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  • Review Article
  • OPEN ACCESS

Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease

  • Ye Hu1,* ,
  • Chao Sun1,
  • Ying Chen2,
  • Yu-Dong Liu3 and
  • Jian-Gao Fan1,* 
 Author information  Cite
Journal of Clinical and Translational Hepatology   2024;12(9):802-814

doi: 10.14218/JCTH.2024.00123

Abstract

Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), the absence of licensed medications is striking. A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available medications. MASLD therapies center on four major pathways. Considering the close relationship between MASLD and type 2 diabetes, the first approach involves antidiabetic medications, including incretins, thiazolidinedione insulin sensitizers, and sodium-glucose cotransporter 2 inhibitors. The second approach targets hepatic lipid accumulation and the resultant metabolic stress. Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs. The third approach focuses on targeting oxidative stress, inflammation, and fibrosis. Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications.

Graphical Abstract

Keywords

NAFLD, MASLD, Clinical trial, Medication, Hypoglycemic agents, Intermediary metabolism

Introduction

In 2020, a group of experts aimed to integrate the understanding of patient heterogeneity and more accurately highlight disease pathogenesis captured under the acronym non-alcoholic fatty liver disease (NAFLD). Consequently, the term metabolic dysfunction-associated fatty liver disease (MAFLD) was introduced as a more appropriate overarching terminology.1 However, concerns were raised about the stigmatizing term “fatty” and the inclusion of two metabolic risk factors, as well as the allowance of more liberal alcohol use, thus distracting our attention from the natural history of the disease. Under the auspices of the American Association for the Study of Liver Diseases (hereinafter referred to as AASLD) and the European Association for the Study of the Liver (hereinafter referred to as EASL), in collaboration with the Asociación Latinoamericana para el Estudio del Hígado and with the engagement of academic professionals worldwide, metabolic dysfunction–associated steatotic liver disease (MASLD) was voted to be the most appropriate replacement in 2023. MASLD is defined as hepatic steatosis with one cardiometabolic risk factor and without any other discernible cause.2 Given the >99% overlap between patients meeting the criteria for NAFLD and those identified as having MASLD, we hereafter use MASLD as the standardized nomenclature instead of NAFLD.3 MASLD is now the most prevalent chronic liver disease in the world, encompassing a continuum of liver abnormalities from MASLD to metabolic dysfunction-associated steatohepatitis (MASH), progressing to cirrhosis and hepatic cancer. MASH is the primary risk factor for progressive hepatic fibrosis and possibly cardiovascular disease and malignancy.4–6 Moreover, patients with moderate to advanced hepatic fibrosis are at increased risk of cirrhosis,7,8 which justifies the need for pharmacotherapy in patients with MASH and advanced fibrosis.

According to the AASLD and EASL practice guidelines, the main goal of most lifestyle interventions is 5–10% weight loss in overweight/obese MASLD patients.3,9,10 In clinical trials, MASLD treatments generally target glucose and lipid metabolism to alleviate inflammation and improve hepatic histology. MASLD treatments targeting the enterohepatic axis and gut microbiota are gradually emerging, and a variety of new metabolism-modulating drugs are also under clinical development. Potential medications and targets for MASLD are shown in Figure 1. Here we will explore the latest relevant literature from January 2019 to April 2024 in the database PubMed/MEDLINE, with the results enriched by manual searches and citation mining, and discuss the ongoing therapeutic options for MASLD focused on treating T2DM, insulin resistance, and intermediary metabolism to address the global health burden of these highly relevant diseases. Due to the large number of medications tested only in preclinical models, the review will center on potential medications that have progressed to clinical trials (Table 1).11–54 Current phase 2 and 3 clinical trials are summarized in Table 2.

Potential candidates for MASLD and their mechanisms of action.
Fig. 1  Potential candidates for MASLD and their mechanisms of action.

ACC, Acetyl-CoA Carboxylase; PPAR, peroxisome proliferator–activated receptor; MPC, mitochondrial pyruvate carrier; THR, thyroid hormone receptor; ASK-1, apoptosis signaling kinase-1; GLP-1R, glucagon-like peptide-1 receptor; GCGR, glucagon receptor; GIPR, glucose-dependent insulinotropic polypeptide receptor; PDE, phosphodiesterase; SGLT, sodium–glucose cotransporter; FXR, farnesoid X receptor; SCD1, stearoyl-CoA desaturase 1; FGFR4/1, fibroblast growth factor receptor4/1.

Table 1

Main agents and their characteristics for treating MASLD

AgentsMechanisms of actionPositive endpoint (s), RefNegative endpoint (s), RefComments
LiraglutideGLP-1 receptor agonist requiring daily injectionImproved MASH histology in a small pilot study11Decrease in weight, hepatic steatosis, and hepatocellular apoptosis in obese adults with MASLD not sustained if discontinued (NCT02654665).12
SemaglutideGLP-1 receptor agonist with weekly injectionContributed to a significant MASH resolution (NCT02970942)13Lacking an improvement in the fibrosis stage (NCT02970942).13 For MASH-related compensated cirrhosis, did not achieve MASH resolution or improve fibrosis (NCT03987451)14
TirzepatideDual GLP-1 and GIP agonistsPronounced reduction in body weight (NCT04184622).15 Decreased liver fat by 8.1% over 52 weeks associated with reduction in ALT, AST, and γ-GT (NCT03882970).16–
RetatrutideNovel triple agonist peptide at GCGR, GIPR, and GLP-1RSignificant body weight loss in obese patients (NCT04881760).17 Reduce plasma ALT and hepatic triglycerides in obese mice.18–
Pioglitazone and rosiglitazonePPAR-gamma and the MPC agonistLong-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and MASLD (NCT00994682).19–The main side effect is weight gain
MSDC-0602KPreferentially suppress the MPC while minimizing direct binding to PPARγThe substantial decrease in glucose, insulin, liver enzymes, and NAS effects on patients with biopsy-confirmed MASH and fibrosis (F1-F3).20–
PXL065A novel PPARγ agonistImprove liver fat content, PIIINP, and NAFLD fibrosis score, as well as histological parameters including NAS and fibrosis, with a favorable safety profile.21–
Canagliflozin, dapagliflozin, empagliflozin ertugliflozinSGLT2 inhibitorsImprove hepatic lipid content, liver enzymes, and fibrosis.22–26 Dapagliflozin 10 mg for 12 weeks, significantly reduced intrahepatic lipid contents and ALT in patients with T2DM.27–Reduce cardiovascular disease risk and improve renal function in T2DM patients
LicogliflozinPotent SGLT1 and SGLT2 inhibitorImprove serum ALT in patients with MASH (NCT03205150).28–
OCAThe nuclear FXR agonistRapid and sustained improvements in liver enzymes and stiffness with OCA 25 mg qd treatment.29Failed to show OCA’s superiority compared to placebo at improving liver fibrosis in patients with compensated MASH-related cirrhosis (NCT03439254).FDA rejected the application for OCA as a treatment for MASH-related pre-cirrhotic liver fibrosis in June 2023 due to its unfavorable benefit/risk profile.
EDP-305A novel oral FXR agonistReduced ALT level and liver fat content at week 12 (NCT03421431).30–
Tropifexor (LJN452)Non-bile acid FXR agonistImprovement in ALT and hepatic fat fraction was sustained up to 48 weeks of treatment (NCT02855164).31–Dose-dependent pruritus was also the most common side effect.
Nidufexor (LMB763)Non-bile acid agent with partial FXR agonistic activity–A multicenter study to assess the safety, tolerability, pharmacokinetics, and efficacy of nidufexor in patients with MASH was terminated without results posted (NCT02913105).
NGM282FGF19 analogTwelve weeks contributed to rapid and significant reductions in liver fat content, ALT and AST, and serum markers of fibrogenesis.32 Improved the histological features of MASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.33–
AldaferminEngineered FGF19 analogReduced liver fat and had a trend toward fibrosis improvement.34–
EfruxiferminBivalent Fc-FGF21 analogImproved hepatic inflammation and fibrosis over 24 weeks in patients with F2 or F3 fibrosis, with acceptable safety (NCT04767529).35–
Pegbelfermin (BMS-986036)PEGylated human FGF21 analogSubcutaneous administration of pegbelfermin consistently for 16 weeks was well tolerated and decreased hepatic fat fraction based on MRI in MASH subjects (NCT02413372).36Once a week for 48 weeks did not achieve a one-stage or greater improvement in the NASH Clinical Research Network fibrosis without NASH worsening (NCT03486912).37
LanifibranorPan-PPAR agonistThe percentage of patients who achieved at least a two-point reduction in the SAF-A score without fibrosis progression was higher among those who received the 1,200 mg dose (NCT03008070).38–
SaroglitazarPPAR-α/γ agonistImproved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in patients with MASLD/MASH (NCT03060721)39–Saroglitazar is an authorized medication for non-cirrhotic MASH in India
NDI-010976Inhibitor of ACC1 and ACC2Dose-dependent inhibition of hepatic DNL in overweight male adults–
AramcholInhibition of stearoyl-CoA desaturase (SCD) 1Improve liver fibrosis and ALT level (NCT02279524).40Lacks impact on liver fat fraction (NCT02279524).40
BelapectinGalectin-3 inhibitorIn a subgroup analysis of patients without esophageal varices, belapectin 2 mg/kg suppressed HVPG and development of varices (NCT02462967).41Lacks favorable effects on HVPG or fibrosis in patients with MASH, cirrhosis, and portal hypertension (NCT02462967).41
Resmetirom (MGL-3196)liver-targeted THRβ agonistProduced excellent reductions in hepatic lipid fraction and fibrosis, as well as plasma lipid and enzyme levels in patients with MASH (NCT02912260).42,43 Significant effects on MASH resolution, fibrosis improvement, and LDL cholesterol reduction (NCT03900429).44–Potential FDA approval of resmetirom for MASH treatment.
VK2809THRβ agonistReduce liver lipid content in patients with MASLD (NCT02927184).–
Vitamin EAntioxidantCombination of pioglitazone and vitamin E therapy exerts favorable impact on hepatic inflammation and ballooning.45Lack of efficacy in attenuating hepatic fibrosis in a large randomized controlled trial. A combination of pioglitazone and vitamin EA therapy has no effect on fibrosis.45
EmricasanPan-caspase inhibitorLowered serum ALT in the short-term.46 Generally safe and well-tolerated in patients with decompensated MASH cirrhosis (NCT03205345).47Did not improve liver histology in MASH-related fibrosis, which may have exacerbated ballooning and fibrosis (NCT02686762). In patients with decompensated MASH cirrhosis, it had no significant effect on the MELD-Na score, international normalized ratio, total serum bilirubin, albumin level, or Child-Pugh score (NCT03205345).47 Patients with MASH-related cirrhosis and severe portal hypertension could not improve either HVPG or clinical outcomes (NCT02960204).48
SelonsertibASK-1 inhibitorAmeliorated MASH and improved fibrosis in some patients in a short-term clinical trial.49Lack of efficacy in MASH adults with stage 3 (NCT03053050) and stage 4 (NCT03053063) fibrosis.
CVCCCR2/CCR5 inhibitorReduced 2-year liver fibrosis progression in a clinical trial of MASH (NCT02217475).50,51The treatment of liver fibrosis in adult MASH subjects was terminated early due to lack of efficacy (NCT03028740).
PTXNonspecific PDE inhibitorImproved hepatic histological features including fibrosis in patients with MASH (NCT00590161).52–
ZSP1601Pan-PDE inhibitorImproved serum liver enzymes, fat content, and Fibroscan parameters in patients with MASLD.53–
IMM-124eProduct of bovine colostrum enriched in IgGIn biopsy-proven MASH showed a reduction in AST and ALT (NCT02316717).No change in hepatic fat content in biopsy-proven MASH (NCT02316717).
AWRK6Developed on the antimicrobial peptide Dybowskin-2CDYaImproved lipid and glucose metabolism homeostasis in the mouse model.54novel GLP-1 receptor agonist candidate
SolithromycinA new generation macrolide antibioticImprove NAS and ALT levels in a phase 2 13-week open-label MASH trial (NCT02510599).–
Cilofexor and firsocostatCombine ACC inhibitor and FXR agonistWell tolerated, improves MASH disease parameters, may improve fibrosis.–
PF-06865571 and PF-05221304Combine DGAT2 inhibitor and ACC1/2 inhibitorPF-06865571 could mitigate The effect of PF-05221304 on serum triglycerides (NCT03776175).–

ALT, alanine aminotransferase; MPC, mitochondrial pyruvate carrier; NAS, non-alcoholic fatty liver disease activity score; PIIINP, procollagen III N-terminal propeptide; FXR, farnesoid X receptor; OCA, obeticholic acid; FGF, factor fibroblast growth factor; AST, aspartate aminotransferase; γ-GT, gamma-glutamyltransferase; HVPG, hepatic venous pressure gradient; OCA, obeticholic acid; ASK-1, apoptosis signaling kinase-1; CCR, C–C motif chemokine receptor; CVC, cenicriviroc; PTX, pentoxifylline; PDE, phosphodiesterase; GCGR, glucagon receptor.

Table 2

Ongoing major clinical trials of pharmacotherapies for the treatment of MASLD

Agent (trial name)Primary mechanismMajor inclusion criteriaPrimary outcome (s)Estimated completionPhaseTrial number
Lanifibranor (NATiV3)pan-PPAR agonistMASH on biopsy with stage 2 or 3 fibrosisResolution of MASH without worsening fibrosis2026/9/303NCT04849728
MGL-3196 (MAESTRO-NASH)THR-β agonistMASH with fibrosisResolves MASH and/or reduces fibrosis on liver biopsy and prevents progression to cirrhosis and/or advanced liver disease2028/1/283NCT03900429
MSDC 0602KmTOT inhibitorSubjects with pre-T2D or T2D and evidence of MASLD/MASHImproved glycemic control and cardiovascular Outcomes2024/9/13NCT03970031
PentoxifyllinePhosphodiesterase inhibitorPatients with MASHNot specified2022/10/13NCT05284448
Aramchol (ARMOR)SCD-1 inhibitorMASH and fibrosis confirmed by liver histology (F1-F3)MASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease.2027/6/13NCT04104321
Belapectin (NAVIGATE)Galectin-3 inhibitorMASH CirrhosisPrevention of Esophageal Varices2024/12/12B/3NCT04365868
VK2809 (VOYAGE)THR-β agonistBiopsy proven MASHEfficacy and Safety2024/6/12BNCT04173065
PF-05221304 combined with PF-06865571 (MIRNA)ACC inhibitor and DGAT2 inhibitorAdult with biopsy-confirmed MASH and fibrosis stage 2 or 3Resolution of MASH or improvement in liver fibrosis by histology2024/2/242NCT04321031
Gastric Inhibitory Polypeptide combined with Glucagon Like Peptide-1 AnalogueGIP and GLP-1 agonistMASH with advanced liver fibrosis and T2DMReduction in liver fat and liver stiffness on imaging2025/2/11/2NCT05751720

MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; T2D, type 2 diabete; ACC, Acetyl-CoA Carboxylase; DGAT2, diacylglycerol acyltransferase 2.

Antidiabetic agents

The definition of MASLD includes hepatic steatosis and meets at least one of three criteria: T2DM, obesity, or metabolic disorder.55 MASLD and T2DM share many common pathophysiological mechanisms. Given that MASLD and T2DM often coexist, various antidiabetic agents have been investigated as potential therapeutics for MASH. Numerous clinical trials are exploring the therapeutic roles of glucagon-like peptide (GLP)-1 modulators, insulin-sensitizing thiazolidinediones, and sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with MASLD, which will be discussed in this section. Metformin, a biguanide drug and first-line therapy for T2DM, lacks histological benefits in human MASH; therefore, we will not explore it here, despite its potential to inhibit high-fat diet-induced HCC progression.56

Incretins: GLP-1R agonist/glucose-dependent insulinotropic polypeptide (GIP) analog/glucagon receptor (GCGR) agonist

Incretins are gut-derived peptide hormones that are promptly induced after a meal, with GIP and GLP-1 being the two major components. GLP-1 is produced through the proteolytic processing of proglucagon, promoting insulin secretion while inhibiting glucagon production. The effects of GLP-1 agonists on MASH may be indirect, resulting from reductions in calorie intake, body weight, and insulin resistance, all of which help decrease liver lipid accumulation and hepatic inflammation.11,57 Liraglutide, a GLP-1 receptor agonist requiring daily injection, improved MASH histology in a small pilot study.12 However, the benefits of liraglutide in reducing weight, hepatic steatosis, and hepatocellular apoptosis in obese adults with MASLD were not sustained upon discontinuation, especially when compared to lifestyle modifications (NCT02654665).13 A phase 2 trial showed that semaglutide, a GLP-1 receptor agonist administered weekly, contributed to significant MASH resolution; however, it did not improve the fibrosis stage (NCT02970942).14 In cases of MASH-related compensated cirrhosis, semaglutide did not significantly achieve MASH resolution or improve fibrosis (NCT03987451).15 Dual GLP-1 and GIP agonists are expected to have more profound effects. Statistics from the phase 3 SURMOUNT study, which recruited over 5,000 adults globally, demonstrated a pronounced reduction in body weight in the tirzepatide-treated group compared to placebo (NCT04184622).16 A sub-study of the SURPASS-3 trial on overweight/obese patients with T2DM demonstrated that tirzepatide decreased liver fat by 8.1% over 52 weeks, along with significant reductions in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (NCT03882970),17 indicating that tirzepatide may improve liver steatosis or inflammation. A phase 1/2 clinical trial investigating the effect of a GIP/GLP-1 dual agonist on MASLD with T2DM was recently carried out (NCT05751720). Retatrutide (LY3437943) is a novel triple agonist peptide targeting the GCGR, GIPR, and GLP-1R. In vitro, retatrutide exhibits balanced GCGR and GLP-1R activity but higher GIPR activity. GCGR-mediated energy expenditure, combined with GIPR- and GLP-1R-driven calorie intake reduction, contributes to enhanced body weight loss. A phase 2 clinical trial showed that retatrutide treatment for 48 weeks led to significant body weight loss in obese patients (NCT04881760).18 Retatrutide also improved liver health, as indicated by reductions in plasma ALT and hepatic triglycerides in obese mice.58 Currently, several phase 3 clinical trials are focused on the effects of retatrutide on obese patients (NCT05929066, NCT05882045, NCT05929079).

Thiazolidinedione insulin sensitizers

Pioglitazone and rosiglitazone are older thiazolidinediones, characterized by their thiazolidinedione ring, used to treat T2DM by improving insulin sensitivity. They are potent activators of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ, which is most enriched in adipose tissue and plays a critical role in adipocyte differentiation, lipid and glucose metabolism, and anti-inflammation.19 The therapeutic effects of pioglitazone on MASLD have been well studied20; however, these benefits are compromised by PPARγ-mediated side effects, primarily weight gain. Pioglitazone has lower PPARγ agonism compared with rosiglitazone but has more profound effects on MASH, potentially mediated by the mitochondrial target of thiazolidinediones, specifically the mitochondrial pyruvate carrier. MSDC-0602K is a second-generation thiazolidinedione designed to preferentially suppress the mitochondrial pyruvate carrier while minimizing direct binding to PPARγ. MSDC-0602K has shown substantial decreases in glucose, insulin, liver enzymes, and the non-alcoholic fatty liver disease activity score (NAS) in patients with biopsy-confirmed MASH and fibrosis (F1-F3) with minimal side effects,21 prompting a phase 3 study to assess the benefits of MSDC-0602K on glycemic control and cardiovascular outcomes in patients with pre-T2D or T2D and MASLD/MASH (NCT03970031). PXL065 is another novel oral agent. Results from a phase 2 study support that PXL065 improves liver fat content, procollagen III N-terminal propeptide, and NAFLD fibrosis score, as well as histological parameters, including NAS and fibrosis, with a favorable safety profile.22 These findings indicate that PXL065 warrants further clinical testing in pivotal MASH trials.

SGLT2 inhibitors

SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) increase urinary glucose excretion and are approved anti-hyperglycemic treatments for T2DM. This drug class offers significant benefits in reducing cardiovascular disease risk and improving renal function in T2DM patients. Patients treated with SGLT2i also demonstrate improvements in hepatic lipid content, liver enzymes, and fibrosis.23–26,59 The efficacy of SGLT2i in reducing body weight and hepatic lipid content has been extensively studied.26,59,60 SGLT2i has the potential to treat MASH through four main mechanisms: decreasing hepatic de novo lipogenesis by lowering insulin levels, increasing fatty acid β-oxidation by stimulating glucagon secretion, suppressing glucose-induced oxidative stress, and inhibiting liver fibrosis by lowering transforming growth factor-beta levels.27 Dapagliflozin (10 mg for 12 weeks) significantly reduced intrahepatic lipid content and ALT in patients with T2DM.28 Licogliflozin, a potent SGLT1 and SGLT2 inhibitor, blocks glucose absorption in the intestine (mediated by SGLT1) and reabsorption in the kidney (90% mediated by SGLT2 and to a lesser extent by SGLT1). Treatment with licogliflozin (150 mg for 12 weeks) resulted in significant improvement in serum ALT levels in patients with MASH (NCT03205150).61 Overall, SGLT2 are effective in controlling glycemic levels and lowering hepatic lipid content, but histological analyses are necessary to evaluate their effects on MASH.

Targeting intermediary metabolism

Farnesoid X receptor (FXR) agonists

The nuclear FXR agonists may treat MASLD through various mechanisms, including alleviating insulin resistance and exerting direct anti-inflammatory and antifibrotic effects on MASH in both mouse models and human tissues.62,63 Intestinal FXR mediates suppression of lipid absorption, while hepatic FXR inhibits lipid synthesis.29 The prototype for this class of compounds is obeticholic acid (OCA), which has been extensively investigated and shown to significantly improve the histological features of MASH, although it can cause side effects such as pruritus and increased low-density lipoprotein (LDL) cholesterol. Although OCA was the first medication to enter phase 3 clinical trials for MASH treatment, the U.S. Food and Drug Administration (hereinafter referred to as FDA) issued a complete response letter to Intercept, rejecting the company’s new drug application for OCA as a treatment for MASH-related pre-cirrhotic liver fibrosis in June 2023 due to an unfavorable benefit/risk profile. However, the phase 3 global study (REGENERATE) interim analysis at 18 months reported rapid and sustained improvements in liver enzymes and stiffness with OCA (25 mg qd) treatment.30 Another phase 3 study (REVERSE) failed to demonstrate OCA’s superiority over placebo in improving liver fibrosis in patients with compensated MASH-related cirrhosis (NCT03439254). EDP-305 is a novel oral FXR agonist under development for the treatment of MASH. A phase 2 study revealed that EDP-305 reduced ALT levels and liver fat content at week 12. The most common adverse event (≥ 5%) associated with EDP-305 was also pruritus (NCT03421431).31 In contrast, several small-molecule FXR agonists without a bile acid structural backbone may not worsen LDL cholesterol or cause pruritus, although this remains unproven. Tropifexor (LJN452) is the most potent non-bile acid FXR agonist currently in clinical studies. The safety and efficacy of tropifexor in patients with MASH (FLIGHT-FXR) were investigated. Improvements in ALT and hepatic fat fraction were sustained up to 48 weeks of treatment with tropifexor, but dose-dependent pruritus was also the most common side effect (NCT02855164).64 Nidufexor (LMB763) is another non-bile acid agent with partial FXR agonistic activity in vitro and FXR-dependent gene regulation in vivo.65 However, a controlled, randomized, double-blind, multicenter study assessing the safety, tolerability, pharmacokinetics, and efficacy of nidufexor in patients with MASH was terminated without results posted (NCT02913105).

Another potential pathway that enhances FXR activity involves the release of the growth factor fibroblast growth factor (FGF) 19 from the intestine upon bile acid binding to FXR,66 which has shown beneficial effects on MASH in animal models, although results are conflicting.32,67 Several recombinant analogs have been developed to preserve the favorable metabolic effects of FGF19 while avoiding its detrimental proliferative and protumorigenic effects. The FGF19 analog resulted in a substantial reduction in hepatic fat and enzymes in patients with biopsy-confirmed MASH, as shown in a phase 2A study.33 In a randomized, double-blind, placebo-controlled trial involving patients with MASH, treatment with NGM282 (an engineered FGF19 analog) for 12 weeks led to rapid and significant reductions in liver fat content, ALT, AST, and serum markers of fibrogenesis.33 In a phase 2 open-label study, NGM282 improved the histological features of MASH within 12 weeks, demonstrating significant reductions in NAS and fibrosis scores, along with improvements in noninvasive imaging and serum markers.34 In another phase 2 trial of patients with MASH, aldafermin (an engineered FGF19 analog) reduced liver fat and showed a trend toward fibrosis improvement.68 FGF21 is another member of the FGF family that preserves insulin-sensitizing and antifibrotic properties without mitogenic effects.35 It has improved steatosis, insulin resistance, and liver stiffness in short-term trials and is actively under clinical investigation as a treatment for MASH. A phase 2B clinical trial (HARMONY) revealed that efruxifermin, a bivalent Fc-FGF21 analog, improved hepatic inflammation and fibrosis over 24 weeks in patients with F2 or F3 fibrosis, with an acceptable safety profile, warranting further investigation in phase 3 trials (NCT04767529).69 Pegozafermin, a long-acting glycopegylated FGF21 analog, demonstrated improvement in liver fibrosis in MASH as shown in a 24-week phase 2B clinical trial (NCT04929483).36 Pegbelfermin (BMS-986036), a PEGylated human FGF21 analog, has been suggested to ameliorate metabolic parameters and liver fibrosis in obese patients with T2DM. Subcutaneous administration of pegbelfermin over 16 weeks was generally well tolerated and significantly decreased hepatic fat fraction based on MRI in MASH subjects during a phase 2 study (NCT02413372).37 However, pegbelfermin administered weekly for 48 weeks did not achieve a one-stage or greater improvement in the NASH Clinical Research Network fibrosis score without worsening NASH, as assessed via biopsy in the phase 2B FALCON 2 study (NCT03486912).70 B1344, a novel FGF21 analog was under phase 1 study for MASH (NCT05655221).

Experimental PPAR agonists

PPARs are nuclear receptors that modulate key regulatory pathways in metabolism, inflammation, and fibrogenesis.38,71 Lanifibranor is a pan-PPAR agonist. In a phase 2B study of lanifibranor, the percentage of patients who achieved at least a two-point reduction in the SAF-A score without fibrosis progression was significantly higher among those receiving the 1,200-mg dose compared to placebo (1,200-mg dose vs. placebo: 55% vs. 33%, P = 0.007). However, this was not the case for those receiving the 800-mg dose (800-mg dose vs. placebo: 48% vs. 33%, P = 0.07) (NCT03008070).39 Therefore, a phase 3 study examining the efficacy and safety of lanifibranor in adult patients with MASH and fibrosis stages F2 and F3 (NATiV3) is currently underway (NCT04849728). Saroglitazar, a PPAR-α/γ agonist, at a dosage of 4 mg qd significantly improved ALT, liver fat content (LFC), insulin resistance, and atherogenic dyslipidemia in patients with MASLD/MASH (NCT03061721).72 Currently, saroglitazar is an authorized medication for non-cirrhotic MASH in India.73

Target lipid homeostasis and fibrogenesis

Allosteric inhibitors of acetyl-coenzyme A carboxylases (ACC) ACC1 and ACC2 were suggested to inhibit hepatic de novo lipogenesis and improve steatosis, inflammation, and fibrosis. NDI-010976 is an inhibitor of both ACC1 and ACC2, which was well tolerated and resulted in profound dose-dependent inhibition of hepatic de novo lipogenesis in overweight male adults in a randomized, controlled crossover trial.40

Inhibition of stearoyl-CoA desaturase 1 expression in hepatocytes enhances AMPK activity and lipophagy, as well as attenuates lipid deposition. Aramchol is a stearoyl-CoA desaturase 1 modulator. A phase 2B trial (NCT02279524) showed that although aramchol 600 mg had no impact on liver fat fraction, it provided favorable outcomes in liver fibrosis and ALT levels, suggesting it may be a promising therapy for MASH with fibrosis. This effect is currently being investigated in a phase 3 clinical trial (NCT04104321).41

Galectin-3 has been implicated in the pathophysiology of hepatic inflammation and fibrosis through both intracellular effects (such as antiapoptotic activity and macrophage differentiation) and extracellular functions (acting as a chemokinetic/chemotactic factor). Belapectin, a galectin-3 inhibitor, was well tolerated in a year-long biweekly infusion but showed no significant effects on hepatic venous pressure gradient (HVPG) or fibrosis in a phase 2B study involving 162 patients with MASH, cirrhosis, and portal hypertension. However, in a subgroup analysis of patients without esophageal varices, belapectin at 2 mg/kg did suppress HVPG and the development of varices (NCT02462967).74 Consequently, a clinical trial evaluating the efficacy and safety of belapectin for the prevention of esophageal varices due to MASH-related cirrhosis (NAVIGATE) is currently underway (NCT04365868).

Thyroid hormone receptor (THR) β agonists

The THR is a nuclear receptor that regulates pivotal pathways for cell growth and metabolism. The two isoforms of THR, THRα, and THRβ, are encoded by the genes THRA and THRB, respectively.75 While excessive activation of THRα may lead to cardiac abnormalities,42 specific THRβ activators primarily target the liver, inducing hepatic fatty acid oxidation and reducing steatosis and hyperlipidemia in rats and mice with genetically or diet-induced T2DM. The liver-targeted THRβ agonist resmetirom (MGL-3196) demonstrated significant reductions in hepatic lipid fraction and fibrosis, as well as plasma lipid and enzyme levels in patients with MASH, without affecting blood glucose or insulin levels (NCT02912260).43,76 The results of the 52-week MAESTRO-NAFLD-1 trial supported the efficacy and safety of resmetirom at doses of 80 mg and 100 mg qd (NCT04197479), which are being applied in the ongoing phase 3 MASH study, MAESTRO-NASH.44 The 52-week data from 966 patients with MASH and F1B, F2, or F3 fibrosis in the MAESTRO-NASH trial revealed significant effects of resmetirom on MASH resolution, fibrosis improvement, and LDL cholesterol reduction (NCT03900429),77 forming the basis for potential FDA approval of resmetirom for MASH treatment.

VK2809, another THRβ agonist, reduced hepatic steatosis in mice45 and liver lipid content in patients with MASLD (NCT02927184). The additional potential of THRβ agonists to improve cardiometabolic outcomes has warranted further investigation through an ongoing phase 2B clinical trial (NCT04173065) for MASH lasting 52 weeks.

Medications affecting oxidative stress and inflammation

Cell stress and apoptosis

Oxidative stress and activation of the unfolded protein response are two well-recognized cell stress pathways that cause cell death in MASH. Vitamin E is a prototypic antioxidant and has the most profound anti-steatohepatitic effect of any drug studied to date.78 However, its appeal is limited by its lack of efficacy in attenuating hepatic fibrosis in a large randomized controlled trial.78 Combining pioglitazone with vitamin E therapy has a more favorable impact on hepatic inflammation and ballooning than vitamin E alone, but unfortunately, it has no effect on fibrosis.

Apoptosis induces tissue injury and fibrosis in MASH and many other chronic liver injuries,79 establishing a rationale for inhibiting apoptosis as a therapeutic strategy. Emricasan, a pan-caspase inhibitor, reduces apoptosis and can attenuate inflammation and fibrosis.46 However, a phase 2B clinical trial (NCT02686762) revealed that emricasan treatment did not improve liver histology in patients with MASH-related fibrosis and may have exacerbated ballooning and fibrosis. Caspase inhibition lowered serum ALT in the short term but may have redirected cells to alternative mechanisms of cell death, resulting in more hepatocyte ballooning and liver fibrosis.47 A phase 2 trial revealed that emricasan was generally safe and well-tolerated in patients with decompensated MASH cirrhosis; however, it had no significant effect on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level, or Child-Pugh score (NCT03205345).48 In patients with MASH-related cirrhosis and severe portal hypertension, emricasan could not improve either HVPG or clinical outcomes (NCT02960204).49

Immune targets

Inflammatory cells and cytokines are involved in MASH pathogenesis. Compared with adaptive immune systems, most studies focus on the innate immune system for the pathogenesis of MASH. Pro-inflammatory pathways, including apoptosis signaling kinase-1 (ASK-1)-JNK, MAP kinases, extracellular signal-regulated kinase, and Nuclear Factor-kappa B, are potent mediators of inflammation and thus potential targets for MASLD therapy. The ubiquitous expression of pro-inflammatory pathways in all cells and their critical role in maintaining defenses against tissue injury raise concerns about ‘off-target’ effects. Fortunately, clinical trials in MASH have not revealed any such effects to date. In particular, the inhibition of ASK-1 ameliorated MASH and improved fibrosis in some patients in a short-term clinical trial.50 However, two phase 3 trials of selonsertib (an ASK-1 inhibitor) were terminated early due to a lack of efficacy in MASH adults with stage 3 (NCT03053050) and stage 4 (NCT03053063) fibrosis.

Activation of the C–C motif chemokine receptor (CCR) 2–CCR5 chemokine axis exaggerates the liver’s innate immune response, activates hepatic stellate cells, and leads to fibrogenesis. Usage of the CCR2/CCR5 inhibitor cenicriviroc was shown to reduce two-year liver fibrosis progression in a clinical trial of MASH (NCT02217475).51,52 However, a phase 3 study of cenicriviroc for the treatment of liver fibrosis in adult MASH subjects was terminated early due to a lack of efficacy (NCT03028740).

Pentoxifylline (PTX) is a nonspecific phosphodiesterase (PDE) inhibitor that can regulate cyclic AMP levels and suppress TNF-α gene transcription, which are vital mechanisms for inflammation and hepatocellular damage in the progression of MASLD. A phase 2 trial showed that PTX improved hepatic histological features, including fibrosis, in patients with MASH (NCT00590161).80 A phase 3 study investigating the effect of PTX on MASH is underway (NCT05284448). ZSP1601 is a first-in-class pan-phosphodiesterase (pan-PDE) inhibitor specially designed for MASH by Guangdong Raynovent Biotech Co., Ltd (Guangdong, Guangzhou, China). ZSP1601 suppresses inflammatory responses in MASH, with its maximum inhibitory effect occurring on PDE2 as shown by both in vitro and in vivo studies.53,81 A randomized, double-blinded, placebo-controlled, multiple-dose phase 1B/2A trial revealed ZSP1601 improved serum liver enzymes, fat content, and Fibroscan parameters in patients with MASLD.54 ZSP1601 could be a potential novel agent used in the treatment of MASLD.

Gut microbiome

Gut microbiome dysbiosis renders the gut more permeable, thereby exposing hepatocytes to endotoxins that can eventually result in hepatocyte inflammation and scarring. IMM-124e is a product of bovine colostrum enriched in IgG obtained from cows immunized against LPS. A phase 2 study evaluating the effects of 24 weeks of IMM-124e in patients with biopsy-proven MASH showed a reduction in AST and ALT but no change in hepatic fat content (NCT02316717). A synthetic peptide, AWRK6, developed based on the antimicrobial peptide Dybowskin-2CDYa, was reported to attenuate hyperglycemia as a novel GLP-1 receptor agonist candidate. AWRK6 ameliorates MASLD by improving lipid and glucose metabolism homeostasis, which may be mediated by the PI3K/AKT/AMPK/ACC signaling pathway in the mouse model.82 Solithromycin, a new-generation macrolide antibiotic, was suggested to improve the NAS and ALT level in a phase 2, 13-week open-label MASH trial (NCT02510599).83 The application of gut microbiome-based therapy for MASLD seems to have a long way to go.

Combination therapies

Besides the combination therapies described above, in patients with bridging fibrosis and cirrhosis, combining cilofexor (ACC inhibitor) and firsocostat (FXR agonist) for 48 weeks was well tolerated, showed beneficial effects on MASH disease parameters, and might improve fibrosis. This combination offers potential for fibrosis regression in patients with MASH and subsequent advanced fibrosis (NCT03449446).84

ACC inhibitors reduce hepatic steatosis in patients with MASLD, but they also increase serum triglycerides.85 A phase 2A trial showed that PF-06865571 (a DGAT2 inhibitor) could mitigate the effect of PF-05221304 (a novel ACC1/2 inhibitor) on serum triglycerides (NCT03776175).85 As a result, a phase 2 study specifically aimed to compare the effects of various doses of DGAT2i alone, and in combination with ACCi, on the resolution of MASH or anti-fibrosis via biopsy is underway (NCT04321031).

Conclusions

Recently, remarkable progress has been made in unveiling the pathogenesis of MASLD/MASH, and consequently, in developing drugs to effectively treat the disease. The heterogeneous nature of MASLD means it cannot be investigated or managed as a single condition with a “one size fits all” approach to therapy. Considering the high heterogeneity of MASLD, precisely defining the natural history of its phenotypes and appropriately selecting subjects for clinical trials will help demonstrate significant benefits. Additionally, comparing or pooling results from meaningful trials will aid in discovering effective therapies.1 The current medications for MASLD are mainly focused on its pathogenic factors, critical links of pathogenesis, and relevant metabolic diseases. Due to the close association between MASLD and T2DM, many agents prescribed for hyperglycemia contribute to the improvement of some MASLD disease parameters, but their application for MASLD treatment warrants further validation by phase 3 trials. The overall benefit of metabolic-targeted therapies for MASLD is appealing, as these agents might also reduce other cardiometabolic risk factors that contribute to cardiovascular disease, which is the leading cause of death in patients with MASLD. However, medications targeting aspects of intermediary metabolism may have to overcome high rates of adverse effects before being approved for MASLD treatment. Standardization of clinical trial designs and validation of noninvasive procedures will greatly accelerate the pace of discovering effective therapies. The possibility of drug combinations as a therapeutic option is highly likely due to superior efficacy and safety compared to a single approach. For instance, the benefits of agents targeting metabolic pathways may be enhanced by adding drugs with anti-inflammatory and anti-fibrotic effects.11 Combined therapy from long-term, controlled clinical trials is highly needed. In the coming years, the availability of therapeutic options for MASLD will hopefully curb the rising incidence of MASLD-related diseases.

Declarations

Funding

This research was supported by the Shanghai Jiao Tong University School of Medicine Digestive Academy of Science Grant (KY-2023-04-01) to YH.

Conflict of interest

JGF has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2013. The other authors have no conflict of interests related to this publication.

Authors’ contributions

Writing and revising the manuscript (YH), assisting with the writing of the manuscript (CS, YC, YDL), supervising and revising the manuscript (JGF). All authors have approved the final version and publication of the manuscript.

References

  1. Eslam M, Sanyal AJ, George J, International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020;158(7):1999-2014.e1 View Article PubMed/NCBI
  2. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 2023;78(6):1966-1986 View Article PubMed/NCBI
  3. Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella ME. Metabolic dysfunction-associated steatotic liver disease: Update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease. Hepatology 2024;79(5):1212-1219 View Article PubMed/NCBI
  4. Kleiner DE, Brunt EM, Wilson LA, Behling C, Guy C, Contos M, et al. Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. JAMA Netw Open 2019;2(10):e1912565 View Article PubMed/NCBI
  5. 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(2):522-531 View Article PubMed/NCBI
  6. Lindenmeyer CC, McCullough AJ. The Natural History of Nonalcoholic Fatty Liver Disease-An Evolving View. Clin Liver Dis 2018;22(1):11-21 View Article PubMed/NCBI
  7. Pierantonelli I, Svegliati-Baroni G. Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH. Transplantation 2019;103(1):e1-e13 View Article PubMed/NCBI
  8. Loomba R, Adams LA. The 20% Rule of NASH Progression: The Natural History of Advanced Fibrosis and Cirrhosis Caused by NASH. Hepatology 2019;70(6):1885-1888 View Article PubMed/NCBI
  9. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328-357 View Article PubMed/NCBI
  10. European Association for the Study of the Liver (EASL)., European Association for the Study of Diabetes (EASD)., European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-1402 View Article PubMed/NCBI
  11. Newsome PN, Ambery P. Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver. J Hepatol 2023;79(6):1557-1565 View Article PubMed/NCBI
  12. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690 View Article PubMed/NCBI
  13. Khoo J, Hsiang JC, Taneja R, Koo SH, Soon GH, Kam CJ, et al. Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease. Liver Int 2019;39(5):941-949 View Article PubMed/NCBI
  14. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med 2021;384(12):1113-1124 View Article PubMed/NCBI
  15. Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, et al. 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(6):511-522 View Article PubMed/NCBI
  16. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022;387(3):205-216 View Article PubMed/NCBI
  17. Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022;10(6):393-406 View Article PubMed/NCBI
  18. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med 2023;389(6):514-526 View Article PubMed/NCBI
  19. Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol 2017;13(1):36-49 View Article PubMed/NCBI
  20. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, 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(5):305-315 View Article PubMed/NCBI
  21. Harrison SA, Alkhouri N, Davison BA, Sanyal A, Edwards C, Colca JR, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study. J Hepatol 2020;72(4):613-626 View Article PubMed/NCBI
  22. Harrison SA, Thang C, Bolze S, Dewitt S, Hallakou-Bozec S, Dubourg J, et al. Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). J Hepatol 2023;78(5):914-925 View Article PubMed/NCBI
  23. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care 2018;41(8):1801-1808 View Article PubMed/NCBI
  24. Shimizu M, Suzuki K, Kato K, Jojima T, Iijima T, Murohisa T, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab 2019;21(2):285-292 View Article PubMed/NCBI
  25. Latva-Rasku A, Honka MJ, Kullberg J, Mononen N, Lehtimäki T, Saltevo J, et al. The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients. Diabetes Care 2019;42(5):931-937 View Article PubMed/NCBI
  26. Cusi K, Bril F, Barb D, Polidori D, Sha S, Ghosh A, et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab 2019;21(4):812-821 View Article PubMed/NCBI
  27. Zachou M, Flevari P, Nasiri-Ansari N, Varytimiadis C, Kalaitzakis E, Kassi E, et al. The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review. Eur J Clin Pharmacol 2024;80(1):127-150 View Article PubMed/NCBI
  28. Phrueksotsai S, Pinyopornpanish K, Euathrongchit J, Leerapun A, Phrommintikul A, Buranapin S, et al. The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2021;36(10):2952-2959 View Article PubMed/NCBI
  29. Clifford BL, Sedgeman LR, Williams KJ, Morand P, Cheng A, Jarrett KE, et al. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab 2021;33(8):1671-1684.e4 View Article PubMed/NCBI
  30. 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(3):536-548 View Article PubMed/NCBI
  31. Ratziu V, Rinella ME, Neuschwander-Tetri BA, Lawitz E, Denham D, Kayali Z, et al. EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study. J Hepatol 2022;76(3):506-517 View Article PubMed/NCBI
  32. Hartmann P, Hochrath K, Horvath A, Chen P, Seebauer CT, Llorente C, et al. Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology 2018;67(6):2150-2166 View Article PubMed/NCBI
  33. Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, 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 View Article PubMed/NCBI
  34. Harrison SA, Rossi SJ, Paredes AH, Trotter JF, Bashir MR, Guy CD, et al. NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis. Hepatology 2020;71(4):1198-1212 View Article PubMed/NCBI
  35. Staiger H, Keuper M, Berti L, Hrabe de Angelis M, Häring HU. Fibroblast Growth Factor 21-Metabolic Role in Mice and Men. Endocr Rev 2017;38(5):468-488 View Article PubMed/NCBI
  36. 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(11):998-1008 View Article PubMed/NCBI
  37. Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, 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;392(10165):2705-2717 View Article PubMed/NCBI
  38. Francque S, Szabo G, Abdelmalek MF, Byrne CD, Cusi K, Dufour JF, et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol 2021;18(1):24-39 View Article PubMed/NCBI
  39. Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N Engl J Med 2021;385(17):1547-1558 View Article PubMed/NCBI
  40. Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G, Harwood HJ, et al. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study. Hepatology 2017;66(2):324-334 View Article PubMed/NCBI
  41. Ratziu V, de Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med 2021;27(10):1825-1835 View Article PubMed/NCBI
  42. Wikström L, Johansson C, Saltó C, Barlow C, Campos Barros A, Baas F, et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 1998;17(2):455-461 View Article PubMed/NCBI
  43. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, 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 View Article PubMed/NCBI
  44. Harrison SA, Taub R, Neff GW, Lucas KJ, Labriola D, Moussa SE, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med 2023;29(11):2919-2928 View Article PubMed/NCBI
  45. Zhou J, Waskowicz LR, Lim A, Liao XH, Lian B, Masamune H, et al. A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia. Thyroid 2019;29(8):1158-1167 View Article PubMed/NCBI
  46. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 2015;35(3):953-966 View Article PubMed/NCBI
  47. 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(5):816-827 View Article PubMed/NCBI
  48. Frenette C, Kayali Z, Mena E, Mantry PS, Lucas KJ, Neff G, et al. Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis. J Hepatol 2021;74(2):274-282 View Article PubMed/NCBI
  49. Garcia-Tsao G, Bosch J, Kayali Z, Harrison SA, Abdelmalek MF, Lawitz E, et al. Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension. J Hepatol 2020;72(5):885-895 View Article PubMed/NCBI
  50. Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology 2018;67(2):549-559 View Article PubMed/NCBI
  51. 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(5):1754-1767 View Article PubMed/NCBI
  52. 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(3):892-905 View Article PubMed/NCBI
  53. Schandené L, Vandenbussche P, Crusiaux A, Alègre ML, Abramowicz D, Dupont E, et al. Differential effects of pentoxifylline on the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by monocytes and T cells. Immunology 1992;76(1):30-34 PubMed/NCBI
  54. Hu Y, Li H, Zhang H, Chen X, Chen J, Xu Z, et al. ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial. Nat Commun 2023;14(1):6409 View Article PubMed/NCBI
  55. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020;73(1):202-209 View Article PubMed/NCBI
  56. de Oliveira S, Houseright RA, Graves AL, Golenberg N, Korte BG, Miskolci V, et al. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol 2019;70(4):710-721 View Article PubMed/NCBI
  57. Jinnouchi H, Sugiyama S, Yoshida A, Hieshima K, Kurinami N, Suzuki T, et al. Liraglutide, a glucagon-like peptide-1 analog, increased insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp examination in patients with uncontrolled type 2 diabetes mellitus. J Diabetes Res 2015;2015:706416 View Article PubMed/NCBI
  58. Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab 2022;34(9):1234-1247.e9 View Article PubMed/NCBI
  59. Kahl S, Gancheva S, Straßburger K, Herder C, Machann J, Katsuyama H, et al. Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial. Diabetes Care 2020;43(2):298-305 View Article PubMed/NCBI
  60. Bica IC, Stoica RA, Salmen T, Janež A, Volčanšek Š, Popovic D, et al. The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials. Medicina (Kaunas) 2023;59(6):1136 View Article PubMed/NCBI
  61. Harrison SA, Manghi FP, Smith WB, Alpenidze D, Aizenberg D, Klarenbeek N, et al. Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study. Nat Med 2022;28(7):1432-1438 View Article PubMed/NCBI
  62. Kong B, Luyendyk JP, Tawfik O, Guo GL. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 2009;328(1):116-122 View Article PubMed/NCBI
  63. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, 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(3):574-82.e1 View Article PubMed/NCBI
  64. 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(2):392-400 View Article PubMed/NCBI
  65. Chianelli D, Rucker PV, Roland J, Tully DC, Nelson J, Liu X, et al. Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis. J Med Chem 2020;63(8):3868-3880 View Article PubMed/NCBI
  66. Nies VJ, Sancar G, Liu W, van Zutphen T, Struik D, Yu RT, et al. Fibroblast Growth Factor Signaling in Metabolic Regulation. Front Endocrinol (Lausanne) 2015;6:193 View Article PubMed/NCBI
  67. Jiang C, Xie C, Li F, Zhang L, Nichols RG, Krausz KW, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015;125(1):386-402 View Article PubMed/NCBI
  68. Harrison SA, Neff G, Guy CD, Bashir MR, Paredes AH, Frias JP, 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(1):219-231.e1 View Article PubMed/NCBI
  69. Harrison SA, Frias JP, Neff G, Abrams GA, Lucas KJ, Sanchez W, et al. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol 2023;8(12):1080-1093 View Article PubMed/NCBI
  70. 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(1):113-123.e9 View Article PubMed/NCBI
  71. Boubia B, Poupardin O, Barth M, Binet J, Peralba P, Mounier L, et al. Design, Synthesis, and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate. J Med Chem 2018;61(6):2246-2265 View Article PubMed/NCBI
  72. Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology 2021;74(4):1809-1824 View Article PubMed/NCBI
  73. Sharma M, Premkumar M, Kulkarni AV, Kumar P, Reddy DN, Rao NP. Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail. J Clin Transl Hepatol 2021;9(1):40-50 View Article PubMed/NCBI
  74. Chalasani N, Abdelmalek MF, Garcia-Tsao G, Vuppalanchi R, Alkhouri N, Rinella M, et al. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension. Gastroenterology 2020;158(5):1334-1345.e5 View Article PubMed/NCBI
  75. Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol 2018;14(5):259-269 View Article PubMed/NCBI
  76. 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(4):573-588 View Article PubMed/NCBI
  77. Harrison S, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, Labriola D, et al. Primary results from maestro-nash a pivotal phase 3 52-week serial liver biopsy study in 966 patients with nash and fibrosis. J Hepato 2023;78:S1 View Article
  78. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-1685 View Article PubMed/NCBI
  79. Alkhouri N, Carter-Kent C, Feldstein AE. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol 2011;5(2):201-212 View Article PubMed/NCBI
  80. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54(5):1610-1619 View Article PubMed/NCBI
  81. Diehl AM, Li ZP, Lin HZ, Yang SQ. Cytokines and the pathogenesis of non-alcoholic steatohepatitis. Gut 2005;54(2):303-306 View Article PubMed/NCBI
  82. Jin L, Sun Y, Li Y, Zhang H, Yu W, Li Y, et al. A synthetic peptide AWRK6 ameliorates metabolic associated fatty liver disease: involvement of lipid and glucose homeostasis. Peptides 2021;143:170597 View Article PubMed/NCBI
  83. Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 2018;53(3):362-376 View Article PubMed/NCBI
  84. 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(2):625-643 View Article PubMed/NCBI
  85. Calle RA, Amin NB, Carvajal-Gonzalez S, Ross TT, Bergman A, Aggarwal 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 View Article PubMed/NCBI
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  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

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Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease

Ye Hu, Chao Sun, Ying Chen, Yu-Dong Liu, Jian-Gao Fan
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