Skip to main content

Advertisement

Springer Nature Link
Log in

Overview of Clinical Treatment Trials for NASH

  • Fatty Liver Disease (S Harrison and J George, Section Editors)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Non-alcoholic fatty liver disease (NAFLD) is one of the most prominent forms of chronic liver disease. Non-alcoholic steatohepatitis (NASH) represents a subgroup of patients with steatosis and necro-inflammation with or without fibrosis. Currently, there are no FDA-approved therapies. This review provides an overview of treatments in clinical trials for NAFLD and NASH.

Recent Findings

Therapies aimed at reducing hepatic steatosis focus on lipogenesis, insulin resistance, and metabolism of free fatty acids. Therapeutics targeting necro-inflammation have focused on pathways of immune activation and hepatocyte injury, while anti-fibrotic agents have focused on preventing fibrosis development via actions on stellate cells or reducing existing fibrosis.

Summary

There are multiple agents in mid-to-late stage clinical trials to treat NAFLD and NASH. Many have shown promising results. If safety and efficacy are established, these medications will provide a much needed pharmacologic treatment approach for this burgeoning patient population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387–95.

    Article  PubMed  Google Scholar 

  2. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–85.

    Article  CAS  PubMed  Google Scholar 

  3. Dunn W, Xu R, Wingard DL, Rogers C, Angulo P, Younossi ZM, et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol. 2008;103(9):2263–71.

    Article  PubMed  PubMed Central  Google Scholar 

  4. •• Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2017. https://doi.org/10.1002/hep.29367. Updated guidelines from AASLD on management of NAFLD/NASH.

  5. Koehler E, Watt K, Charlton M. Fatty liver and liver transplantation. Clin Liver Dis. 2009;13(4):621–30.

    Article  PubMed  Google Scholar 

  6. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49(4):608–12.

    Article  PubMed  Google Scholar 

  7. • Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389–97.e10. Demonstrates impact of fibrosis stage on overall clinical outcomes.

    Article  PubMed  PubMed Central  Google Scholar 

  8. • Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547–54. Demonstrates impact of fibrosis stage on overall clinical outcomes.

    Article  CAS  PubMed  Google Scholar 

  9. Sato K, Gosho M, Yamamoto T, Kobayashi Y, Ishii N, Ohashi T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015;31(7–8):923–30.

    Article  CAS  PubMed  Google Scholar 

  10. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297(8):842–57.

    Article  CAS  PubMed  Google Scholar 

  11. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37–46.

    Article  CAS  PubMed  Google Scholar 

  12. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kristal AR, Darke AK, Morris JS, Tangen CM, Goodman PJ, Thompson IM, et al. Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst. 2014;106(3):djt456.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66–75.

    Article  CAS  PubMed  Google Scholar 

  15. Mahady SE, Webster AC, Walker S, Sanyal A, George J. The role of thiazolidinediones in non-alcoholic steatohepatitis—a systematic review and meta analysis. J Hepatol. 2011;55(6):1383–90.

    Article  CAS  PubMed  Google Scholar 

  16. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–8.

    Article  CAS  PubMed  Google Scholar 

  17. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.

    Article  PubMed  Google Scholar 

  18. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56(5):1751–9.

    Article  PubMed  Google Scholar 

  19. Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54(1):344–53.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Fuchs M. Non-alcoholic Fatty liver disease: the bile acid-activated farnesoid x receptor as an emerging treatment target. J Lipids. 2012;2012:934396.

    Article  PubMed  Google Scholar 

  21. •• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–65. FLINT trial assessing OCA for treatment of NASH.

    Article  CAS  PubMed  Google Scholar 

  22. •• Ratziu V, Sanyal AJ, MacConell L, Shringarpure R, Marmon T, Shapiro D, et al. Regenerate: a phase 3, double-blind, randomized, placebo-controlled multicenter study of obeticholic acid therapy for nonalcoholic steatohepatitis. J Hepatol. 2016;64(2):S294–S5. Regenerate trial of OCA in NASH.

    Article  Google Scholar 

  23. •• Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147–59.e5. GOLDEN-505 trial evaluating impact of elafibranor in NASH.

    Article  CAS  PubMed  Google Scholar 

  24. Clinical Trials.gov. Randomized global phase 3 study to evaluate the impact on NASH with fibrosis of obeticholic acid treatment (REGENERATE). 2017.

  25. Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12(12):2085–91.e1.

    Article  CAS  PubMed  Google Scholar 

  26. Clinical Trials.gov. A clinical trial to evaluate the efficacy and safety of two aramchol doses versus placebo in patients with NASH (Aramchol_005). 2017.

  27. Harrison SA Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, Kugelmas M, Bashir MB, Ling L, Rossi SJ, DePaoli AM, Rinella ME, Loomba R. NGM282, a novel variant of FGF19, significantly reduces hepatic steatosis and key biomarkers of NASH: results of a phase 2, multicenter, randomized, double-blinded, placebo controlled trial in biopsy-confirmed NASH patients. EASL 2017.

  28. Sanyal A, Charles ED , Neuschwander-Tetri B, Loomba R, Harrison S, Abdelmalek MF, Lawitz E, Halegoua-Demarzio D, Dong Y, Noviello S, Krishnamoorthy S, Luo Y, Christian R. BMS-986036 (pegylated FGF21) in patients with non-alcoholic steatohepatitis: a phase 2 study. EASL 2017.

  29. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–90.

    Article  CAS  PubMed  Google Scholar 

  30. Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. GS-US-384-1497 Investigators. The ASK1 Inhibitor Selonsertib in Patients with Nonalcoholic Steatohepatitis: A Randomized, Phase 2 Trial. Hepatology. 2017. https://doi.org/10.1002/hep.29514

  31. Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50(1):185–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11(6):e0158156.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2017.

  34. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35(3):953–66.

    Article  CAS  PubMed  Google Scholar 

  35. Clinical Trials.gov. Emricasan, a Caspase Inhibitor, For evaluation in subjects with non-alcoholic steatohepatitis (NASH) fibrosis (ENCORE-NF). 2017.

  36. Garcia-Tsao F, McGuire Shiffman ML, Chan JL, Morris M, Yamashita M, Spada AP, Hagerty D. TITLE: Emricaaan (IDN-8556) administered orally for 28 days lowers portal pi'II88Ure in patients with compensated cirrhosis and severe portal hypertension AASLD Liver Meeting 2015.

  37. Clinical Trials.gov. Clinical trial to evaluate efficacy of GR-MD-02 for treatment of liver fibrosis in patients with NASH with advanced fibrosis (NASH-FX). 2017.

  38. Clinical Trials.gov. Clinical trial to evaluation the safety and efficacy of GR-MD-02 for the treatment of liver fibrosis and resultant portal hypertension in patients with Nash cirrhosis (NASH-CX). 2017.

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, SPC 5362, Ann Arbor, MI, 48109, USA

    Monica A. Konerman

  2. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Stephen A. Harrison

Authors
  1. Monica A. Konerman
    View author publications

    Search author on:PubMed Google Scholar

  2. Stephen A. Harrison
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Monica A. Konerman.

Ethics declarations

Conflict of Interest

Monica A. Konerman declares no potential conflicts of interest.

Stephen A. Harrison is a consultant/advisor to Gilead, Intercept, Genfit, HistoIndex, Axcella, BMS, Pfizer, Madrigal, NGM Bio, Cirius, Novartis, Novo Nordisk, Chronic Liver Disease Foundation, Echosens, and Perspectum. He has received research support from Gilead, Intercept, Genfit, Cirius, Madrigal, NGM Bio, Conatus, Galmed, Immuron, and Tobira/Allergan. Dr. Harrison is a section editor for Current Hepatology Reports.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

This article is part of the Topical Collection on Fatty Liver Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Konerman, M.A., Harrison, S.A. Overview of Clinical Treatment Trials for NASH. Curr Hepatology Rep 16, 366–373 (2017). https://doi.org/10.1007/s11901-017-0375-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-017-0375-5

Keywords