Perspectives of Drug Therapy for Non-Alcoholic Steatohepatitis-Related Liver Fibrosis

Abstract

Liver fibrosis (LF) is an adverse event of the natural course of non-alcoholic steatohepatitis (NASH) since its progression leads to the development of liver cirrhosis, which is associated with poor prognosis. In addition, there is evidence that the presence of advanced LF may be a strong independent predictor and risk factor for cardiovascular disease in NASH patients, which is the main cause of their death. Based on the severity of the problem, the study and implementation of drugs for the treatment of NASH-related LF is extremely necessary. The purpose of this review was to describe phase II and III randomized controlled trials (RCTs) evaluating the efficacy and safety of drug therapy for NASH-related LF. To date, the possibilities for pharmacological treatment of NASH-related LF are very limited. However, in recent years, several drugs have been evaluated in NASH patients with LF (F2-3), and in some cases with compensated liver cirrhosis, in large phase II and III RCTs, and they have shown promise. It can be assumed that drugs that have shown efficacy and safety in phase II and III RCTs will be recommended for testing and confirming practical benefits in phase IV RCTs. Besides, an in-depth study of the cellular and molecular mechanisms of NASH-related LF will contribute to the development of new medications, the introduction of which will expand the possibilities of its drug therapy.

Keywords

Non-alcoholic fatty liver disease / Nonalcoholic steatohepatitis / Liver fibrosis / Liver cirrhosis / Drug therapy

Author Contributions

D.V.G. contributed to the conception, design, acquisition, analysis, interpretation of data, wrote the manuscript and approved the final version.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Funding

This research received no external funding.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Younossi ZM, Paik JM, Henry L, Yang J, Fernandes G, Stepanova M, Nader F. The Growing Economic and Clinical Burden of Nonalcoholic Steatohepatitis (NASH) in the United States. J. Clin. Exp. Hepatol. 2023, 13, 454-467.

[2] Noureddin M, Harrison SA. NASH cirrhosis trials and major adverse liver outcomes: Big data needed. J. Hepatol. 2023, 78, 5-7.

[3] Garbuzenko DV. Liver fibrosis as an independent cardiovascular risk factor in non-alcoholic fatty liver disease. J. Transl. Gastroenterol. 2024, 2, 21-29.

[4] Anania FA, Dimick-Santos L, Mehta R, Toerner J, Beitz J. Nonalcoholic Steatohepatitis: Current Thinking From the Division of Hepatology and Nutrition at the Food and Drug Administration. Hepatology 2021, 73, 2023-2027.

[5] Garbuzenko DV. Non-invasive diagnosis of liver fibrosis associated with nonalcoholic steatohepatitis. Russ. J. Evid. Based Gastroenterol. 2021, 10, 75-81.

[6] Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023, 77, 1797-1835.

[7] Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41, 1313-1321.

[8] Brunt EM, Kleiner DE, Wilson LA, Sanyal AJ, Neuschwander-Tetri BA, Nonalcoholic Steatohepatitis Clinical Research Network. Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials. Hepatology 2019, 70, 522-531.

[9] Kleiner DE, Brunt EM, Wilson LA, Behling C, Guy C, Contos M, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. JAMA Netw Open. 2019, 2, e1912565.

[10] Sinakos E, Liava C, Loomba R. Emerging advances in the pharmacologic treatment of nonalcoholic steatohepatitis and related cirrhosis. Ann. Gastroenterol. 2022, 35, 213-225.

[11] Adorini L, Trauner M. FXR agonists in NASH treatment. J. Hepatol. 2023, 79, 1317-1331.

[12] Keshvani C, Kopel J, Goyal H. Obeticholic Acid-A Pharmacological and Clinical Review. Fut. Pharmacol. 2023, 3, 238-251.

[13] Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, 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, 956-965.

[14] Loomba R, Sanyal AJ, Kowdley KV, Terrault N, Chalasani NP, Abdelmalek MF, et al. Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. Gastroenterology 2019, 156, 88-95.

[15] Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomized, placebo-controlled phase 3 trial. Lancet 2019, 394, 2184-2196.

[16] Sanyal AJ, Ratziu V, Loomba R, Anstee QM, Kowdley KV, Rinella ME, et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J. Hepatol. 2023, 79, 1110-1120.

[17] Rinella ME, Dufour JF, Anstee QM, Goodman Z, Younossi Z, Harrison SA, et al. Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study. J. Hepatol. 2022, 76, 536-548.

[18] Younossi ZM, Stepanova M, Nader F, Loomba R, Anstee QM, Ratziu V, et al. RandomizEd Global Phase 3 Study to Evaluate the Impact on NASH with FibRosis of Obeticholic Acid TreatmEnt (REGENERATE) Study Investigators. Obeticholic Acid Impact on Quality of Life in Patients With Nonalcoholic Steatohepatitis: REGENERATE 18-Month Interim Analysis. Clin. Gastroenterol. Hepatol. 2022, 20, 2050-2058.

[19] Badman MK, Chen J, Desai S, Vaidya S, Neelakantham S, Zhang J, et al. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers. Clin. Pharmacol. Drug Dev. 2020, 9, 395-410.

[20] Sanyal AJ, Lopez P, Lawitz EJ, Lucas KJ, Loeffler J, Kim W, et al. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat. Med. 2023, 29, 392-400.

[21] Patel K, Harrison SA, Elkhashab M, Trotter JF, Herring R, Rojter SE, et al. Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. Hepatology 2020, 72, 58-71.

[22] Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. J. Adv. Pharm. Technol. Res. 2011, 2, 236-240.

[23] Westerouen Van Meeteren MJ, Drenth JPH, Tjwa ETTL. Elafibranor: A potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin. Investig. Drugs. 2020, 29, 117-123.

[24] Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, 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, 1147-1159.

[25] Lefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J. Hepatol. 2020, 73, 757-770.

[26] Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. NATIVE Study Group. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N. Engl. J. Med. 2021, 385, 1547-1558.

[27] Tacke F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Expert Opin. Investig. Drugs. 2018, 27, 301-311.

[28] Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 2018, 67, 1754-1767.

[29] Ratziu V, Sanyal A, Harrison SA, Wong VW, Francque S, Goodman Z, et al. Cenicriviroc Treatment for Adults With Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study. Hepatology 2020, 72, 892-905.

[30] Anstee QM, Neuschwander-Tetri BA, Wai-Sun Wong V, Abdelmalek MF, Rodriguez-Araujo G, Landgren H, et al. Cenicriviroc Lacked Efficacy to Treat Liver Fibrosis in Nonalcoholic Steatohepatitis: AURORA Phase III Randomized Study. Clin. Gastroenterol. Hepatol. 2024, 22, 124-134.

[31] Francque SM, Hodge A, Boursier J, Younes ZH, Rodriguez-Araujo G, Park GS, et al. Phase 2, open-label, rollover study of cenicriviroc for liver fibrosis associated with metabolic dysfunction-associated steatohepatitis. Hepatol. Commun. 2024, 8, e0335.

[32] Phan P, Ternier G, Edirisinghe O, Kumar TKS. Exploring endocrine FGFs-structures, functions and biomedical applications. Int. J. Biochem. Mol. Biol. 2024, 15, 68-99.

[33] Henriksson E, Andersen B. FGF19 and FGF21 for the Treatment of NASH-Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human. Front. Endocrinol. 2020, 11, 601349.

[34] Harrison SA, Neff G, Guy CD, Bashir MR, Paredes AH, Frias JP, et al. Efficacy and Safety of Aldafermin, an Engineered FGF 19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis. Gastroenterology 2021, 160, 219-231.

[35] Harrison SA, Abdelmalek MF, Neff G, Gunn N, Guy CD, Alkhouri N, et al. Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol. Hepatol. 2022, 7, 603-616.

[36] Rinella ME, Lieu HD, Kowdley KV, Goodman ZD, Alkhouri N, Lawitz E, et al. A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis. Hepatology 2024, 79, 674-689.

[37] Abdelmalek MF, Charles ED, Sanyal AJ, Harrison SA, Neuschwander-Tetri BA, Goodman Z, et al. The FALCON program: Two phase 2b randomized, double-blind, placebo-controlled studies to assess the efficacy and safety of pegbelfermin in the treatment of patients with nonalcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis. Contemp. Clin. Trials. 2021, 104, 106335.

[38] Loomba R, Sanyal AJ, Nakajima A, Neuschwander-Tetri BA, Goodman ZD, Harrison SA, et al. Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study. Clin. Gastroenterol. Hepatol. 2024, 22, 102-112.

[39] Abdelmalek MF, Sanyal AJ, Nakajima A, Neuschwander-Tetri BA, Goodman ZD, Lawitz EJ, et al. Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study. Clin. Gastroenterol. Hepatol. 2024, 22, 113-123.

[40] Loomba R, Lawitz EJ, Frias JP, Ortiz-Lasanta G, Johansson L, Franey BB, et al. Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: A randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study. Lancet Gastroenterol. Hepatol. 2023, 8, 120-132.

[41] Loomba R, Sanyal AJ, Kowdley KV, Bhatt DL, Alkhouri N, Frias JP, et al. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH. N. Engl. J. Med. 2023, 389, 998-1008.

[42] Harrison SA, Ruane PJ, Freilich BL, Neff G, Patil R, Behling CA, et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial. Nat. Med. 2021, 27, 1262-1271.

[43] Harrison SA, Frias JP, Neff G, Abrams GA, Lucas KJ, Sanchez W, et al. HARMONY Study Group. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): A multicentre, randomized, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol. Hepatol. 2023, 8, 1080-1093.

[44] Harrison SA, Ruane PJ, Freilich B, Neff G, Patil R, Behling C, et al. A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis. JHEP Rep. 2022, 5, 100563.

[45] Budas G, Wu F, Turner S, Zagorska A, Li L, Breckenridge D. Characterization of ASK 1 signaling in human NASH liver and human hepatic stellate cells. J. Hepatol. 2018, 68, S351.

[46] Budas G, Karnik S, Jonnson T, Shafizadeh T, Watkins S, Breckenridge D, et al. Reduction of liver steatosis and fibrosis with an ASK1 inhibitor in a murine model of NASH is accomplished by improvements in cholesterol, bile acid and lipid metabolism. J. Hepatol. 2016, 64, S170.

[47] Harrison SA, Wong VW, Okanoue T, Bzowej N, Vuppalanchi R, Younes Z, et al. STELLAR-3; 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, 26-39.

[48] Liu SB, Ikenaga N, Peng ZW, Sverdlov DY, Greenstein A, Smith V, et al. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J. 2016, 30, 1599-1609.

[49] Harrison SA, Goodman ZD, Ratziu V, Loomba R, Diehl AM, Lawitz E, et al. Serum lysyl oxidase-like-2 (sLOXL2) levels correlate with fibrosis stage in patients with nonalcoholic steatohepatitis (NASH). Hepatology 2015, 62, 910.

[50] Rodriguez HM, Vaysberg M, Mikels A, McCauley S, Velayo AC, Garcia C, et al. Modulation of lysyl oxidase-like 2 enzymatic activity by an allosteric antibody inhibitor. J. Biol. Chem. 2010, 285, 20964-20974.

[51] Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, 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, 1140-1153.

[52] Al Attar A, Antaramian A, Noureddin M. Review of galectin-3 inhibitors in the treatment of nonalcoholic steatohepatitis. Expert Rev. Clin. Pharmacol. 2021, 14, 457-464.

[53] Chalasani N, Abdelmalek MF, Garcia-Tsao G, Vuppalanchi R, Alkhouri N, Rinella M, 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, 1334-1345.

[54] Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015, 35, 953-966.

[55] Harrison SA, Goodman Z, Jabbar A, Vemulapalli R, Younes ZH, Freilich B, et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J. Hepatol. 2020, 72, 816-827.

[56] Garcia-Tsao G, Bosch J, Kayali Z, Harrison SA, Abdelmalek MF, Lawitz E, et al. For the IDN-6556-14 Investigators. Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension. J. Hepatol. 2020, 72, 885-895.

[57] Malik A, Nadeem M, Amjad W, Malik MI, Javaid S, Farooq U, et al. Effects of Aramchol in patients with nonalcoholic fatty liver disease (NAFLD). A systematic review and meta-analysis. Prz. Gastroenterol. 2023, 18, 67-75.

[58] Ratziu V, de Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, et al. ARREST investigator study group; Sanyal AJ. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat. Med. 2021, 27, 1825-1835.

[59] Mantovani A, Targher G. Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic steatohepatitis: new insights from subcutaneous semaglutide. Hepatob. Surg. Nutr. 2021, 10, 518-521.

[60] Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2021, 384, 1113-1124.

[61] Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjar MS, Krarup N, et al. NN9931-4492 investigators. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol. Hepatol. 2023, 8, 511-522.

[62] Karim G, Bansal MB. Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, β-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. Touch. Rev. Endocrinol. 2023, 19, 60-70.

[63] Noureddin M, Charlton MR, Harrison SA, Bansal MB, Alkhouri N, Loomba R, et al. Expert Panel Recommendations: Practical Clinical Applications for Initiating and Monitoring Resmetirom in Patients With MASH/NASH and Moderate to Noncirrhotic Advanced Fibrosis. Clin. Gastroenterol. Hepatol. 2024, 22, 2367-2377.

[64] Harrison SA, Bashir M, Moussa SE, McCarty K, Pablo Frias J, Taub R, et al. Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients With NASH. Hepatol. Commun. 2021, 5, 573-588.

[65] Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. MAESTRO-NASH Investigators. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N. Engl. J. Med. 2024, 390, 497-509.

[66] Lambrecht J, Tacke F. Acetyl-CoA Carboxylase Inhibition as a Therapeutic Tool in the Battle Against NASH: Hitting More Than Just One Mechanism? Cell Mol. Gastroenterol. Hepatol. 2020, 10, 859-861.

[67] Matsumoto M, Yashiro H, Ogino H, Aoyama K, Nambu T, Nakamura S, et al. Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis. PLoS ONE 2020, 15, e0228212.

[68] Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ, et al. Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis. Clin. Gastroenterol. Hepatol. 2018, 16, 1983-1991.

[69] Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, et al. GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2018, 155, 1463-1473.

[70] Abe N, Kato S, Murata Y, Kikkawa K, Oka K. MT-3995, a novel non-steroidal mineralocorticoid receptor antagonist, has beneficial effects on the progression of non-alcoholic steatohepatitis in choline-deficient L-amino acid-defined diet-fed F344 rats and trans-fat diet-fed ob/ob mice. In Proceedings of the American Association for the Study of Liver Diseases (AASLD) Annual Meeting, virtual, 13-16 November 2020.

[71] Okanoue T, Sakamoto M, Harada K, Inagaki M, Totsuka N, Hashimoto G, et al. Efficacy and safety of apararenone (MT-3995) in patients with nonalcoholic steatohepatitis: A randomized controlled study. Hepatol. Res. 2021, 51, 943-956.

[72] Syed-Abdul MM, Parks EJ, Gaballah AH, Bingham K, Hammoud GM, Kemble G, et al. Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities. Hepatology 2020, 72, 103-118.

[73] Loomba R, Mohseni R, Lucas KJ, Gutierrez JA, Perry RG, Trotter JF, et al. TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial. Gastroenterology 2021, 161, 1475-1486.

[74] Federico A, Dallio M, Loguercio C. Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules 2017, 22, 191.

[75] Navarro VJ, Belle SH, D’Amato M, Adfhal N, Brunt EM, Fried MW, et al. Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial. PLoS ONE 2019, 14, e0221683.

[76] Dufour JF, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut 2020, 69, 1877-1884.

[77] Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. GS-US-384-1497 Investigators. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology 2018, 67, 549-559.

[78] Anstee QM, Lucas KJ, Francque S, Abdelmalek MF, Sanyal AJ, Ratziu V, et al. Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study. Hepatology 2023, 78, 1223-1239.

[79] Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, et al. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology 2021, 73, 625-643.

[80] Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, et al. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J. Hepatol. 2022, 77, 607-618.

[81] Study to Evaluate the Efficacy and Safety of K-877-ER and CSG452 in Participants With NASH With Liver Fibrosis. Available online: https://clinicaltrials.gov/study/NCT05327127 (accessed on 14 November 2022).

[82] 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). Available online: https://clinicaltrials.gov/study/NCT04065841 (accessed on 19 august 2019).

[83] Saroglitazar Magnesium for the Treatment of Nonalcoholic Steatohepatitis with Fibrosis (NASH). Available online: https://clinicaltrials.gov/study/NCT05011305 (accessed on 11 July 2021).