Difficulties and challenges in the clinical trial of new drugs for nonalcoholic steatohepatitis

Yingshuo HUANG; Ruihua DONG; Hong YOU

doi:10.3969/j.issn.1001-5256.2021.08.044

Volume 37 Issue 8

Aug. 2021

Turn off MathJax

Article Contents

Abstract

References

Article Navigation > Journal of Clinical Hepatology > 2021 > 37(8): 1948-1952

PDF( 2745 KB)

Difficulties and challenges in the clinical trial of new drugs for nonalcoholic steatohepatitis

DOI: 10.3969/j.issn.1001-5256.2021.08.044

1.
Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
2.
Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing 100050, China

Research funding:

Project of Beijing Municipal Science & Technology Commission (Z191100007619037);

National Science and Technology Major Project during the 13th Five-Year Plan Period (2018ZX09201016);

Demonstration Construction Units of Beijing Research Wards (BCRW202010)

Received Date: 2021-01-01
Accepted Date: 2021-01-22
Published Date: 2021-08-20

Abstract

Abstract

The incidence rate of nonalcoholic steatohepatitis (NASH) keeps increasing in recent years, and there is still a lack of effective therapeutic drugs in clinical practice. This article analyzes the difficulties in the clinical trial of new drugs for NASH from the aspects of the heterogeneity of NASH (body weight, sex, age, and metabolic factors), the influence of confounding factors, and the diagnostic consistency of quantitative indicators, and it is pointed out that conducting a stratified analysis, reducing the influence of confounding factors, and improving diagnostic consistency can help to improve the quality of the clinical trials of new drugs for NASH. Combination therapy including lifestyle improvement may be an effective treatment strategy for NASH, and therapies aiming at improving NASH, exerting an anti-fibrosis effect, and obtaining long-term metabolic benefits are the direction for drug research and development in the future.
- Non-Alcoholic Steatohepatitis,
- Drugs, Investigational,
- Therapeutics

FullText(HTML)

References(40)

References

[1]	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.
[2]	CHALASANI N, YOUNOSSI Z, LAVINE JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases[J]. Hepatology, 2018, 67(1): 328-357. DOI: 10.1002/hep.29367.
[3]	European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease[J]. J Hepatol, 2016, 64(6): 1388-1402. DOI: 10.1016/j.jhep.2015.11.004.
[4]	RINELLA ME, LOOMBA R, CALDWELL SH, et al. Controversies in the diagnosis and management of NAFLD and NASH[J]. Gastroenterol Hepatol (N Y), 2014, 10(4): 219-227.
[5]	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.
[6]	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.
[7]	KONERMAN MA, JONES JC, HARRISON SA. Pharmacotherapy for NASH: Current and emerging[J]. J Hepatol, 2018, 68(2): 362-375. DOI: 10.1016/j.jhep.2017.10.015.
[8]	SIDDIQUI MS, IDOWU MO, PARMAR D, et al. A phase 2 double blinded, randomized controlled trial of saroglitazar in patients with nonalcoholic steatohepatitis[J]. Clin Gastroenterol Hepatol, 2020. DOI: 10.1016/j.cgh.2020.10.051.[Onlineaheadofprint]
[9]	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.
[10]	HARRISON SA, WONG VW, OKANOUE T, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase Ⅲ STELLAR trials[J]. J Hepatol, 2020, 73(1): 26-39. DOI: 10.1016/j.jhep.2020.02.027.
[11]	Gilead Science. Safety and efficacy of selonsertib in adults with nonalcoholic steatohepatitis (NASH) and bridging (F3) fibrosis (STELLAR-3)[EB/OL]. [2021-01-21]. https://clinicaltrials.gov/ct2/show/NCT03053050.
[12]	Gilead Science. Safety and efficacy of selonsertib in adults with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH) (STELLAR-4)[EB/OL]. [2021-01-21]. https://clinicaltrials.gov/ct2/show/NCT03053063.
[13]	Genfit. Phase 3 study to evaluate the efficacy and safety of elafibranor versus placebo in patients with nonalcoholic steatohepatitis (NASH) (RESOLVE-IT)[EB/OL]. [2021-01-21]. https://clinicaltrials.gov/ct2/show/NCT02704403.
[14]	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.
[15]	Tobira Therapeutics Inc. AURORA: Phase 3 study for the efficacy and safety of CVC for the treatment of liver fibrosis in adults with NASH[EB/OL]. [2021-01-21]. https://clinicaltrials.gov/ct2/show/NCT03028740.
[16]	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.
[17]	Madrigal Pharmaceuticals Inc. Phase 2 study of MGL-3196 in patients with non-alcoholic steatohepatitis (NASH)[EB/OL]. [2021-01-21]. https://clinicaltrials.gov/ct2/show/NCT02912260.
[18]	CHIANELLI D, RUCKER PV, ROLAND J, et al. Nidufexor (LMB763), a novel FXR modulator for the treatment of nonalcoholic steatohepatitis[J]. J Med Chem, 2020, 63(8): 3868-3880. DOI: 10.1021/acs.jmedchem.9b01621.
[19]	Sagimet Biosciences Inc. Study of TVB 2640 in subjects with non-alcoholic steatohepatitis (NASH)[EB/OL]. [2021-01-21]. https://clinicaltrials.gov/ct2/show/NCT03938246.
[20]	A study of HTD1801 in adults with nonalcoholic steatohepatitis (NASH) and type 2 diabetes mellitus (T2DM)[EB/OL]. [2021-01-21]. https://clinicaltrials.gov/ct2/show/NCT03656744.
[21]	Guangdong Zhongsheng Pharmaceutical Co. Ltd. Tolerability, pharmacokinetics, and early pharmacodynamics of ZSP1601 tablets in NASH patients: A multicenter, randomized, double-blind, dose-escalation, and placebo-controlled phase Ib/Ⅱa clinical trial[EB/OL]. [2021-01-21]. http://www.chinadrugtrials.org.cn. 广东众生药业股份有限公司. 评价ZSP1601片在NASH患者多中心、随机、双盲、剂量递增、安慰剂对照的耐受性、药代动力学和早期药效学Ib/Ⅱa期临床试验[EB/OL]. [2021-01-21]. http://www.chinadrugtrials.org.cn.
[22]	YOUNES R, BUGIANESI E. NASH in lean individuals[J]. Semin Liver Dis, 2019, 39(1): 86-95. DOI: 10.1055/s-0038-1677517.
[23]	SHI Y, WANG Q, SUN Y, et al. The prevalence of lean/nonobese nonalcoholic fatty liver disease: A systematic review and meta-analysis[J]. J Clin Gastroenterol, 2020, 54(4): 378-387. DOI: 10.1097/MCG.0000000000001270.
[24]	HAGSTRÖM H, NASR P, EKSTEDT M, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study[J]. Hepatol Commun, 2018, 2(1): 48-57. DOI: 10.1002/hep4.1124.
[25]	WANG Q, YOU H, OU X, et al. Non-obese histologically confirmed NASH patients with abnormal liver biochemistry have more advanced fibrosis[J]. Hepatol Int, 2019, 13(6): 766-776. DOI: 10.1007/s12072-019-09982-z.
[26]	TOBARI M, HASHIMOTO E, TANIAI M, et al. Characteristics of non-alcoholic steatohepatitis among lean patients in Japan: Not uncommon and not always benign[J]. J Gastroenterol Hepatol, 2019, 34(8): 1404-1410. DOI: 10.1111/jgh.14585.
[27]	CURCIC IB, BERKOVIC MC, KUNA L, et al. Obesity paradox in chronic liver diseases: Product of bias or a real thing?[J]. J Clin Transl Hepatol, 2019, 7(3): 275-279. DOI: 10.14218/JCTH.2019.00029.
[28]	LONARDO A, NASCIMBENI F, BALLESTRI S, et al. Sex differences in nonalcoholic fatty liver disease: State of the art and identification of research gaps[J]. Hepatology, 2019, 70(4): 1457-1469. DOI: 10.1002/hep.30626.
[29]	SHEEDFAR F, DI BIASE S, KOONEN D, et al. Liver diseases and aging: Friends or foes?[J]. Aging Cell, 2013, 12(6): 950-954. DOI: 10.1111/acel.12128.
[30]	YOUNOSSI ZM, GOLABI P, de AVILA L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis[J]. J Hepatol, 2019, 71(4): 793-801. DOI: 10.1016/j.jhep.2019.06.021.
[31]	BAZICK J, DONITHAN M, NEUSCHWANDER-TETRI BA, et al. Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: Guidelines for referral in NAFLD[J]. Diabetes Care, 2015, 38(7): 1347-1355. DOI: 10.2337/dc14-1239.
[32]	SUNG KC, WILD SH, BYRNE CD. Resolution of fatty liver and risk of incident diabetes[J]. J Clin Endocrinol Metab, 2013, 98(9): 3637-3643. DOI: 10.1210/jc.2013-1519.
[33]	LONARDO A, NASCIMBENI F, MANTOVANI A, et al. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence?[J]. J Hepatol, 2018, 68(2): 335-352. DOI: 10.1016/j.jhep.2017.09.021.
[34]	AMPUERO J, ALLER R, GALLEGO-DURáN R, et al. The effects of metabolic status on non-alcoholic fatty liver disease-related outcomes, beyond the presence of obesity[J]. Aliment Pharmacol Ther, 2018, 48(11-12): 1260-1270. DOI: 10.1111/apt.15015.
[35]	VILAR-GOMEZ E, MARTINEZ-PEREZ Y, CALZADILLA-BERTOT L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis[J]. Gastroenterology, 2015, 149(2): 367-378. DOI: 10.1053/j.gastro.2015.04.005.
[36]	ROMERO-GÓMEZ M, ZELBER-SAGI S, TRENELL M. Treatment of NAFLD with diet, physical activity and exercise[J]. J Hepatol, 2017, 67(4): 829-846. DOI: 10.1016/j.jhep.2017.05.016.
[37]	DAVISON BA, HARRISON SA, COTTER G, et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials[J]. J Hepatol, 2020, 73(6): 1322-1332. DOI: 10.1016/j.jhep.2020.06.025.
[38]	HOOKER JC, HAMILTON G, PARK CC, et al. Inter-reader agreement of magnetic resonance imaging proton density fat fraction and its longitudinal change in a clinical trial of adults with nonalcoholic steatohepatitis[J]. Abdom Radiol (NY), 2019, 44(2): 482-492. DOI: 10.1007/s00261-018-1745-3.
[39]	HONG CW, MARSH A, WOLFSON T, et al. Reader agreement and accuracy of ultrasound features for hepatic steatosis[J]. Abdom Radiol (NY), 2019, 44(1): 54-64. DOI: 10.1007/s00261-018-1683-0.
[40]	RATZIU V, FRIEDMAN SL. Why do so many NASH trials fail?[J]. Gastroenterology, 2020. DOI: 10.1053/j.gastro.2020.05.046.[Onlineaheadofprint]

Relative Articles

[1]	Zhenyang SHEN, Xiaobo CAI, Lungen LU. Application of farnesoid X receptor agonists in treatment of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2022, 38(6): 1402-1405. doi: 10.3969/j.issn.1001-5256.2022.06.038
[2]	Yingshuo HUANG, Wei WEI, Xiaofei TONG, Yameng SUN, Jianxiong ZHANG, Ruihua DONG, Jidong JIA, Hong YOU. Clinical trial protocols of new drugs for nonalcoholic steatohepatitis: A systematic review[J]. Journal of Clinical Hepatology, 2022, 38(4): 798-804. doi: 10.3969/j.issn.1001-5256.2022.04.012
[3]	Rui JIN, Xiaoxiao WANG, Feng LIU, Huiying RAO. Research advances in pharmacotherapy for nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2022, 38(7): 1634-1640. doi: 10.3969/j.issn.1001-5256.2022.07.033
[4]	Yu WANG, Xuebing YAN. Advances in phase Ⅲ drug studies on the pipeline in nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2022, 38(6): 1398-1401. doi: 10.3969/j.issn.1001-5256.2022.06.037
[5]	Xinyu AN, Lingxi HU, Jie QIAO, Rongqi WANG, Yuemin NAN. Role of microRNAs in the development and progression of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2021, 37(12): 2963-2966. doi: 10.3969/j.issn.1001-5256.2021.12.048
[6]	Kun XU, Xu ZHANG, Ying LI, Zhenbin HU. Advances in investigational new drugs for nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2021, 37(7): 1699-1703. doi: 10.3969/j.issn.1001-5256.2021.07.047
[7]	Ziming AN, Qin FENG. Magnetic resonance imaging-proton density fat fraction: A potential surrogate endpoint for nonalcoholic steatohepatitis clinical trials[J]. Journal of Clinical Hepatology, 2021, 37(6): 1445-1448. doi: 10.3969/j.issn.1001-5256.2021.06.047
[8]	Song QingLian, Tan YuE, Liu JingJing, Yuan BeiBei, Li Min, He LiQin, Dai GuangRong. Establishment of a rat model of nonalcoholic steatohepatitis and histopathological changes of the pancreas and the kidney[J]. Journal of Clinical Hepatology, 2020, 36(1): 140-144. doi: 10.3969/j.issn.1001-5256.2020.01.031
[9]	QIAN ShuaiJie, GU JingYue, GAO JinHang, TONG Huan. Advances in therapeutic drugs for nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2020, 36(12): 2826-2830. doi: 10.3969/j.issn.1001-5256.2020.12.039
[10]	Chen Jun, Li LiangPing, Fu WanZhi. Value of microparticles in the diagnosis of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2019, 35(9): 2026-2031. doi: 10.3969/j.issn.1001-5256.2019.09.028
[11]	Chang Yue, Li Hai. The role of gut microbiota in the development and progression of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2018, 34(6): 1343-1346. doi: 10.3969/j.issn.1001-5256.2018.06.045
[12]	Jiang Yu, Hu JuLong, Ma JiaLi, Li Ping, Zhou YuLing, Liang XiuXia, Ai ZhengLin, Yao ShuKun. Antioxidant effect of berberine in a rat model of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2018, 34(6): 1273-1276. doi: 10.3969/j.issn.1001-5256.2018.06.028
[13]	Hu Ying, Li LiangPing. Serological noninvasive diagnosis of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2018, 34(9): 2004-2007. doi: 10.3969/j.issn.1001-5256.2018.09.037
[14]	Hu MengQi, Xu YouQing, Zhang Tao, Xu HongTuan. Research advances in noninvasive diagnostic methods for nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2017, 33(12): 2288-2291. doi: 10.3969/j.issn.1001-5256.2017.12.006
[15]	Mao YiMin. Clinical trials of investigational new drugs for nonalcoholic steatohepatitis:challenges in design and practice[J]. Journal of Clinical Hepatology, 2017, 33(12): 2292-2295. doi: 10.3969/j.issn.1001-5256.2017.12.007
[16]	Huang Ning, Wu WanChun. The effect of low iron loads on Nonalcoholic Steatohepatitis in rats[J]. Journal of Clinical Hepatology, 2009, 25(6): 427-430.
[18]	Wang HuiChao, Ye HongJun, Wei ShiLiang, Liu XiaoYi, Wan HuiJuan, Du YiPing. Therapeutic effects of compound glycyrrhizin liposome on rats with nonalcoholic steatohepatitis.[J]. Journal of Clinical Hepatology, 2008, 24(3): 199-201.
[20]	Dai Lin, Deng Bin, Li AiPing, Yu HongBo, Bai Cheng, Lu ShengMing. Experimental study on the pathogenesis of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2004, 20(5): 285-286.

Supplements(0)

Cited By

Cited by

Periodical cited type(4)

1.	罗昕，陆伦根，茅益民. 代谢功能障碍相关脂肪性肝病新药临床试验现状和挑战. 中华肝脏病杂志. 2024(04): 300-302 .
2.	汪云，崔桅. 非酒精性脂肪性肝炎在研新药的现状及进展. 中国处方药. 2023(08): 190-193 .
3.	万一心，赵文霞，刘晓彦. 消脂护肝胶囊对痰湿瘀阻型非酒精性脂肪性肝炎患者肝脂肪变的影响. 中医学报. 2023(09): 1985-1991 .
4.	马海林，权莉，蒋升. 非酒精性脂肪性肝病合并2型糖尿病患者的临床特征及危险因素分析. 中国医药导报. 2022(21): 70-73+82 .

Other cited types(3)

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Figures(1) / Tables(1)

Get Citation

PDF

XML

Article Metrics

Article views (1202) PDF downloads(262)

Difficulties and challenges in the clinical trial of new drugs for nonalcoholic steatohepatitis

DOI: 10.3969/j.issn.1001-5256.2021.08.044