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Review

Novel targeted therapies for the management of liver fibrosis

ORCID Icon, &
Pages 59-70 | Received 18 Jan 2020, Accepted 24 Feb 2020, Published online: 04 Mar 2020

References

  • Trautwein C, Friedman SL, Schuppan D, et al. Hepatic fibrosis: concept to treatment. J Hepatol. 2015 Apr;62(1 Suppl):S15–24.
  • Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut. 2015 May;64(5):830–841.
  • Garcia-Tsao G, Friedman S, Iredale J, et al. Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis. Hepatology. 2010 Apr;51(4):1445–1449.
  • Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013 Feb 9;381(9865):468–475.
  • D’Ambrosio R, Aghemo A, Rumi MG, et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology. 2012 Aug;56(2):532–543.
  • Bachofner JA, Valli PV, Kroger A, et al. Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers fibrosis-4 score and aspartate aminotransferase-platelet ratio index. Liver Int. 2017 Mar;37(3):369–376.
  • Beste LA, Leipertz SL, Green PK, et al. Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001–2013. Gastroenterology. 2015 Nov;149(6):1471–1482. e5; quiz e17-8.
  • Kabbany MN, Conjeevaram Selvakumar PK, Watt K, et al. Prevalence of nonalcoholic steatohepatitis-associated cirrhosis in the United States: an analysis of national health and nutrition examination survey data. Am J Gastroenterol. 2017 Apr;112(4):581–587.
  • Neff GW, Duncan CW, Schiff ER. The current economic burden of cirrhosis. Gastroenterol Hepatol. 2011 Oct;7(10):661–671.
  • Mellinger JL, Shedden K, Winder GS, et al. The high burden of alcoholic cirrhosis in privately insured persons in the United States. Hepatology. 2018 Sep;68(3):872–882.
  • Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010 Sep;52(3):886–893.
  • Schiff ER, Lee SS, Chao YC, et al. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2011 Mar;9(3):274–276.
  • Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016 Jan;63(1):261–283.
  • Akhtar E, Manne V, Saab S. Cirrhosis regression in hepatitis C patients with sustained virological response after antiviral therapy: a meta-analysis. Liver Int. 2015 Jan;35(1):30–36.
  • Dolmazashvili E, Abutidze A, Chkhartishvili N, et al. Regression of liver fibrosis over a 24-week period after completing direct-acting antiviral therapy in patients with chronic hepatitis C receiving care within the national hepatitis C elimination program in Georgia: results of hepatology clinic HEPA experience. Eur J Gastroenterol Hepatol. 2017 Nov;29(11):1223–1230.
  • Kutala B, Darrigrand NB, Corinne C, et al. The impact of direct antiviral agent therapy on liver fibrosis in patient with advanced fibrosis related chronic hepatitis C. J Hepatol. 2018;68:S541.
  • Lens S, Alvarado-Tapias E, Marino Z, et al. Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis. Gastroenterology. 2017 Nov;153(5):1273–1283 e1.
  • Nahon P, Bourcier V, Layese R, et al. Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications. Gastroenterology. 2017 Jan;152(1):142–156 e2.
  • Di Marco V, Calvaruso V, Ferraro D, et al. Effects of eradicating hepatitis C virus infection in patients with cirrhosis differ with stage of portal hypertension. Gastroenterology. 2016 Jul;151(1):130–139 e2.
  • Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology. 2010 Jun;51(6):2069–2076.
  • Flemming JA, Kim WR, Brosgart CL, et al. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology. 2017 Mar;65(3):804–812.
  • Friedman SL. Liver fibrosis – from bench to bedside. J Hepatol. 2003;38(Suppl 1):S38–53.
  • Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017 Nov 1;121:27–42.
  • Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008 May;134(6):1655–1669.
  • Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010 Aug;7(8):425–436.
  • Barker HE, Cox TR, Erler JT. The rationale for targeting the LOX family in cancer. Nat Rev Cancer. 2012 Jul 19;12(8):540–552.
  • 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 Sep;43(3):499–507.
  • Ikenaga N, Peng ZW, Vaid KA, et al. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut. 2017 Sep;66(9):1697–1708.
  • Harrison SA, Abdelmalek MF, Caldwell S, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology. 2018 Oct;155(4):1140–1153.
  • Muir AJ, Levy C, Janssen HLA, et al. Simtuzumab for primary sclerosing cholangitis: phase 2 study results with insights on the natural history of the disease. Hepatology. 2019 Feb;69(2):684–698.
  • Lipson KE, Wong C, Teng Y, et al. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair. 2012;5(Suppl 1):S24.
  • Paradis V, Dargere D, Vidaud M, et al. Expression of connective tissue growth factor in experimental rat and human liver fibrosis. Hepatology. 1999 Oct;30(4):968–976.
  • Paradis V, Dargere D, Bonvoust F, et al. Effects and regulation of connective tissue growth factor on hepatic stellate cells. Lab Invest. 2002 Jun;82(6):767–774.
  • Weston CJ, Shepherd EL, Claridge LC, et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Invest. 2015 Feb;125(2):501–520.
  • Trivedi PJ, Tickle J, Vesterhus MN, et al. Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner. Gut. 2018 Jun;67(6):1135–1145.
  • Arndtz K, Corrigan M, Rowe A, et al. Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): a single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol. BMJ Open. 2017 Jul 3;7(6):e015081.
  • Wang Y, Cheetham AG, Angacian G, et al. Peptide-drug conjugates as effective prodrug strategies for targeted delivery. Adv Drug Deliv Rev. 2017;110–111:112–126.
  • Garnett MC. Targeted drug conjugates: principles and progress. Adv Drug Deliv Rev. 2001 Dec 17;53(2):171–216.
  • Bartneck M, Warzecha KT, Tacke F. Therapeutic targeting of liver inflammation and fibrosis by nanomedicine. Hepatobiliary Surg Nutr. 2014 Dec;3(6):364–376.
  • Sato Y, Murase K, Kato J, et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol. 2008 Apr;26(4):431–442.
  • Lawitz E, Tanaka F, Poordad F. Safety, pharmacokinetics, and biologic activity of ND-L02-s0201, a novel targeted lipid-nanoparticle to deliver HSP47 siRNA for the treatment of patients with advanced liver fibrosis: interim results from clinical phase 1b/2 studies. Poster session 3: clinical and translational fibrosis research; encephalopathy and other complications of cirrhosis. Hepatology. 2015;62(S1):903A–950A.
  • Soule B, Tirucherai G, Kavita U, et al. Safety, tolerability, and pharmacokinetics of BMS-986263/ND-L02-s0201, a novel targeted lipid nanoparticle delivering HSP47 siRNA, in healthy participants: a randomised, placebo-controlled, double-blind, phase 1 study. J Hepatol. 2018;68:S112.
  • Ganellin CR, Jefferis R, Roberts SM. Introduction to biological and small molecule drug research and development: theory and case studies. London, UK: Elsevier; 2013.
  • Quintero P, Arrese M. Nuclear control of inflammation and fibrosis in nonalcoholic steatohepatitis: therapeutic potential of dual peroxisome proliferator-activated receptor alpha/delta agonism. Hepatology. 2013 Dec;58(6):1881–1884.
  • Miyahara T, Schrum L, Rippe R, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem. 2000 Nov 17;275(46):35715–35722.
  • Yang L, Chan CC, Kwon OS, et al. Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2006 Nov;291(5):G902–11.
  • Hazra S, Xiong S, Wang J, et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem. 2004 Mar 19;279(12):11392–11401.
  • Musso G, Cassader M, Paschetta E, et al. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 2017 May 1;177(5):633–640.
  • Ratziu V, Harrison SA, Francque 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 May;150(5):1147–1159 e5.
  • McHutchison J, Goodman Z, Patel K, et al. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology. 2010 Apr;138(4):1365–73, 1373 e1–2.
  • Jain MR, Giri SR, Bhoi B, et al. Dual PPARalpha/gamma agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 2018 Jun;38(6):1084–1094.
  • Newsome PN. Entering the GOLDEN age for therapies in NASH. Gastroenterology. 2016 May;150(5):1073–1076.
  • 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 Dec;58(6):1941–1952.
  • Boubia B, Poupardin O, Barth M, et al. Design, synthesis, and evaluation of a novel series of indole sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) alpha/gamma/delta triple activators: discovery of lanifibranor, a new antifibrotic clinical candidate. J Med Chem. 2018 Mar 22;61(6):2246–2265.
  • Aristu P, Boyer-Diaz Z, Broqua P, et al. The pan-ppar agonist lanifibranor Improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease. Oral abstracts (Abstracts 1–288). Hepatology. 2019;70(S1):1–187.
  • Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012 Mar 14;13(4):213–224.
  • Wang YD, Chen WD, Wang M, et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology. 2008 Nov;48(5):1632–1643.
  • Schwabl P, Budas G, Hambruch E, et al. The FXR agonist GS-9674 reduces fibrosis and portal hypertension in a rat model of NASH. J Hepatol. 2018;68:S471–S472.
  • Fiorucci S, Antonelli E, Rizzo G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology. 2004 Nov;127(5):1497–1512.
  • Goto T, Itoh M, Suganami T, et al. Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis. Sci Rep. 2018 May 25;8(1):8157.
  • Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016 Aug 18;375(7):631–643.
  • Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018 May;67(5):1890–1902.
  • 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 Mar 14;385(9972):956–965.
  • Younossi Z, Ratziu V, Loomba R, et al. GS-06-positive results from REGENERATE: a phase 3 international, randomized, placebo-controlled study evaluating obeticholic acid treatment for NASH. J Hepatol. 2019;70(1):e5.
  • Trauner M, Gulamhusein A, Hameed B, et al. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatology. 2019 Jan 19;70:788–801.
  • Yoshiji H, Kuriyama S, Fukui H. Blockade of renin-angiotensin system in antifibrotic therapy. J Gastroenterol Hepatol. 2007 Jun;22(Suppl 1):S93–5.
  • Paizis G, Cooper ME, Schembri JM, et al. Up-regulation of components of the renin-angiotensin system in the bile duct-ligated rat liver. Gastroenterology. 2002 Nov;123(5):1667–1676.
  • Yang L, Bataller R, Dulyx J, et al. Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol. 2005 Aug;43(2):317–323.
  • Bataller R, Gines P, Nicolas JM, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 2000 Jun;118(6):1149–1156.
  • Oakley F, Teoh V, Ching ASG, et al. Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology. 2009 Jun;136(7):2334–2344 e1.
  • Colmenero J, Bataller R, Sancho-Bru P, et al. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol. 2009 Oct;297(4):G726–34.
  • Kim MY, Baik SK, Park DH, et al. Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model. J Gastroenterol. 2008;43(11):889–896.
  • Kim G, Kim J, Lim YL, et al. Renin-angiotensin system inhibitors and fibrosis in chronic liver disease: a systematic review. Hepatol Int. 2016 Sep;10(5):819–828.
  • Doycheva I, Watt KD, Gulamhusein AF. Autoimmune hepatitis: current and future therapeutic options. Liver Int. 2019 Jun;39(6):1002–1013.
  • Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014 Sep;147(3):577–594 e1.
  • Wasmuth HE, Tacke F, Trautwein C. Chemokines in liver inflammation and fibrosis. Semin Liver Dis. 2010 Aug;30(3):215–225.
  • Seki E, de Minicis S, Inokuchi S, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009 Jul;50(1):185–197.
  • Berres ML, Koenen RR, Rueland A, et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J Clin Invest. 2010 Nov;120(11):4129–4140.
  • Ambade A, Lowe P, Kodys K, et al. Pharmacological Inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis, and inflammation in mice. Hepatology. 2019 Mar;69(3):1105–1121.
  • Krenkel O, Puengel T, Govaere O, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018 Apr;67(4):1270–1283.
  • Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018 May;67(5):1754–1767.
  • Li LC, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014 Nov;351(2):336–343.
  • Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009 Jul;230(1):160–171.
  • Hsieh WC, Mackinnon AC, Lu WY, et al. Galectin-3 regulates hepatic progenitor cell expansion during liver injury. Gut. 2015 Feb;64(2):312–321.
  • Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One. 2013;8(12):e83481.
  • 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(10):e75361.
  • Harrison SA, Marri SR, Chalasani N, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther. 2016 Dec;44(11–12):1183–1198.
  • 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. PLoS One. 2018;13(9):e0203054.
  • Zein CO, Yerian LM, Gogate P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011 Nov;54(5):1610–1619.
  • Van Wagner LB, Koppe SW, Brunt EM, et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol. 2011 Jul-Sep;10(3):277–286.
  • Preaux AM, Mallat A, Rosenbaum J, et al. Pentoxifylline inhibits growth and collagen synthesis of cultured human hepatic myofibroblast-like cells. Hepatology. 1997 Aug;26(2):315–322.
  • Singh S, Khera R, Allen AM, et al. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: a systematic review and network meta-analysis. Hepatology. 2015 Nov;62(5):1417–1432.
  • Mehendale HM, Limaye PB. Calpain: a death protein that mediates progression of liver injury. Trends Pharmacol Sci. 2005 May;26(5):232–236.
  • Limaye PB, Apte UM, Shankar K, et al. Calpain released from dying hepatocytes mediates progression of acute liver injury induced by model hepatotoxicants. Toxicol Appl Pharmacol. 2003 Sep 15;191(3):211–226.
  • Sojoodi M, Krishnan S, Razavi AA, et al. THU-093-the calpain inhibitor, BLD-2660, has robust anti-fibrotic activity in a rat model of non-alcoholic steatohepatitis. J Hepatol. 2019;70(1):e201–e202.
  • Chong L-W, Hsu Y-C, Lee T-F, et al. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol. 2015 Feb 15;15(1):22.
  • Schierwagen R, Maybuchen L, Hittatiya K, et al. Statins improve NASH via inhibition of RhoA and Ras. Am J Physiol Gastrointest Liver Physiol. 2016 Oct 1;311(4):G724–G733.
  • Marrone G, Maeso-Diaz R, Garcia-Cardena G, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut. 2015 Sep;64(9):1434–1443.
  • Dold S, Laschke MW, Lavasani S, et al. Simvastatin protects against cholestasis-induced liver injury. Br J Pharmacol. 2009 Feb;156(3):466–474.
  • Klein S, Klösel J, Schierwagen R, et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest. 2012 Oct 01;92(10):1440–1450.
  • Trebicka J, Hennenberg M, Odenthal M, et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol. 2010;53(4):702–712.
  • Kamal S, Khan MA, Seth A, et al. Beneficial effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: a systematic review and meta-analysis. Am J Gastroenterol. 2017 Oct;112(10):1495–1505.
  • Roglans N, Verd JC, Peris C, et al. High doses of atorvastatin and simvastatin induce key enzymes involved in VLDL production. Lipids. 2002 May;37(5):445–454.
  • Dongiovanni P, Petta S, Mannisto V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015 Sep;63(3):705–712.
  • Nascimbeni F, Aron-Wisnewsky J, Pais R, et al. Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol. 2016;3(1):e000075.
  • Mohanty A, Tate JP, Garcia-Tsao G. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C-related compensated cirrhosis. Gastroenterology. 2016 Feb;150(2):430–40 e1.
  • Huang YW, Lee CL, Yang SS, et al. Statins reduce the risk of cirrhosis and its decompensation in chronic hepatitis B patients: a Nationwide Cohort study. Am J Gastroenterol. 2016 Jul;111(7):976–985.
  • Abraldes JG, Villanueva C, Aracil C, et al. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology. 2016 May;150(5):1160–1170 e3.
  • Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835–844.
  • Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378–390.
  • Hennenberg M, Trebicka J, Kohistani Z, et al. Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis. Lab Invest. 2011 Feb;91(2):241–251.
  • Wang Y, Gao J, Zhang D, et al. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J Hepatol. 2010 Jul;53(1):132–144.
  • Mejias M, Garcia-Pras E, Tiani C, et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology. 2009 Apr;49(4):1245–1256.
  • Yang YY, Liu RS, Lee PC, et al. Anti-VEGFR agents ameliorate hepatic venous dysregulation/microcirculatory dysfunction, splanchnic venous pooling and ascites of NASH-cirrhotic rat. Liver Int. 2014 Apr;34(4):521–534.
  • Pinter M, Sieghart W, Reiberger T, et al. The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma–a pilot study. Aliment Pharmacol Ther. 2012 Jan;35(1):83–91.
  • Fuchs BC, Hoshida Y, Fujii T, et al. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology. 2014 Apr;59(4):1577–1590.
  • Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. 2017 Sep 11;67:549–559.
  • Budas G, Karnik S, Jonnson T, et al. Reduction of liver steatosis and fibrosis with an Ask1 inhibitor in a murine model of nash is accompanied by improvements in cholesterol, bile acid and lipid metabolism. J Hepatol. 2016;64(2):S170.
  • Jayakumar S, Middleton MS, Lawitz EJ, et al. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: analysis of data from a phase II trial of selonsertib. J Hepatol. 2019 Jan;70(1):133–141.
  • Rahimi RA, Andrianifahanana M, Wilkes MC, et al. Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta. Cancer Res. 2009 Jan 1;69(1):84–93.
  • Villamil FG, Gadano AC, Zingale F, et al. Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors. Liver Int. 2014 Nov;34(10):1513–1521.
  • Kang KW, Kim YG, Cho MK, et al. Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein-mediated stellate cell inactivation. Faseb J. 2002 Dec;16(14):1988–1990.
  • Kim SG, Kim YM, Choi YH, et al. Pharmacokinetics of oltipraz and its major metabolite (RM) in patients with liver fibrosis or cirrhosis: relationship with suppression of circulating TGF-beta1. Clin Pharmacol Ther. 2010 Sep;88(3):360–368.
  • Di Sario A, Bendia E, Svegliati Baroni G, et al. Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production. J Hepatol. 2002 Nov;37(5):584–591.
  • Flores-Contreras L, Sandoval-Rodriguez AS, Mena-Enriquez MG, et al. Treatment with pirfenidone for two years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C. BMC Gastroenterol. 2014 Jul 27;14:131.
  • Lin X, Liu YB, Hu H. Metabolic role of fibroblast growth factor 21 in liver, adipose and nervous system tissues. Biomed Rep. 2017 May;6(5):495–502.
  • Lee KJ, Jang YO, Cha SK, et al. Expression of fibroblast growth factor 21 and beta-Klotho Regulates hepatic fibrosis through the nuclear factor-kappaB and c-Jun N-terminal kinase pathways. Gut Liver. 2018 Jul 15;12(4):449–456.
  • Ekladious I, Colson YL, Grinstaff MW. Polymer-drug conjugate therapeutics: advances, insights and prospects. Nat Rev Drug Discov. 2019 Apr;18(4):273–294.
  • Charles ED, Neuschwander-Tetri BA, Pablo Frias J, et al. Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity (Silver Spring). 2019 Jan;27(1):41–49.
  • Sanyal A, Charles ED, Neuschwander-Tetri BA, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2019 Dec 22;392(10165):2705–2717.
  • Teixeira-Clerc F, Julien B, Grenard P, et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med. 2006 Jun;12(6):671–676.
  • Mallat A, Lotersztajn S. Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver. Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G9–G12.
  • Patsenker E, Sachse P, Chicca A, et al. Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation. Int J Mol Sci. 2015 Mar 27;16(4):7057–7076.
  • Caraceni P, Pertosa AM, Giannone F, et al. Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischaemia-reperfusion injury complicated by endotoxaemia. Gut. 2009 Aug;58(8):1135–1143.
  • Giannone FA, Baldassarre M, Domenicali M, et al. Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl(4)-induced advanced cirrhosis. Lab Invest. 2012 Mar;92(3):384–395.
  • Teixeira-Clerc F, Belot MP, Manin S, et al. Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration. Hepatology. 2010 Sep;52(3):1046–1059.
  • Hezode C, Roudot-Thoraval F, Nguyen S, et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology. 2005 Jul;42(1):63–71.
  • Boesten JE, Kaper J, Stoffers HE, et al. Rimonabant improves obesity but not the overall cardiovascular risk and quality of life; results from CARDIO-REDUSE (CArdiometabolic Risk reDuctIOn by Rimonabant: the Effectiveness in Daily practice and its USE). Fam Pract. 2012 Oct;29(5):521–527.
  • Christensen R, Kristensen PK, Bartels EM, et al. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007 Nov 17;370(9600):1706–1713.
  • Barreyro FJ, Holod S, Finocchietto PV, 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 Mar;35(3):953–966.
  • Pockros PJ, Schiff ER, Shiffman ML, et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology. 2007 Aug;46(2):324–329.
  • Gracia-Sancho J, Manicardi N, Ortega-Ribera M, et al. Emricasan ameliorates portal hypertension and liver fibrosis in cirrhotic rats through a hepatocyte-mediated paracrine mechanism. Hepatol Commun. 2019 Apr;3(7):987–1000.
  • Garcia-Tsao G, Fuchs M, Shiffman M, et al. Emricasan (IDN-6556) lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. Hepatology. 2019 Feb;69(2):717–728.
  • Witek RP, Stone WC, Karaca GF, et al. T1616 pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of non-alcoholic steatohepatitis. Gastroenterology. 2009;136(5):A–850.

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