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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 6
Jun.  2022
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Advances in phase Ⅲ drug studies on the pipeline in nonalcoholic steatohepatitis

DOI: 10.3969/j.issn.1001-5256.2022.06.037
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  • Corresponding author: YAN Xuebing, yxbxuzhou@126.com(ORCID: 0000-0002-9307-3879)
  • Received Date: 2021-10-26
  • Accepted Date: 2021-11-28
  • Published Date: 2022-06-20
  • Nonalcoholic steatohepatitis (NASH) can cause end-stage liver diseases such as liver cirrhosis and liver cancer, and therefore, it is urgent to treat NASH, reverse hepatic steatosis, and delay the onset of end-stage liver diseases. NASH has a complex pathogenesis and there are currently no effective drugs for treatment. At present, new drugs still have huge market potential and are the research hotspots of various pharmaceutical companies in China and globally. This article mainly reviews and summarizes the clinical research status, drug types, mechanism of action, and future market prospects of the new drugs for NASH in existing phase Ⅲ studies.

     

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  • [1]
    NEGRO F. Natural history of NASH and HCC[J]. Liver Int, 2020, 40(Suppl 1): 72-76. DOI: 10.1111/liv.14362.
    [2]
    CHITTURI S, WONG VW, CHAN WK, et al. The Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 2: Management and special groups[J]. J Gastroenterol Hepatol, 2018, 33(1): 86-98. DOI: 10.1111/jgh.13856.
    [3]
    PENG C, STEWART AG, WOODMAN OL, et al. Non-alcoholic steatohepatitis: A review of its mechanism, models and medical treatments[J]. Front Pharmacol, 2020, 11: 603926. DOI: 10.3389/fphar.2020.603926.
    [4]
    MOTA M, BANINI BA, CAZANAVE SC, et al. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease[J]. Metabolism, 2016, 65(8): 1049-1061. DOI: 10.1016/j.metabol.2016.02.014.
    [5]
    QIAO B, ZHOU Y, MA WJ, et al. Intestinal microflora imbalance in non-alcoholic fatty liver disease[J/CD]. Chin J Liver Dis: Electronic Edition, 2020, 12(4): 29-33. DOI: 10.3969/j.issn.1674-7380.2020.04.005.

    乔兵, 周永, 马文洁, 等. 肠道菌群失调在非酒精性脂肪性肝病中研究进展[J/CD]. 中国肝脏病杂志(电子版), 2020, 12(4): 29-33. DOI: 10.3969/j.issn.1674-7380.2020.04.005.
    [6]
    BOURSIER J, MUELLER O, BARRET M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota[J]. Hepatology, 2016, 63(3): 764-775. DOI: 10.1002/hep.28356.
    [7]
    PAWLAK M, LEFEBVRE P, STAELS B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease[J]. J Hepatol, 2015, 62(3): 720-733. DOI: 10.1016/j.jhep.2014.10.039.
    [8]
    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.
    [9]
    KRISHNAPPA M, PATIL K, PARMAR K, et al. Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: A 56-week, randomized, double blind, phase 3 study (PRESS XⅡ study)[J]. Cardiovasc Diabetol, 2020, 19(1): 93. DOI: 10.1186/s12933-020-01073-w.
    [10]
    SVEN MF, PIERRE B, MANAL FA, et al. A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study[J]. Contemp Clin Trials, 2020, 98: 106170. DOI: 10.1016/j.cct.2020.106170.
    [11]
    ZAREI M, AGUILAR-RECARTE D, PALOMER X, et al. Revealing the role of peroxisome proliferator-activated receptor β/δ in nonalcoholic fatty liver disease[J]. Metabolism, 2021, 114: 154342. DOI: 10.1016/j.metabol.2020.154342.
    [12]
    MCCOMMIS KS, HODGES WT, BRUNT EM, et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis[J]. Hepatology, 2017, 65(5): 1543-1556. DOI: 10.1002/hep.29025.
    [13]
    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.
    [14]
    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.
    [15]
    BHATTACHARYA D, BASTA B, MATO JM, et al. Aramchol downregulates stearoyl CoA-desaturase 1 in hepatic stellate cells to attenuate cellular fibrogenesis[J]. JHEP Rep, 2021, 3(3): 100237. DOI: 10.1016/j.jhepr.2021.100237.
    [16]
    FERNÁNDEZ-RAMOS D, LOPITZ-OTSOA F, DELACRUZ-VILLAR L, et al. Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation[J]. World J Gastroenterol, 2020, 26(34): 5101-5117. DOI: 10.3748/wjg.v26.i34.5101.
    [17]
    SAFADI R, KONIKOFF FM, MAHAMID M, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease[J]. Clin Gastroenterol Hepatol, 2014, 12(12): 2085-2091. e1. DOI: 10.1016/j.cgh.2014.04.038.
    [18]
    ALKHOURI N. Thyromimetics as emerging therapeutic agents for nonalcoholic steatohepatitis: Rationale for the development of resmetirom (MGL-3196)[J]. Expert Opin Investig Drugs, 2020, 29(2): 99-101. DOI: 10.1080/13543784.2020.1708899.
    [19]
    HARRISON SA, BASHIR M, MOUSSA SE, et al. Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH[J]. Hepatol Commun, 2021, 5(4): 573-588. DOI: 10.1002/hep4.1657.
    [20]
    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.
    [21]
    KNUDSEN LB, LAU J. The discovery and development of liraglutide and semaglutide[J]. Front Endocrinol (Lausanne), 2019, 10: 155. DOI: 10.3389/fendo.2019.00155.
    [22]
    GHAZANFAR H, KANDHI SD, NAWAZ I, et al. Role of glucagon-like peptide-1 receptor agonists in the management of non-alcoholic steatohepatitis: A clinical review article[J]. Cureus, 2021, 13(5): e15141. DOI: 10.7759/cureus.15141.
    [23]
    LEFERE S, DEVISSCHER L, TACKE F. Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: Opportunities and challenges[J]. Expert Opin Investig Drugs, 2020, 29(2): 89-92. DOI: 10.1080/13543784.2020.1718106.
    [24]
    KRUGER AJ, FUCHS BC, MASIA R, et al. Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis[J]. Hepatol Commun, 2018, 2(5): 529-545. DOI: 10.1002/hep4.1160.
    [25]
    KRENKEL O, PUENGEL T, GOVAERE O, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis[J]. Hepatology, 2018, 67(4): 1270-1283. DOI: 10.1002/hep.29544.
    [26]
    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.
    [27]
    AL ATTAR A, ANTARAMIAN A, NOUREDDIN M. Review of galectin-3 inhibitors in the treatment of nonalcoholic steatohepatitis[J]. Expert Rev Clin Pharmacol, 2021, 14(4): 457-464. DOI: 10.1080/17512433.2021.1894127.
    [28]
    HENDERSON NC, MACKINNON AC, FARNWORTH SL, et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis[J]. Proc Natl Acad Sci U S A, 2006, 103(13): 5060-5065. DOI: 10.1073/pnas.0511167103.
    [29]
    HARRISON SA, DENNIS A, FIORE MM, et al. Utility and variability of three non-invasive liver fibrosis imaging modalities to evaluate efficacy of GR-MD-02 in subjects with NASH and bridging fibrosis during a phase-2 randomized clinical trial[J]. PLoS One, 2018, 13(9): e0203054. DOI: 10.1371/journal.pone.0203054.
    [30]
    ZHU Y, LIU H, ZHANG M, et al. Fatty liver diseases, bile acids, and FXR[J]. Acta Pharm Sin B, 2016, 6(5): 409-412. DOI: 10.1016/j.apsb.2016.07.008.
    [31]
    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.
    [32]
    CARIOU B, ZAÏR Y, STAELS B, et al. Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism[J]. Diabetes Care, 2011, 34(9): 2008-2014. DOI: 10.2337/dc11-0093.
    [33]
    RATZIU V, HARRISON SA, FRANCQUE S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and-δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening[J]. Gastroenterology, 2016, 150(5): 1147-1159. e5. DOI: 10.1053/j.gastro.2016.01.038.
    [34]
    ClinicalTrials. gov. Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH)[EB/OL]. [2022-03-23]. https://clinicaltrials.gov/ct2/show/NCT02704403?term=RESOLVE-IT&draw=1&rank=1
    [35]
    XIANG M, WANG PX, WANG AB, et al. Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis[J]. J Hepatol, 2016, 64(6): 1365-1377. DOI: 10.1016/j.jhep.2016.02.002.
    [36]
    LOOMBA R, LAWITZ E, MANTRY PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial[J]. Hepatology, 2018, 67(2): 549-559. DOI: 10.1002/hep.29514.
    [37]
    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.
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