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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

黄樱硕,董瑞华,尤红. 非酒精性脂肪性肝炎新药临床试验的难度与挑战[J]. 临床肝胆病杂志, 2021, 37(8): 1948-1952. DOI: 10.3969/j.issn.1001-5256.2021.08.044
引用本文: 黄樱硕,董瑞华,尤红. 非酒精性脂肪性肝炎新药临床试验的难度与挑战[J]. 临床肝胆病杂志, 2021, 37(8): 1948-1952. DOI: 10.3969/j.issn.1001-5256.2021.08.044
HUANG YS, DONG RH, YOU H. Difficulties and challenges in the clinical trial of new drugs for nonalcoholic steatohepatitis[J]. J Clin Hepatol, 2021, 37(8): 1948-1952. DOI: 10.3969/j.issn.1001-5256.2021.08.044
Citation: HUANG YS, DONG RH, YOU H. Difficulties and challenges in the clinical trial of new drugs for nonalcoholic steatohepatitis[J]. J Clin Hepatol, 2021, 37(8): 1948-1952. 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
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

详细信息
    通讯作者:

    尤红,youhongliver@ccmu.edu.cn

  • 中图分类号: R575.5

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

Funds: 

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: 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。

     

  • 图  1  NAFLD/NASH药物治疗的作用机制

    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。
    下载: 导出CSV
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    [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.
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    [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.
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  • 收稿日期:  2021-01-01
  • 修回日期:  2021-01-22
  • 刊出日期:  2021-08-20
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