Nonalcoholic Steatohepatitis Drug Development Pipeline: An Update

Nicholas W. S. Chew; Cheng Han Ng; Emily Truong; Mazen Noureddin; Kris V. Kowdley

doi:10.1055/a-1877-9656

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2022; 42(03): 379-400
DOI: 10.1055/a-1877-9656

Review Article

Nonalcoholic Steatohepatitis Drug Development Pipeline: An Update

Autor*innen

Nicholas W. S. Chew

¹Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore
Cheng Han Ng

²Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Emily Truong

³Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Mazen Noureddin

⁴Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Fatty Liver Program, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California
Kris V. Kowdley

⁵Liver Institute Northwest and Elson S. Floyd College of Medicine, Washington State University, Seattle, Washington

Abstract

Nonalcoholic steatohepatitis (NASH) is a burgeoning global health crisis that mirrors the obesity pandemic. This global health crisis has stimulated active research to develop novel NASH pharmacotherapies targeting dysregulated inflammatory, cellular stress, and fibrogenetic processes that include (1) metabolic pathways to improve insulin sensitivity, de novo lipogenesis, and mitochondrial utilization of fatty acids; (2) cellular injury or inflammatory targets that reduce inflammatory cell recruitment and signaling; (3) liver–gut axis targets that influence bile acid enterohepatic circulation and signaling; and (4) antifibrotic targets. In this review, we summarize several of the therapeutic agents that have been studied in phase 2 and 3 randomized trials. In addition to reviewing novel therapeutic drugs targeting nuclear receptor pathways, liver chemokine receptors, liver lipid metabolism, lipotoxicity or cell death, and glucagon-like peptide-1 receptors, we also discuss the rationale behind the use of combination therapy and the lessons learned from unsuccessful or negative clinical trials.

Keywords

pharmacology - nonalcoholic fatty liver disease - nonalcoholic steatohepatitis - intervention

Volltext

Referenzen

References
1 Younossi Z, Tacke F, Arrese M. et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2019; 69 (06) 2672-2682
2 Younossi Z, Anstee QM, Marietti M. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15 (01) 11-20
3 Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 2012; 307 (05) 491-497
4 Noureddin M, Vipani A, Bresee C. et al. NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances. Am J Gastroenterol 2018; 113 (11) 1649-1659
5 Chalasani N, Younossi Z, Lavine JE. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67 (01) 328-357
6 Stepanova M, Rafiq N, Makhlouf H. et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2013; 58 (10) 3017-3023
7 Muthiah MD, Sanyal AJ. Current management of non-alcoholic steatohepatitis. Liver Int 2020; 40 (Suppl 1): 89-95
8 Albhaisi S, Noureddin M. Current and potential therapies targeting inflammation in NASH. Front Endocrinol (Lausanne) 2021; 12: 767314
9 Siddiqui MS, Harrison SA, Abdelmalek MF. et al; Liver Forum Case Definitions Working Group. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science. Hepatology 2018; 67 (05) 2001-2012
10 Noureddin M, Muthiah MD, Sanyal AJ. Drug discovery and treatment paradigms in nonalcoholic steatohepatitis. Endocrinol Diabetes Metab 2019; 3 (04) e00105
11 Eslam M, Newsome PN, Sarin SK. et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 2020; 73 (01) 202-209
12 Vuppalanchi R, Noureddin M, Alkhouri N, Sanyal AJ. Therapeutic pipeline in nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 2021; 18 (06) 373-392
13 Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339 (17) 1217-1227
14 Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol 2018; 13: 321-350
15 Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018; 24 (07) 908-922
16 Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010; 52 (02) 774-788
17 Hirschfield GM, Heathcote EJ, Gershwin ME. Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology 2010; 139 (05) 1481-1496
18 Jansen PL, Ghallab A, Vartak N. et al. The ascending pathophysiology of cholestatic liver disease. Hepatology 2017; 65 (02) 722-738
19 Natarajan SK, Ingham SA, Mohr AM. et al. Saturated free fatty acids induce cholangiocyte lipoapoptosis. Hepatology 2014; 60 (06) 1942-1956
20 Bruschi FV, Claudel T, Tardelli M. et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 2017; 65 (06) 1875-1890
21 Hirsova P, Ibrabim SH, Gores GJ, Malhi H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 2016; 57 (10) 1758-1770
22 Liu R, Li X, Zhu W. et al. Cholangiocyte-derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis. Hepatology 2019; 70 (04) 1317-1335
23 Pizarro M, Balasubramaniyan N, Solís N. et al. Bile secretory function in the obese Zucker rat: evidence of cholestasis and altered canalicular transport function. Gut 2004; 53 (12) 1837-1843
24 Geier A, Dietrich CG, Grote T. et al. Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat. J Hepatol 2005; 43 (06) 1021-1030
25 Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 2017; 65 (01) 350-362
26 Qi Y, Jiang C, Cheng J. et al. Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice. Biochim Biophys Acta 2015; 1851 (01) 19-29
27 Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009; 50 (10) 1955-1966
28 Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14 (07) 397-411
29 Trauner M, Fuchs CD, Halilbasic E, Paumgartner G. New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology 2017; 65 (04) 1393-1404
30 Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009; 89 (01) 147-191
31 Rudraiah S, Zhang X, Wang L. Nuclear receptors as therapeutic targets in liver disease: Are we there yet?. Annu Rev Pharmacol Toxicol 2016; 56: 605-626
32 Makishima M, Okamoto AY, Repa JJ. et al. Identification of a nuclear receptor for bile acids. Science 1999; 284 (5418): 1362-1365
33 Parks DJ, Blanchard SG, Bledsoe RK. et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999; 284 (5418): 1365-1368
34 Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999; 3 (05) 543-553
35 Trautwein C, Friedman SL, Schuppan D, Pinzani M. Hepatic fibrosis: concept to treatment. J Hepatol 2015; 62 (1, Suppl): S15-S24
36 Noureddin M, Anstee QM, Loomba R. Review article: emerging anti-fibrotic therapies in the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2016; 43 (11) 1109-1123
37 Karpen SJ, Trauner M. The new therapeutic frontier–nuclear receptors and the liver. J Hepatol 2010; 52 (03) 455-462
38 Inagaki T, Choi M, Moschetta A. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2 (04) 217-225
39 Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011; 54 (06) 1263-1272
40 Trauner M, Fuchs CD. Novel therapeutic targets for cholestatic and fatty liver disease. Gut 2022; 71 (01) 194-209
41 Anstee QM, Lawitz EJ, Alkhouri N. et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology 2019; 70 (05) 1521-1530
42 Sanyal AJ, Harrison SA, Ratziu V. et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology 2019; 70 (06) 1913-1927
43 Fuchs CD, Traussnigg SA, Trauner M. Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis 2016; 36 (01) 69-86
44 Keitel V, Häussinger D. Role of TGR5 (GPBAR1) in liver disease. Semin Liver Dis 2018; 38 (04) 333-339
45 Legry V, Francque S, Haas JT. et al. Bile acid alterations are associated with insulin resistance, but not with NASH, in obese subjects. J Clin Endocrinol Metab 2017; 102 (10) 3783-3794
46 Segovia-Miranda F, Morales-Navarrete H, Kücken M. et al. Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression. Nat Med 2019; 25 (12) 1885-1893
47 Puri P, Sanyal AJ. The intestinal microbiome in nonalcoholic fatty liver disease. Clin Liver Dis 2018; 22 (01) 121-132
48 Yoshimoto S, Loo TM, Atarashi K. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499 (7456): 97-101
49 Fiorucci S, Cipriani S, Mencarelli A, Baldelli F, Bifulco G, Zampella A. Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA. Mini Rev Med Chem 2011; 11 (09) 753-762
50 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 (03) 574-82.e1
51 Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med 2015; 3 (01) 5
52 Carr RM, Reid AE. FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. Curr Atheroscler Rep 2015; 17 (04) 500
53 Neuschwander-Tetri BA, Loomba R, Sanyal AJ. et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-965
54 Younossi ZM, Ratziu V, Loomba R. et al; REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019; 394 (10215): 2184-2196
55 Shah RA, Kowdley KV. Obeticholic acid for the treatment of nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2020; 14 (05) 311-321
56 US Food and Drug Administration. . FDA Drug Safety Communication. Accessed June 1, 2022 at: https://www.fda.gov/media/149516/download
57 A Randomized, Double-Blind Study to Assess the Safety and Efficacy of EDP-305 in Subjects with Liver-biopsy Proven NASH. Accessed June 1, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04378010
58 Enanta Pharmaceuticals Provides Update on NASH FXR Agonist Programs. Accessed June 1, 2022 at: https://s22.q4cdn.com/306858242/files/doc_news/Enanta-Pharmaceuticals-Provides-Update-on-NASH-FXR-Agonist-Programs-2021.pdf
59 Study to Evaluate MET642 in Patients With NASH. Accessed June 1, 2022 at: https://www.clinicaltrials.gov/ct2/show/NCT04773964
60 Metacrine Reports Interim Results for MET642 Phase 2a Trial in Patients with NASH and Announces a Strategic Re-Prioritization of Its Clinical Development Programs. Accessed June 1, 2022 at: https://investors.metacrine.com/news-releases/news-release-details/metacrine-reports-interim-results-met642-phase-2a-trial-patients
61 Gege C, Hambruch E, Hambruch N, Kinzel O, Kremoser C. Nonsteroidal FXR ligands: current status and clinical applications. Handb Exp Pharmacol 2019; 256: 167-205
62 Lucas KJ, Lopez P, Lawitz E. et al. Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 weeks of therapy: FLIGHT-FXR Part C interim results. Dig Liver Dis 2020; 52: e38
63 Pedrosa M, Seyedkazemi S, Francque S. et al. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial. Contemp Clin Trials 2020; 88: 105889
64 Harrison Sr V, White A, Reiss GM. et al. Vonafexor, a FXR agonist, induced hepatic and renal improvement in the randomized, double-blind, placebo-controlled LIVIFY NASH trial. Conference paper. Hepatology 2021;74(06):
65 Efficacy, Safety and Tolerability of the Combination of Tropifexor & Licogliflozin and Each Monotherapy, Compared With Placebo in Adult Patients With NASH and Liver Fibrosis. National Library of Medicine; 2022
66 LIFT Study: A Safety, Tolerability, Efficacy, and Pharmacokinetics Study of TERN-101 in Subjects with Non-Cirrhotic Non-Alcoholic Steatohepatitis (NASH). Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04328077
67 Study to Evaluate MET409 Alone or in Combination With Empagliflozin in Patients With Type 2 Diabetes and NASH. Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04702490
68 Traussnigg S, Halilbasic E, Hofer H. et al. Open-label phase II study evaluating safety and efficacy of the non-steroidal farnesoid X receptor agonist PX-104 in non-alcoholic fatty liver disease. Wien Klin Wochenschr 2021; 133 (9-10): 441-451
69 Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Participants with Nonalcoholic Steatohepatitis (NASH). National Library of Medicine; 2019
70 Patel K, Harrison SA, Elkhashab M. et al. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial. Hepatology 2020; 72 (01) 58-71
71 Loomba R, Noureddin M, Kowdley KV. et al; ATLAS Investigators. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology 2021; 73 (02) 625-643
72 A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Non-Alcoholic Steatohepatitis. National Library of Medicine; 2021
73 Safety, Tolerability, . Pharmacokinetics and Efficacy of LMB763 in Patients with NASH. National Library of Medicine; 2021
74 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 Hepatol 2015; 62 (03) 720-733
75 Dubois V, Eeckhoute J, Lefebvre P, Staels B. Distinct but complementary contributions of PPAR isotypes to energy homeostasis. J Clin Invest 2017; 127 (04) 1202-1214
76 Francque S, Szabo G, Abdelmalek MF. et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol 2021; 18 (01) 24-39
77 Yki-Järvinen Y. Thiazolidinediones. N Engl J Med 2004; 351 (11) 1106-1118
78 Sanyal AJ, Chalasani N, Kowdley KV. et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
79 Bril F, Kalavalapalli S, Clark VC. et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol 2018; 16 (04) 558-566.e2
80 Cusi K, Orsak B, Bril F. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016; 165 (05) 305-315
81 Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med 2017; 177 (05) 633-640
82 Ratziu V, Caldwell S, Neuschwander-Tetri BA. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology 2010; 52 (06) 2206-2215
83 Belfort R, Harrison SA, Brown K. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355 (22) 2297-2307
84 Nissen SE, Nicholls SJ, Wolski K. et al; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008; 299 (13) 1561-1573
85 Jacques V, Bolze S, Hallakou-Bozec S. et al. Deuterium-stabilized (R)-pioglitazone (PXL065) is responsible for pioglitazone efficacy in NASH yet exhibits little to no PPARγ activity. Hepatol Commun 2021; 5 (08) 1412-1425
86 Study of PXL065 in Patients With Nonalcoholic Steatohepatitis (NASH). Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04321343
87 Francque SM, Bedossa P, Ratziu V. et al; NATIVE Study Group. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med 2021; 385 (17) 1547-1558
88 Ratziu V, Harrison SA, Francque S. et al; GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150 (05) 1147-1159.e5
89 Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH). National Library of Medicine; 2022
90 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. Hepatology 2021; 74 (04) 1809-1824
91 Sinha RA, Bruinstroop E, Singh BK, Yen PM. Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists. Thyroid 2019; 29 (09) 1173-1191
92 Layden TJ, Boyer JL. The effect of thyroid hormone on bile salt-independent bile flow and Na+, K+ -ATPase activity in liver plasma membranes enriched in bile canaliculi. J Clin Invest 1976; 57 (04) 1009-1018
93 Yuan C, Lin JZ, Sieglaff DH. et al. Identical gene regulation patterns of T3 and selective thyroid hormone receptor modulator GC-1. Endocrinology 2012; 153 (01) 501-511
94 Sinha RA, Bruinstroop E, Singh BK, Yen PM. Thyroid hormones and thyromimetics: a new approach to nonalcoholic steatohepatitis?. Hepatology 2020; 72 (02) 770-771
95 Gautherot J, Claudel T, Cuperus F, Fuchs CD, Falguières T, Trauner M. Thyroid hormone receptor β1 stimulates ABCB4 to increase biliary phosphatidylcholine excretion in mice. J Lipid Res 2018; 59 (09) 1610-1619
96 Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol 2018; 14 (05) 259-269
97 Sinha RA, You SH, Zhou J. et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest 2012; 122 (07) 2428-2438
98 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. Lancet 2019; 394 (10213): 2012-2024
99 A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis (MAESTRO-NASH). National Library of Medicine; 2021
100 A Phase 3 Study to Evaluate the Safety and Biomarkers of Resmetirom (MGL-3196) in Non Alcoholic Fatty Liver Disease (NAFLD) Patients (MAESTRO-NAFLD1). National Library of Medicine; 2020
101 A Study to Assess the Efficacy and Safety of VK2809 for 52 Weeks in Subjects With Biopsy Proven NASH (VOYAGE). Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04173065
102 Ratziu V, de Guevara L, Safadi R. et al; ARREST Investigator Study Group. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med 2021; 27 (10) 1825-1835
103 A Phase 3/4 Clinical Study to Evaluate the Efficacy and Safety of Aramchol Versus Placebo in Subjects With NASH (ARMOR) (ARMOR). Accessed June 1, 2022 at: https://clinicaltrials.gov/ct2/history/NCT04104321?V_1=View
104 Galmed Pharmaceuticals. Galmed updates business and clinical development strategy to better leverage Aramchol's anti-fibrotic effects. Accessed June 1, 2022 at: https://galmedpharma.investorroom.com/2022-05-17-Galmed-updates-business-and-clinical-development-strategy-to-better-leverage-Aramchols-anti-fibrotic-effects
105 Lefere S, Tacke F. Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. JHEP Rep 2019; 1 (01) 30-43
106 Lefere S, Devisscher L, Tacke F. Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges. Expert Opin Investig Drugs 2020; 29 (02) 89-92
107 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. Hepatology 2020; 72 (03) 892-905
108 AURORA. Phase 3 Study for the Efficacy and Safety of CVC for the Treatment of Liver Fibrosis in Adults With NASH. National Library of Medicine; 2022
109 Barritt IV AS, Marshman E, Noureddin M. Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes-what hepatologists need to know. Aliment Pharmacol Ther 2022; 55 (08) 944-959
110 Petit JM, Vergès B. GLP-1 receptor agonists in NAFLD. Diabetes Metab 2017; 43 (1, Suppl 1): S28-S33
111 Samson SL, Bajaj M. Potential of incretin-based therapies for non-alcoholic fatty liver disease. J Diabetes Complications 2013; 27 (04) 401-406
112 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 (05) 1584-1592
113 Flock G, Baggio LL, Longuet C, Drucker DJ. Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes 2007; 56 (12) 3006-3013
114 Dutour A, Abdesselam I, Ancel P. et al. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes Metab 2016; 18 (09) 882-891
115 Petit JM, Cercueil JP, Loffroy R. et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the Lira-NAFLD study. J Clin Endocrinol Metab 2017; 102 (02) 407-415
116 Sanyal AJ, Van Natta ML, Clark J. et al; NASH Clinical Research Network (CRN). Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med 2021; 385 (17) 1559-1569
117 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 (02) 367-78.e5 , quiz e14–e15
118 Ishii S, Iizuka K, Miller BC, Uyeda K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci U S A 2004; 101 (44) 15597-15602
119 Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; 55 (04) 885-904
120 Ratner RE, Maggs D, Nielsen LL. et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2006; 8 (04) 419-428
121 Meier JJ, Gethmann A, Götze O. et al. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia 2006; 49 (03) 452-458
122 Parlevliet ET, Wang Y, Geerling JJ. et al. GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice. PLoS One 2012; 7 (11) e49152
123 Armstrong MJ, Hull D, Guo K. et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol 2016; 64 (02) 399-408
124 Liu Y, Wei R, Hong T-P. Potential roles of glucagon-like peptide-1-based therapies in treating non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20 (27) 9090-9097
125 Trevaskis JL, Griffin PS, Wittmer C. et al. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 2012; 302 (08) G762-G772
126 Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH). (ESSENCE). Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04822181
127 Armstrong MJ, Gaunt P, Aithal GP. et al; LEAN Trial Team. 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): 679-690
128 Newsome PN, Buchholtz K, Cusi K. et al; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 2021; 384 (12) 1113-1124
129 Wong C, Lee MH, Yaow CYL. et al. Glucagon-like peptide-1 receptor agonists for non-alcoholic fatty liver disease in type 2 diabetes: a meta-analysis. Front Endocrinol (Lausanne) 2021; 12: 609110
130 Boyle JG, Livingstone R, Petrie JR. Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review. Clin Sci (Lond) 2018; 132 (15) 1699-1709
131 Brown JM, Everett BM. Cardioprotective diabetes drugs: what cardiologists need to know. Cardiovasc Endocrinol Metab 2019; 8 (04) 96-105
132 Marso SP, Daniels GH, Brown-Frandsen K. et al; LEADER Steering Committee, LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375 (04) 311-322
133 Marso SP, Bain SC, Consoli A. et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375 (19) 1834-1844
134 Clegg LE, Penland RC, Bachina S. et al. Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial. Cardiovasc Diabetol 2019; 18 (01) 138
135 Husain M, Bain SC, Jeppesen OK. et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab 2020; 22 (03) 442-451
136 Han MAT, Altayar O, Hamdeh S. et al. Rates of and factors associated with placebo response in trials of pharmacotherapies for nonalcoholic steatohepatitis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2019; 17 (04) 616-629.e26
137 Ng CH, Xiao J, Lim WH. et al. Placebo effect on progression and regression in NASH: evidence from a meta-analysis. Hepatology 2022; 75 (06) 1647-1661
138 A Research Study on How Semaglutide Works in People With Fatty Liver Disease and Liver Damage. National Library of Medicine; 2022
139 A Study of Tirzepatide (LY3298176) in Participants With Nonalcoholic Steatohepatitis (NASH) (SYNERGY-NASH). National Library of Medicine; 2022
140 Hartman ML, Sanyal AJ, Loomba R. et al. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care 2020; 43 (06) 1352-1355
141 A Study to Evaluate Safety and Pharmacodynamic Efficacy of 0382 in Obese Subjects With NAFLD/NASH. National Library of Medicine; 2022
142 Robertson D, Challis B, Daniels JS. et al. PROXYMO demonstrates safety and efficacy of cotadutide, a novel incretin co-agonist in biopsy-proven non-cirrhotic NASH with fibrosis. Oral abstract. Hepatology 2021; 74: 1383A
143 Study to Evaluate Efficacy. Safety and Tolerability of HM15211 in Subjects. Accessed April 29, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04505436
144 Jepsen MM, Christensen MB. Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. Expert Opin Emerg Drugs 2021; 26 (03) 231-243
145 Degirolamo C, Sabbà C, Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 2016; 15 (01) 51-69
146 Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology 2016; 63 (03) 914-929
147 Mayo MJ, Wigg AJ, Leggett BA. et al. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun 2018; 2 (09) 1037-1050
148 Luo J, Ko B, Elliott M. et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014; 6 (247) 247ra100
149 Zhou M, Wang X, Phung V. et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 2014; 74 (12) 3306-3316
150 Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol Commun 2017; 1 (10) 1024-1042
151 Harrison SA, Neff GW, Guy CD. et al. Final Analysis of a 24-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Aldafermin (NGM282) in Patients with Nonalcoholic Steatohepatitis. AASLD; 2020
152 Harrison SA, Rossi SJ, Paredes AH. et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology 2020; 71 (04) 1198-1212
153 Harrison SA, Neff G, Guy CD. et al. Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis. Gastroenterology 2021; 160 (01) 219-231.e1
154 Harrison SA, Rinella ME, Abdelmalek MF. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018; 391 (10126): 1174-1185
155 Rinella ME, Trotter JF, Abdelmalek MF. et al. Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis. J Hepatol 2019; 70 (04) 735-744
156 Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 2017; 152 (07) 1679-1694.e3
157 Flippo KH, Potthoff MJ. Metabolic messengers: FGF21. Nat Metab 2021; 3 (03) 309-317
158 Tillman EJ, Rolph T. FGF21: an emerging therapeutic target for non-alcoholic steatohepatitis and related metabolic diseases. Front Endocrinol (Lausanne) 2020; 11: 601290
159 Harrison SA, Ruane PJ, Freilich BL. et al. Efruxifermin (EFX), a Long-Acting Fc-FGF21 Fusion Protein, Administered for 16 Weeks to Patients with NASH Substantially Reduces Liver Fat and ALT, and Improves Liver Histology: Analysis of a Randomized, Placebo-Controlled, Phase 2a Study (BALANCED). New Jersey: Wiley; 2020: 6A-7A
160 Rohit Loomba AJS, Nakajima A, Neuschwander-Tetri BA. et al. Efficacy and safety of pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis: results from the phase 2b, randomized, double-blind, placebo-controlled Falcon 1 study. presented at: AASLD The Liver Meeting; 2021; Accessed June 1, 2022 at: https://www.aasld.org/sites/default/files/2021-11/TLM%202021%20Late%20Breaking%20Abstracts%2011.01.21.pdf
161 Loomba R, Kayali Z, Noureddin M. et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 2018; 155 (05) 1463-1473.e6
162 Bergman A, Carvajal-Gonzalez S, Tarabar S, Saxena AR, Esler WP, Amin NB. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a liver-targeting acetyl-CoA carboxylase inhibitor (PF-05221304): a three-part randomized phase 1 study. Clin Pharmacol Drug Dev 2020; 9 (04) 514-526
163 Huard K, Smith AC, Cappon G. et al. Optimizing the benefit/risk of acetyl-CoA carboxylase inhibitors through liver targeting. J Med Chem 2020; 63 (19) 10879-10896
164 Amin N, Carvajal-Gonzalez S, Aggarwal N. et al. PF-05221304 (PF'1304), a Liver-Targeted Acetyl-CoA Carboxylase Inhibitor (ACCI), in Adults with Nonalcoholic Fatty Liver Disease (NAFLD) Demonstrates Robust Reductions in Liver Fat and ALT - Phase 2a, Dose-Ranging Study. New Jersey: Wiley; 2019: 21A-22A
165 How an abandoned Pfizer NASH drug gave rise to a Novartis-teamed follow-on. Accessed June 1, 2022 at: https://www.fiercebiotech.com/research/abandoned-pfizer-nash-drug-gives-rise-to-novartis-teamed-follow#:~:text=Despite%20generating%20promising%20data%20on,NASH%20patients%2C%20the%20spokesperson%20said
166 Calle RA, Amin NB, Carvajal-Gonzalez S. et al. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. Nat Med 2021; 27 (10) 1836-1848
167 Pfizer Granted FDA Fast Track Designation for Ervogastat/Clesacostat Combination for the Treatment of Non-Alcoholic Steatohepatitis (NASH). Accessed June 1, 2022 at: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-granted-fda-fast-track-designation
168 Futatsugi K, Smith AC, Tu M. et al. Discovery of PF-06835919: a potent inhibitor of ketohexokinase (KHK) for the treatment of metabolic disorders driven by the overconsumption of fructose. J Med Chem 2020; 63 (22) 13546-13560
169 6-Week Safety and PD Study in Adults With NAFLD. Accessed June 1, 2022 at: https://clinicaltrials.gov/ct2/show/NCT03256526
170 Loomba R, Mohseni R, Lucas KJ. et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology 2021; 161 (05) 1475-1486
171 A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224. Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04932512
172 Dufour JF, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut 2020; 69 (10) 1877-1884
173 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 Hepatol 2020; 72 (04) 613-626
174 Chalasani N, Abdelmalek MF, Garcia-Tsao G. et al; Belapectin (GR-MD-02) Study Investigators. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology 2020; 158 (05) 1334-1345.e5
175 Syn WK, Choi SS, Diehl AM. Apoptosis and cytokines in non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13 (04) 565-580
176 Feldstein AE, Gores GJ. Apoptosis in alcoholic and nonalcoholic steatohepatitis. Front Biosci 2005; 10: 3093-3099
177 Harrison SA, Goodman Z, Jabbar A. et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol 2020; 72 (05) 816-827
178 Garcia-Tsao G, Bosch J, Kayali Z. et al; IDN-6556-14 Investigators(‡). Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension. J Hepatol 2020; 72 (05) 885-895
179 Frenette C, Kayali Z, Mena E. et al; IDN-6556-17 Study Investigators. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J Hepatol 2021; 74 (02) 274-282
180 Bennett B, Blease K, Ye Y. et al. CC-90001, a second generation Jun N-terminal kinase (JNK) inhibitor for the treatment of idiopathic pulmonary fibrosis. C38 Understanding Therapeutics in IPF. Am Thorac Soc 2017; A5409
181 Study to Evaluate the Efficacy and Safety of CC-90001 in Participants With Non-alcoholic Steatohepatitis (NASH) and Liver Fibrosis. . Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04048876
182 Ure DR, Trepanier DJ, Mayo PR, Foster RT. Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs 2020; 29 (02) 163-178
183 A Study of CRV431 Dosed Once Daily in NASH Induced F2 and F3 Subjects (AMBITION). Accessed March 20, 2022 at: https://clinicaltrials.gov/ct2/show/NCT04480710
184 Halilbasic E, Steinacher D, Trauner M. Nor-ursodeoxycholic acid as a novel therapeutic approach for cholestatic and metabolic liver diseases. Dig Dis 2017; 35 (03) 288-292
185 Beraza N, Malato Y, Sander LE. et al. Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. J Exp Med 2009; 206 (08) 1727-1737
186 Traussnigg S, Schattenberg JM, Demir M. et al; Austrian/German NAFLD-norUDCA study group. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol 2019; 4 (10) 781-793
187 Norursodeoxycholic Acid vs. Placebo in NASH. National Library of Medicine; 2021
188 Kallai L, Hahn A, Roeder V, Zupanic V. Correlation between histological findings and serum transaminase values in chronic diseases of the liver. Acta Med Scand 1964; 175: 49-56
189 Steinacher D, Claudel T, Trauner M. Therapeutic mechanisms of bile acids and nor-ursodeoxycholic acid in non-alcoholic fatty liver disease. Dig Dis 2017; 35 (03) 282-287
190 Yoneda M, Nakajima A. Norursodeoxycholic acid as a candidate pharmacological therapy for nonalcoholic fatty liver disease. Dig Med Res 2020; 3: 108
191 Noureddin M, Sanyal AJ. Pathogenesis of NASH: the impact of multiple pathways. Curr Hepatol Rep 2018; 17 (04) 350-360
192 Corey KE, Chalasani N. Should combination therapy be the paradigm for future nonalcoholic steatohepatitis clinical trials?. Hepatology 2011; 54 (05) 1503-1505
193 Alonso C, Fernández-Ramos D, Varela-Rey M. et al. Metabolomic identification of subtypes of nonalcoholic steatohepatitis. Gastroenterology 2017; 152 (06) 1449-1461.e7
194 Noureddin M, Mato JM, Lu SC. Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine. Exp Biol Med (Maywood) 2015; 240 (06) 809-820
195 Sanyal AJ. Past, present and future perspectives in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2019; 16 (06) 377-386
196 Gilead Announces Topline Results from Phase . 2 ATLAS Study in Patients With Bridging Fibrosis (F3) and Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH). Gilead; 2019
197 Rinella ME, Noureddin M. STELLAR 3 and STELLAR 4: lessons from the fall of Icarus. J Hepatol 2020; 73 (01) 9-11
198 Neuschwander-Tetri BA, Clark JM, Bass NM. et al; NASH Clinical Research Network. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 2010; 52 (03) 913-924
199 Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2004; 2 (03) 262-265
200 McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62 (05) 1148-1155
201 Wang P, Kang D, Cao W, Wang Y, Liu Z. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 2012; 28 (02) 109-122
202 Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 2014; 59 (02) 713-723
203 Bril F, Biernacki DM, Kalavalapalli S. et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2019; 42 (08) 1481-1488
204 Efficacy, Safety and Tolerability of the Combination of Tropifexor & Licogliflozin and Each Monotherapy, Compared With Placebo in Adult Patients With NASH and Liver Fibrosis. (ELIVATE). National Library of Medicine; 2022
205 Loomba R, Noureddin M, Kowdley VK. et al. Safety and Efficacy of Combination Therapies Including Cilofexor/Firsocostat in Patients With Bridging Fibrosis and Cirrhosis Due to NASH: Results of the Phase 2b ATLAS Trial. European Association for the Study of the Liver (EASL); 2020
206 Pockros PJ, Fuchs M, Freilich B. et al. CONTROL: a randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. Liver Int 2019; 39 (11) 2082-2093
207 Chen W, Yang A, Jia J, Popov YV, Schuppan D, You H. Lysyl oxidase (LOX) family members: rationale and their potential as therapeutic targets for liver fibrosis. Hepatology 2020; 72 (02) 729-741
208 Pollheimer MJ, Racedo S, Mikels-Vigdal A. et al. Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis. J Hepatol 2018; 69 (02) 368-377
209 Harrison SA, Abdelmalek MF, Caldwell S. et al; GS-US-321-0105 and GS-US-321-0106 Investigators. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 2018; 155 (04) 1140-1153
210 Harrison SA, Wong VW, Okanoue T. et al; STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J Hepatol 2020; 73 (01) 26-39
211 GENFIT: announces results from interim analysis of RESOLVE-IT phase 3 trial of elafibranor in adults with NASH and fibrosis. Accessed June 30, 2022 at: https://ir.genfit.com/news-releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3
212 Loomba R, Lawitz E, Mantry PS. et al; GS-US-384-1497 Investigators. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 2018; 67 (02) 549-559
213 Caiazzo R, Lassailly G, Leteurtre E. et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg 2014; 260 (05) 893-898 , discussion 898–899
214 Fakhry TK, Mhaskar R, Schwitalla T, Muradova E, Gonzalvo JP, Murr MM. Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary systematic review and meta-analysis. Surg Obes Relat Dis 2019; 15 (03) 502-511
215 Ng CH, Xiao J, Lim WH. et al. Placebo effect on progression and regression in non-alcoholic steatohepatitis. evidence from a meta-analysis. Hepatology 2022;
216 Dulai PS, Singh S, Patel J. et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 2017; 65 (05) 1557-1565
217 Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V. et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology 2018; 155 (02) 443-457.e17
218 Angulo P, Kleiner DE, Dam-Larsen S. 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 (02) 389-97.e10
219 Hagström H, Nasr P, Ekstedt M. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol 2017; 67 (06) 1265-1273
220 Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not. Metabolism 2013; 62 (03) 352-360
221 Golabi P, Otgonsuren M, de Avila L, Sayiner M, Rafiq N, Younossi ZM. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine (Baltimore) 2018; 97 (13) e0214
222 Madrigal Pharmaceuticals. Madrigal Pharmaceuticals announces first patient dosed in MAESTRO-NAFLD-1, a second phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom (MGL-3196) in patients with non-alcoholic steatohepatitis (NASH) and presumed NASH (NASH/NAFLD (non-alcoholic fatty liver disease)). Accessed June 30, 2022 at: https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-first-patient-dosed-maestro
223 Frias JP, Nauck MA, Van J. et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018; 392 (10160): 2180-2193
224 US Food and Drug Administration. Noncirrhotic Nonalcoholic Steatohepatitis with Liver Fibrosis: Developing Drugs for Treatment – Guidance for Industry. FDA; 2018
225 US Food and Drug Administration. Noncirrhotic Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment – Guidance for Industry. FDA; 2019
226 Alonso R, Cuevas A, Cafferata A. Diagnosis and management of statin intolerance. J Atheroscler Thromb 2019; 26 (03) 207-215
227 Brown AS, Watson KE. Statin intolerance. Rev Cardiovasc Med 2018; 19 (S1): S9-S19
228 Penson PE, Mancini GBJ, Toth PP. et al; Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP). Introducing the 'Drucebo' effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions. J Cachexia Sarcopenia Muscle 2018; 9 (06) 1023-1033
229 Robinson JG. New insights into managing symptoms during statin therapy. Prog Cardiovasc Dis 2019; 62 (05) 390-394
230 Arrese M, Arab JP, Barrera F, Kaufmann B, Valenti L, Feldstein AE. Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity. Thieme Medical Publishers, Inc.; 2021
231 Ampuero J, Romero-Gomez M. Stratification of patients in NASH clinical trials: a pitfall for trial success. JHEP Rep 2020; 2 (05) 100148
232 Lonardo A, Arab JP, Arrese M. Perspectives on precision medicine approaches to NAFLD diagnosis and management. Adv Ther 2021; 38 (05) 2130-2158
233 Sookoian S, Pirola CJ. Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biology. Clin Mol Hepatol 2020; 26 (04) 461-475
234 Brunt EM, Clouston AD, Goodman Z. et al. Complexity of ballooned hepatocyte feature recognition: defining a training atlas for artificial intelligence-based imaging in NAFLD. J Hepatol 2022; 76 (05) 1030-1041