文; 刘峰、王晓晓修改论文; 饶慧瑛、刘峰负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
饶慧瑛，rao.huiying@163.com

计量
- 文章访问数: 879
- HTML全文浏览量: 1012
- PDF下载量: 250
- 被引次数: 0
出版历程
- 收稿日期: 2021-11-22
- 录用日期: 2022-01-06
- 出版日期: 2022-07-20

Research advances in pharmacotherapy for nonalcoholic fatty liver disease

Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Peking University Hepatology Institute, Peking University People's Hospital, Beijing 100044, China

Research funding:

National Nature Science Foundation of China （81870406）

More Information

Corresponding author: RAO Huiying, rao.huiying@163.com (ORCID: 0000-0003-2431-3872)

摘要

摘要: 非酒精性脂肪性肝病(NAFLD)发病率逐年上升，正逐渐成为全球成人和儿童最常见的慢性肝病，其疾病谱中的非酒精性脂肪肝炎(NASH)可导致肝硬化和肝细胞癌。然而因NAFLD发病机制复杂，目前尚无有效的治疗药物。因此，NASH的新药研发是近年来研究的热点。本文总结了NASH发病机制重点阐明NASH潜在的治疗靶点及药物研究进展。
- 非酒精性脂肪性肝病 /
- 非酒精性脂肪性肝炎 /
- 药物疗法 /
- 临床试验
Abstract: The incidence rate of nonalcoholic fatty liver disease (NAFLD) is increasing year by year, and it gradually becomes the most common chronic liver disease in adults and children around the world. Nonalcoholic steatohepatitis (NASH) in its disease spectrum can lead to liver cirrhosis and hepatocellular carcinoma. However, due to the complex pathogenesis of NAFLD, there are currently no effective drugs for treatment. Therefore, the research and development of new drugs for NASH have been a research hotspot in recent years. This article summarizes the pathogenesis of NASH and elaborates on the research advances in potential therapeutic targets and drugs for NASH.
- Non-alcoholic Fatty Liver Disease /
- Nonalcoholic Steatohepatitis /
- Drug Therapy /
- Clinical Trial

HTML全文

图 1 NAFLD的发病机制及药物治疗靶点

Figure 1. Pathogenesis and therapy targets of NAFLD

下载: 全尺寸图片幻灯片

表 1 有治疗潜力的NASH临床试验Ⅱ期药物

Table 1. Pharmacologic agents in phase Ⅱ studies for NASH

药物	作用机制	研究人群	主要结果	NCT代码
Cilofexor (GS-9674)	非甾体FXR激动剂	NASH (F1~F3)	耐受性良好，可显著降低肝脏脂肪变、血清胆汁酸与肝脏生化指标，不改变血清脂质	NCT02854605
Cilofexor+ firsocostat	FXR激动剂+ ACC抑制剂	NASH (F3~F4)	耐受性良好，可改善NASH活性，并可能具有抗纤维化作用	NCT03449446
培马贝特(K-877)	选择性PPARα调节剂	NASH	不会降低LFC，但可以显著降低MRE测得的肝脏硬度	NCT03350165
VK2809	Thr-β激动剂	NAFLD	改善LDL-C和降低肝脏脂肪	NCT02927184
Efruxifermin	Fc-FGF21融合蛋白	NASH (F1~F3)	肝脏脂肪显著减少，纤维化获得逆转	NCT03976401
BIO89-100	FGF21类似物	NASH	安全性及耐受性良好，肝脏脂肪和关键脂质标志物明显降低	NCT04929483
PF-05221304	ACC1/2抑制剂	NAFLD	显著减少肝脏脂肪，并改善了一些NASH相关的生物标志物，可能会引起高脂血症进而增加心脏代谢疾病的风险	NCT03248882
PF-05221304+ PF-06865571	ACC1/2抑制剂+ DGAT2抑制剂	NAFLD	显著减少肝脏脂肪，有效缓解ACC抑制剂介导的TG升高	NCT03776175
PXL770	AMPK激活剂	NAFLD	未达到肝脏脂肪改善的主要结果，但治疗后代谢特征得到改善; 治疗耐受性良好	NCT03763877
TVB-2640 (ASC40)	FASN抑制剂	NASH	以剂量依赖的方式显著降低LFC并改善生化、炎症和纤维化生物标志物	NCT03938246
Tipelukast	PDE抑制剂	NAFLD	显著降低平均血清TG水平	NCT02681055
Namodenoson	A3AR激动剂	NAFLD/NASH	改善ALT、AST和脂联素等各种肝脏参数; 安全性良好	NCT02927314

下载: 导出CSV

表 2 NASH临床试验Ⅲ期在研药物

Table 2. The ongoing phase Ⅲ clinical trials for NASH

药物	作用机制	研究人群	主要终点	NCT代码
奥贝胆酸	FXR激动剂	NASH F2/3期	(1)肝纤维化改善≥1级且无NASH病情恶化，或(2)在无肝纤维化恶化的情况下，NASH病情缓解	NCT02548351
Saroglitazar+ Vitamin E	联合用药	NASH	NAFLD肝纤维化评分在8、16和24周的变化	NCT04193982
Lanifibranor	PPAR泛激动剂	NASH F2/3期	(1)通过肝组织学评估Lanifibranor对脂肪性肝炎缓解和肝纤维化改善的影响; (2)通过复合终点测量评估Lanifibranor对延缓NASH疾病进展的效果	NCT04849728
Resmetirom	THR-β激动剂	NASH F2/3期	(1)NASH消退(NAS降低≥2分且无肝纤维化恶化); (2)对长期复合终点的影响	NCT03900429
Aramchol	SCD1抑制剂	NASH	开放性标签研究：在24、48和72周治疗期间与NASH和纤维化相关的组织学结局指标和测量几种无创检查的动力学; 双盲部分：(1)对肝组织学的影响; (2)对长期复合终点的影响	NCT04104321
Semaglutide	GLP-1受体激动剂	NASH	(1)从随机化(第0周)至第72周，脂肪性肝炎缓解且肝纤维化无恶化(是/否); (2)从随机化(第0周)至第72周，肝纤维化改善且脂肪性肝炎无恶化(是/否); (3)从随机化(第0周)至第240周，至首例肝脏相关临床事件的时间(复合终点)	NCT04822181
MSDC-0602K	MPC	糖尿病前期或糖尿病合并NAFLD或NASH	(1)从基线到第26周糖化血红蛋白(HbA1c) 的变化; (2)从基线到第26周标准化AST、CK-18和HbA1c值的加权平均值(标准偏差)的变化	NCT03970031
GR-MD-02	Galectin-3拮抗剂	NASH	治疗组中在治疗78周时出现新的食管静脉曲张的患者比例	NCT04365868

下载: 导出CSV

参考文献(46)

[1]	HUANG DQ, EL-SERAG HB, LOOMBA R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(4): 223-238. DOI: 10.1038/s41575-020-00381-6.
[2]	Recommendations of the Polish Group of Experts for Non-Alcoholic Fatty Liver Disease (PGE-NAFLD), TOMASIEWICZ K, FLISIAK R, et al. Recommendations for the management of non-alcoholic fatty liver disease (NAFLD)[J]. Clin Exp Hepatol, 2018, 4(3): 153-157. DOI: 10.5114/ceh.2018.78118.
[3]	BERARDO C, di PASQUA LG, CAGNA M, et al. Nonalcoholic fatty liver disease and non-alcoholic steatohepatitis: current issues and future perspectives in preclinical and clinical research[J]. Int J Mol Sci, 2020, 21(24). DOI: 10.3390/ijms21249646.
[4]	PAN M, CEDERBAUM AI, ZHANG YL, et al. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production[J]. J Clin Invest, 2004, 113(9): 1277-1287. DOI: 10.1172/JCI19197.
[5]	BUZZETTI E, PINZANI M, TSOCHATZIS EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)[J]. Metabolism, 2016, 65(8): 1038-1048. DOI: 10.1016/j.metabol.2015.12.012.
[6]	HEBBARD L, GEORGE J. Animal models of nonalcoholic fatty liver disease[J]. Nat Rev Gastroenterol Hepatol, 2011, 8(1): 35-44. DOI: 10.1038/nrgastro.2010.191.
[7]	CAI J, ZHANG XJ, LI H. Progress and challenges in the prevention and control of nonalcoholic fatty liver disease[J]. Med Res Rev, 2019, 39(1): 328-348. DOI: 10.1002/med.21515.
[8]	POWELL EE, WONG VW, RINELLA M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397(10290): 2212-2224. DOI: 10.1016/S0140-6736(20)32511-3.
[9]	SUMIDA Y, OKANOUE T, NAKAJIMA A, et al. Phase 3 drug pipelines in the treatment of non-alcoholic steatohepatitis[J]. Hepatol Res, 2019, 49(11): 1256-1262. DOI: 10.1111/hepr.13425.
[10]	YOUNOSSI ZM, RATZIU V, LOOMBA R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial[J]. Lancet, 2019, 394(10215): 2184-2196. DOI: 10.1016/S0140-6736(19)33041-7.
[11]	POCKROS PJ, FUCHS M, FREILICH B, et al. CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients[J]. Liver Int, 2019, 39(11): 2082-2093. DOI: 10.1111/liv.14209.
[12]	SUMIDA Y, YONEDA M, OGAWA Y, et al. Current and new pharmacotherapy options for non-alcoholic steatohepatitis[J]. Expert Opin Pharmacother, 2020, 21(8): 953-967. DOI: 10.1080/14656566.2020.1744564.
[13]	FIORUCCI S, BIAGIOLI M, SEPE V, et al. Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)[J]. Expert Opin Investig Drugs, 2020, 29(6): 623-632. DOI: 10.1080/13543784.2020.1763302.
[14]	HARRISON SA, ROSSI SJ, PAREDES AH, et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis[J]. Hepatology, 2020, 71(4): 1198-1212. DOI: 10.1002/hep.30590.
[15]	FRANCQUE S, SZABO G, ABDELMALEK MF, et al. Nonalcoholic steatohepatitis: The role of peroxisome proliferator-activated receptors[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(1): 24-39. DOI: 10.1038/s41575-020-00366-5.
[16]	GAWRIEH S, NOUREDDIN M, LOO N, et al. Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: A randomized controlled double-blind phase 2 trial[J]. Hepatology, 2021, 74(4): 1809-1824. DOI: 10.1002/hep.31843.
[17]	STAELS B, RUBENSTRUNK A, NOEL B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J]. Hepatology, 2013, 58(6): 1941-1952. DOI: 10.1002/hep.26461.
[18]	HARRISON S, RATZIU V, ANSTEE QM, et al. Baseline levels of NIS4TM and other fibrosis biomarkers and prediction of histological progression to advanced fibrosis in NASH[J]. Hepatology 72(S1): 896A.
[19]	LEFERE S, PUENGEL T, HUNDERTMARK J, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages[J]. J Hepatol, 2020, 73(4): 757-770. DOI: 10.1016/j.jhep.2020.04.025.
[20]	VATNER DF, WEISMANN D, BEDDOW SA, et al. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways[J]. Am J Physiol Endocrinol Metab, 2013, 305(1): E89- E100. DOI: 10.1152/ajpendo.00573.2012.
[21]	HARRISON SA, BASHIR MR, GUY CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial[J]. Lancet, 2019, 394(10213): 2012-2024. DOI: 10.1016/S0140-6736(19)32517-6.
[22]	KHARITONENKOV A, ADAMS AC. Inventing new medicines: The FGF21 story[J]. Mol Metab, 2014, 3(3): 221-229. DOI: 10.1016/j.molmet.2013.12.003.
[23]	SANYAL A, CHARLES ED, NEUSCHWANDER-TETRI BA, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial[J]. Lancet, 2019, 392(10165): 2705-2717. DOI: 10.1016/S0140-6736(18)31785-9.
[24]	HARRISON SA, RUANE PJ, FREILICH BL, et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial[J]. Nat Med, 2021, 27(7): 1262-1271. DOI: 10.1038/s41591-021-01425-3.
[25]	DOBRZYN P, DOBRZYN A, MIYAZAKI M, et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver[J]. Proc Natl Acad Sci U S A, 2004, 101(17): 6409-6414. DOI: 10.1073/pnas.0401627101.
[26]	LOOMBA R, MOHSENI R, LUCAS KJ, et al. TVB-2640 (FASN Inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial[J]. Gastroenterology, 2021, 161(5): 1475-1486. DOI: 10.1053/j.gastro.2021.07.025.
[27]	KIM CW, ADDY C, KUSUNOKI J, et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation[J]. Cell Metab, 2017, 26(3): 576. DOI: 10.1016/j.cmet.2017.08.011.
[28]	CALLE RA, AMIN NB, CARVAJAL-GONZALEZ S, et al. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: Two parallel, placebo-controlled, randomized phase 2a trials[J]. Nat Med, 2021, 27(10): 1836-1848. DOI: 10.1038/s41591-021-01489-1.
[29]	LOOMBA R, MORGAN E, WATTS L, et al. Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial[J]. Lancet Gastroenterol Hepatol, 2020, 5(9): 829-838. DOI: 10.1016/S2468-1253(20)30186-2.
[30]	CUSI K, ALKHOURI N, HARRISON SA, et al. Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study[J]. Lancet Gastroenterol Hepatol, 2021, 6(11): 889-902. DOI: 10.1016/S2468-1253(21)00300-9.
[31]	ARMSTRONG MJ, GAUNT P, AITHAL GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study[J]. Lancet, 2016, 387(10019): 679-690. DOI: 10.1016/S0140-6736(15)00803-X.
[32]	HARTMAN ML, SANYAL AJ, LOOMBA R, et al. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes[J]. Diabetes Care, 2020, 43(6): 1352-1355. DOI: 10.2337/dc19-1892.
[33]	CUI J, PHILO L, NGUYEN P, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial[J]. J Hepatol, 2016, 65(2): 369-376. DOI: 10.1016/j.jhep.2016.04.021.
[34]	COLCA JR, MCDONALD WG, ADAMS WJ. MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis[J]. Expert Opin Investig Drugs, 2018, 27(7): 631-636. DOI: 10.1080/13543784.2018.1494153.
[35]	HARRISON SA, ALKHOURI N, DAVISON BA, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase Ⅱb study[J]. J Hepatol, 2020, 72(4): 613-626. DOI: 10.1016/j.jhep.2019.10.023.
[36]	SAFADI R, BRAUN M, FRANCIS A, et al. Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis[J]. Aliment Pharmacol Ther, 2021, 54(11-12): 1405-1415. DOI: 10.1111/apt.16664.
[37]	FRIEDMAN SL, RATZIU V, HARRISON SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis[J]. Hepatology, 2018, 67(5): 1754-1767. DOI: 10.1002/hep.29477.
[38]	RATZIU V, SANYAL A, HARRISON SA, et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study[J]. Hepatology, 2020, 72(3): 892-905. DOI: 10.1002/hep.31108.
[39]	ANSTEE QM, NEUSCHWANDER-TETRI BA, WONG VW, et al. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design[J]. Contemp Clin Trials, 2020, 89: 105922. DOI: 10.1016/j.cct.2019.105922.
[40]	BRENNER C, GALLUZZI L, KEPP O, et al. Decoding cell death signals in liver inflammation[J]. J Hepatol, 2013, 59(3): 583-594. DOI: 10.1016/j.jhep.2013.03.033.
[41]	HSU MC, LIU SH, WANG CW, et al. JKB-122 is effective, alone or in combination with prednisolone in Con A-induced hepatitis[J]. Eur J Pharmacol, 2017, 812: 113-120. DOI: 10.1016/j.ejphar.2017.07.012.
[42]	HENDERSON NC, SETHI T. The regulation of inflammation by galectin-3[J]. Immunol Rev, 2009, 230(1): 160-171. DOI: 10.1111/j.1600-065X.2009.00794.x.
[43]	HARRISON SA, MARRI SR, CHALASANI N, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis[J]. Aliment Pharmacol Ther, 2016, 44(11-12): 1183-1198. DOI: 10.1111/apt.13816.
[44]	CHALASANI N, ABDELMALEK MF, GARCIA-TSAO G, et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension[J]. Gastroenterology, 2020, 158(5): 1334-1345. e5. DOI: 10.1053/j.gastro.2019.11.296.
[45]	HARRISON SA, ABDELMALEK MF, CALDWELL S, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis[J]. Gastroenterology, 2018, 155(4): 1140-1153. DOI: 10.1053/j.gastro.2018.07.006.
[46]	MCPHERSON S, WILKINSON N, TINIAKOS D, et al. A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis[J]. PLoS One, 2017, 12(4): e0175717. DOI: 10.1371/journal.pone.0175717.