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Novel Pharmacotherapy Options for NASH

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Abstract

While simple to recommend, diet and lifestyle measures as a first-line therapy for nonalcoholic steatohepatitis (NASH) are hardly a model of successful therapy, as most clinicians can testify. They can be complex to implement, hard to sustain, and of limited efficacy in advanced stages of the disease. The need for specific pharmacotherapy is now acknowledged by practitioners, the pharmaceutical industry, and regulators and is largely expected by patients. The result is a clear move away from products developed second hand for NASH (such as pioglitazone or metformin) or from generic, non-specific hepatoprotectors (such as pentoxifylline, ursodeoxycholic acid, or antioxidants) toward molecules developed and tested specifically for NASH that aim to correct one or several of the pathways of liver injury in this disease. The two most advanced molecules, obeticholic acid and elafibranor, have shown encouraging data on improving hepatic histology. Both compounds appear to clear NASH, with obeticholic acid improving liver fibrosis and elafibranor improving the glycemic and lipid profile. Much larger trials, currently ongoing, will need to confirm these preliminary data and better characterize the safety and tolerability profile. Meanwhile, other compounds are being tested, a few in phase 2b studies (cenicriviroc, aramchol for NASH, and simtuzumab for NASH fibrosis) and many more in earlier, smaller trials. Most of these drug candidates target different pathways, which speaks to the diversity and dynamism of the NASH pipeline.

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References

  1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American association for the study of liver diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–2023.

    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;34:274–285.

    Article  CAS  PubMed  Google Scholar 

  3. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873.

    Article  CAS  PubMed  Google Scholar 

  4. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.

    Article  PubMed  Google Scholar 

  5. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53:372–384.

    Article  PubMed  Google Scholar 

  6. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51:371–379.

    Article  CAS  PubMed  Google Scholar 

  7. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–378 e365; quiz e314–365.

  9. Dixon JB, Bhathal PS, Hughes NR, O’Brien PE. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–1654.

    Article  PubMed  Google Scholar 

  10. Kral JG, Thung SN, Biron S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135:48–58.

    Article  PubMed  Google Scholar 

  11. Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. 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. Hepatology. 2015;61:1392–1405.

    Article  PubMed  Google Scholar 

  12. Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol. 2015;62:S65–S75.

    Article  CAS  PubMed  Google Scholar 

  13. Ratziu V, Bellentani S, Cortez-Pinto H, Day CP, Marchesini G. A position paper on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53:372–384.

    Article  PubMed  Google Scholar 

  14. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications Gastroenterology. 2012;142:711–725 e716.

  15. Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of NASH: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52:774–788.

    Article  PubMed  Google Scholar 

  16. Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci. 2014;15:8591–8638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11:55–67.

    Article  CAS  PubMed  Google Scholar 

  18. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012;17:988–997.

    Article  CAS  PubMed  Google Scholar 

  19. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148:e758.

    Article  Google Scholar 

  20. Lammers WJ, van Buuren HR, Hirschfield GM et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study Gastroenterology. 2014;147:1338–1349 e1335; quiz e1315.

  21. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116:1102–1109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology. 2008;48:1632–1643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol. 2009;51:380–388.

    Article  CAS  PubMed  Google Scholar 

  24. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145:574–582.

    Article  CAS  PubMed  Google Scholar 

  25. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;85:956–965.

    Article  Google Scholar 

  26. Ubeda M, Lario M, Munoz L et al. Obeticholic acid reduces bacterial translocation, restores intestinal barrier and inhibits inflammation in cirrhotic rats J Hepatol. 2016;in press.

  27. Verbeke L, Farre R, Trebicka J, et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology. 2014;59:2286–2298.

    Article  CAS  PubMed  Google Scholar 

  28. Qin X, Xie X, Fan Y, et al. Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology. 2008;48:432–441.

    Article  CAS  PubMed  Google Scholar 

  29. Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest. 2006;116:590–597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bojic LA, Huff MW. Peroxisome proliferator-activated receptor delta: a multifaceted metabolic player. Curr Opin Lipidol. 2013;24:171–177.

    Article  CAS  PubMed  Google Scholar 

  31. Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62:720–733.

    Article  CAS  PubMed  Google Scholar 

  32. Staels B, Rubenstrunk A, Noel B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2013;58:1941–1952.

    Article  CAS  PubMed  Google Scholar 

  33. Cariou B, Zair Y, Staels B, Bruckert E. Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care. 2011;34:2008–2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Staels B, Rubenstrunk A, Noel B, et al. Hepato-protective effects of the dual PPARalpha/delta agonist GFT505 in rodent models of NAFLD/NASH. Hepatology. 2013;58:1941–1952.

    Article  CAS  PubMed  Google Scholar 

  35. Cariou B, Hanf R, Lambert-Porcheron S, et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care. 2013;36:2923–2930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ratziu V, Harrison S, Franque S et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor alpha and delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;in press.

  37. Berres ML, Koenen RR, Rueland A, et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J Clin Invest. 2010;120:4129–4140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zimmermann HW, Tacke F. Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets. 2011;10:509–536.

    Article  CAS  PubMed  Google Scholar 

  39. Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1310–G1321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Baeck C, Wehr A, Karlmark KR, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2012;61:416–426.

    Article  CAS  PubMed  Google Scholar 

  41. Lefebvre E, Hashiguchi T, Jenkins H, et al. Anti-fibrotic and anti-inflammatory activity of the dual CCR2 and CCR5 antagonist cenicriviroc in a mouse model of NASH. Hepatology. 2013;58:221A–222A.

    Google Scholar 

  42. Hong F, Chou H, Friedman SL. Significant anti-fibrotic activity of cenicriviroc, a dual CCR2/CCR5 antagonist, in a rat model of thioacetamide-induced liver fibrosis and cirrhosis. Hepatology. 2013;58:S1.

    Google Scholar 

  43. Friedman SL, Sanyal A, Goodman Z et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials. 2016;in press.

  44. Gilat T, Somjen GJ, Mazur Y, et al. Fatty acid bile acid conjugates (FABACs)—new molecules for the prevention of cholesterol crystallisation in bile. Gut. 2001;48:75–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gilat T, Leikin-Frenkel A, Goldiner I, et al. Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC). Hepatology. 2003;38:436–442.

    Article  CAS  PubMed  Google Scholar 

  46. Leikin-Frenkel A, Gonen A, Shaish A, et al. Fatty acid bile acid conjugate inhibits hepatic stearoyl coenzyme A desaturase and is non-atherogenic. Arch Med Res. 2010;41:397–404.

    Article  CAS  PubMed  Google Scholar 

  47. Goldiner I, van der Velde AE, Vandenberghe KE, et al. ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid–bile acid conjugates (FABACs). Biochem J. 2006;396:529–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gutierrez-Juarez R, Pocai A, Mulas C, et al. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J Clin Invest. 2006;116:1686–1695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Powell DA. An overview of patented small molecule stearoyl coenzyme-A desaturase inhibitors (2009–2013). Expert Opin Ther Pat. 2014;24:155–175.

    Article  CAS  PubMed  Google Scholar 

  50. 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. Clin Gastroenterol Hepatol. 2014;12:e2081.

    Article  Google Scholar 

  51. Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42:473–480.

    Article  PubMed  Google Scholar 

  52. Mells JE, Anania FA. The role of gastrointestinal hormones in hepatic lipid metabolism. Semin Liver Dis. 2013;33:343–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34:S279–S284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gupta NA, Mells J, Dunham RM, et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 2010;51:1584–1592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mells JE, Fu PP, Sharma S, et al. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6 J mice fed a Western diet. Am J Physiol Gastrointest Liver Physiol. 2012;302:G225–G235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Svegliati-Baroni G, Saccomanno S, Rychlicki C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int. 2011;31:1285–1297.

    Article  CAS  PubMed  Google Scholar 

  57. Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43:173–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64:399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373:11–22.

    Article  PubMed  Google Scholar 

  60. Armstrong MJ, Houlihan DD, Rowe IA, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther. 2013;37:234–242.

    Article  CAS  PubMed  Google Scholar 

  61. Armstrong MJ, Gaunt P, Aithal GP, 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;387:679–690.

    Article  CAS  PubMed  Google Scholar 

  62. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med. 2008;359:2429–2441.

    Article  PubMed  PubMed Central  Google Scholar 

  63. McHutchison J, Goodman Z, Patel K et al. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection Gastroenterology. 2010;138:1365–1373, 1373 e1361–1362.

  64. Pockros PJ, Jeffers L, Afdhal N, et al. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology. 2007;45:569–578.

    Article  CAS  PubMed  Google Scholar 

  65. Poynard T, Bruix J, Schiff ER, et al. Improved inflammatory activity with peginterferon alfa-2b maintenance therapy in non-cirrhotic prior non-responders: a randomized study. J Hepatol. 2013;58:452–459.

    Article  CAS  PubMed  Google Scholar 

  66. Kagan HM, Li W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem. 2003;88:660–672.

    Article  CAS  PubMed  Google Scholar 

  67. Kagan HM. Lysyl oxidase: mechanism, regulation and relationship to liver fibrosis. Pathol Res Pract. 1994;190:910–919.

    Article  CAS  PubMed  Google Scholar 

  68. Vadasz Z, Kessler O, Akiri G, et al. Abnormal deposition of collagen around hepatocytes in Wilson’s disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 2005;43:499–507.

    Article  CAS  PubMed  Google Scholar 

  69. Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16:1009–1017.

    Article  CAS  PubMed  Google Scholar 

  70. Yang RY, Rabinovich GA, Liu FT. Galectins: structure, function and therapeutic potential. Expert Rev Mol Med. 2008;10:e17.

    Article  PubMed  Google Scholar 

  71. Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009;230:160–171.

    Article  CAS  PubMed  Google Scholar 

  72. Henderson NC, Mackinnon AC, Farnworth SL, et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci USA. 2006;103:5060–5065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Traber PG, Chou H, Zomer E, et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One. 2013;8:e75361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One. 2013;8:e83481.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, associates with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–397.

    Article  PubMed  Google Scholar 

  77. Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53:1874–1882.

    Article  PubMed  Google Scholar 

  78. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.

    Article  PubMed  Google Scholar 

  79. Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014;60:565–575.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant Agreement No. HEALTH-F2-2009-241762 for the Project FLIP.

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  1. Institute for Cardiometabolism and Nutrition (ICAN), Hôpital Pitié Salpêtrière, Service d’hépatogastroentérologie, Université Pierre et Marie Curie, 47-83 Bd de l’Hôpital, 75013, Paris, France

    Vlad Ratziu

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Consultancy for Astra-Zeneca, Boehringer-Ingelheim, Galmed, Genfit, Gilead, Immuron, Intercept, Roche-Genentech, Tobira for VR.

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Ratziu, V. Novel Pharmacotherapy Options for NASH. Dig Dis Sci 61, 1398–1405 (2016). https://doi.org/10.1007/s10620-016-4128-z

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