非酒精性脂肪性肝炎新药临床试验的难度与挑战

黄樱硕; 董瑞华; 尤红

doi:10.3969/j.issn.1001-5256.2021.08.044

非酒精性脂肪性肝炎新药临床试验的难度与挑战

DOI: 10.3969/j.issn.1001-5256.2021.08.044

1.
首都医科大学附属北京友谊医院研究型病房，北京 100050
2.
首都医科大学附属北京友谊医院肝病中心，肝硬化转化医学北京市重点实验室，国家消化系统疾病临床医学研究中心，北京 100050

基金项目:

北京市科委项目 (Z191100007619037);

国家"十三五"科技重大专项课题 (2018ZX09201016);

北京市研究型病房示范建设单位 (BCRW202010)

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：黄樱硕负责查询资料及分析，撰写论文；董瑞华参与修改论文；尤红拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
尤红，youhongliver@ccmu.edu.cn

中图分类号: R575.5
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- 被引次数: 0
出版历程
- 收稿日期: 2021-01-01
- 录用日期: 2021-01-22
- 出版日期: 2021-08-20

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

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)

摘要

摘要: 近年来非酒精性脂肪性肝炎(NASH)的发病率不断增长，且临床上缺乏有效的治疗药物。从NASH的异质性(如体质量、性别、年龄和代谢因素)、混杂因素的影响、量化指标的诊断一致性等方面分析了NASH新药临床试验开发的难度，提出可以通过分层分析、减弱混杂因素影响、提高诊断一致性等方式提高NASH新药临床试验的质量。包括生活方式改善在内的联合治疗可能是有效的NASH治疗策略，以改善NASH和抗纤维化及长期代谢获益为目标的治疗是未来药物研发的研究方向。
- 非酒精性脂肪性肝炎 /
- 药物, 临床试用 /
- 治疗学
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

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图 1 NAFLD/NASH药物治疗的作用机制

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表 1 国内外NASH新药研发情况

药物名称	研发公司	作用机制	研究及分期	研发情况
Obeticholic acid(奥贝胆酸)	Intercept	FXR激动剂	REGENERATE^[9]，3期	美国食品药品监督管理局拒绝上市(中期组织学终点数据带来的获益仍具有不确定性，建议提供后续有效性和安全性数据，以评估是否达到获益风险比)
Selonsertib/GS-0976	Gilead	ACC抑制剂	STELLAR-3^[10-11]和STELLAR-4^[12]，3期	以纤维化伴或不伴NASH恶化作为关键终点。STELLAR-3评估Selonsertib对NASH引起的桥接纤维化(F3)患者的安全性和有效性，未能到达48周的预期临床终点。STELLAR-4评估Selonsertib对NASH引起的代偿性肝硬化(F4)患者的安全性和有效性，亦未达到主要终点
Elafibranor	Genfit	PPARα/δ双重激动剂	RESOLVE-IT^[13]，3期	未能达到NASH病理改善伴或不伴纤维化恶化的关键终点
Cenicriviroc	Allergan	CCR2/CCR5受体抑制剂	AURORA^[14-15]，3期	以纤维化改善伴或不伴NASH恶化作为关键终点，评估CCR相比安慰剂治疗NASH患者的有效性和安全性。目前研究正在进行中
MGL-3196	Magrigal	TRβ激动剂	MAESTRO-NAFLD^[16-17]，3期	评估Resmetirom相比安慰剂治疗NAFLD/NASH患者的安全性和生化标志物。研究正在进行中
LMB763	诺华	FXR激动剂	ELIVATE^[18]，2期	研究终点为提高胰岛素敏感性，减少肝脂肪变、炎症和纤维化。研究正在进行中
ASC40	歌礼 & 3-V Biosciences	脂肪酸合成酶抑制剂	FASCINATE-1^[19]，2期	研究终点为降低肝脏脂肪含量。研究正在进行中
HTD1801^[20]	君圣泰	多功能小分子药物，机制未公布	2期	改善肝组织学特征，降低肝脏胆固醇和甘油三酯。研究正在进行中
ZSP1601^[21]	广东众生药业	小分子化学药物，机制未公布	Ⅰb/Ⅱa期	改善NASH纤维化。研究正在进行中
注：FXR，法尼酯X受体; ACC，乙酰辅酶A羧化酶；PPAR，过氧化物酶体增殖剂激活受体；CCR，Cenicriviroc；TR, 甲状腺受体。

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参考文献(40)

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