Drug treatment for metabolic dysfunction-associated steatotic liver disease: Progress and direction

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), also called non-alcoholic fatty liver disease, is the most epidemic chronic liver disease worldwide. Metabolic dysfunction-associated steatohepatitis (MASH) is the critical stage of MASLD, and early diagnosis and treatment of MASH are crucial for reducing the incidence of intrahepatic and extrahepatic complications. So far, pharmacotherapeutics for the treatment of MASH are still a major challenge, because of the complexity of the pathogenesis and heterogeneity of MASH. Many agents under investigation have shown impressive therapeutic effects by targeting different key pathways, including the attenuation of steatohepatitis or fibrosis or both. It is notable that thyroid hormone receptor-β agonist, resmetirom has become the first officially approved drug for treating MASH with fibrosis. Other agents such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 analogs, and fibroblast growth factor 21 analogs are awaiting approval. This review focuses on the current status of drug therapy for MASH and summarizes the latest results of new medications that have completed phase 2 or 3 clinical trials, and presents the future directions and difficulties of new drug research for MASH.

Introduction

With the continuous rise of obesity rates globally, obesity-related liver diseases, especially non-alcoholic fatty liver disease (NAFLD), are rapidly becoming the major chronic liver disease worldwide and a major challenge in the global health field, and have become the leading cause of liver-related morbidity and mortality.^[1] NAFLD was first named in 1986 and defined as hepatic steatosis affecting at least 5% of hepatocytes without any other etiologies. NAFLD ranges from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis or cirrhosis or even hepatocellular carcinoma (HCC) [Figure 1].^[2] The biggest influencing factors on the occurrence and development of NAFLD are genetic susceptibility, obesity or insulin resistance, and imbalanced gut microbiota.^[3,4] In recent years, hepatologists have engaged in vigorous discourse regarding the nomenclature and diagnostic criteria associated with hepatic steatosis. For a more proactive diagnosis, a new name, metabolic dysfunction-associated fatty liver disease (MAFLD), accompanied by a series of criteria that facilitate a positive diagnosis, has been proposed.^[5] Some concerns persist regarding the mixing or confusion of etiologies and the existence of the potentially stigmatizing word “fatty” in MAFLD. Experts promoted the new consensus for shifting to a novel, refined, and appropriate name in understanding the multifactorial and multisystemic pathophysiology of NAFLD. Regarding the terminology and diagnostic criteria related to liver steatosis, a Delphi consensus statement has proposed new nomenclature for steatotic liver disease (SLD), metabolic dysfunction-associated steatotic liver disease (MASLD), and coexistence with excessive alcohol consumption metabolic and alcohol-related liver disease (MetALD).^[6] Owing to the limited availability of data and study cohorts, there remain numerous concerns that necessitate further verification or elucidation with respect to the novel nomenclature.

Figure 1.

The disease progression spectrum of MASLD. MASLD: Metabolic dysfunction-associated steatotic liver disease.

MASLD not only causes end-stage liver disease but also promotes extrahepatic tissue damage and reduces quality of life.^[4,7] Therefore, conducting a comprehensive evaluation is important for discovering complications and choosing the combined treatment; for example, cardiovascular disease, type 2 diabetes, metabolic syndrome, chronic kidney disease, hyperlipidemia, and hyperuricemia should be detected and evaluated. The complex etiology and pathogenesis of MASLD mean that pharmacotherapy remains a challenge. Comprehensive treatments including non-pharmacological treatment or treatment of comorbidities are currently recommended.^[7] The treatment of MASLD requires multidisciplinary collaboration, including adjusting dietary structure and increasing exercise through health education, reducing body mass and waist circumference, improving insulin resistance, preventing and treating metabolic syndrome, maintaining blood glucose homeostasis, alleviating metabolic dysfunction-associated steatohepatitis (MASH), and reversing fibrosis.^[3] In recent years, many potential agents targeting different intermediate pathways of MASLD have emerged and clinical trials are ongoing, such as thyroid hormone receptor-β (THR-β), farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR), fibroblast growth factor (FGF), and glucagon-like peptide-1 (GLP-1) [Figure 2]. Some of them will hopefully have excellent prospects in the future.^[8] Here, we focus on drug treatment for MASLD, emphasizing current limitations and future directions.

Figure 2.

Potential pharmacologic drugs for MASLD. ACC: Acetyl-CoA carboxylase; ASK1: Apoptosis signal-regulating kinase-1; FASN: Fatty acid synthase; FGF: Fibroblast growth factor; FXR: Farnesoid X receptor; GLP-1: Glucagon-like peptide-1; MASLD: Metabolic dysfunction-associated steatotic liver disease; PPAR: Peroxisome proliferator-activated receptor; SCD1: Stearoyl CoA desaturase-1; THR-β: Thyroid hormone receptor-β.

Traditional Therapeutic Drugs for MASLD

MASLD contains different disease stages. In the early stage, the main treatment strategies are changing lifestyle and correcting metabolic disturbance. MASH, with or without fibrosis is the most important stage that requires drug control.^[9] Clinically, drugs for the treatment of liver injury, including silymarin, polyene phosphatidylcholine, bicyclol, compound glycyrrhizin, and glutathione, can help to improve liver biochemical indicators in MASLD patients, but there is insufficient evidence to confirm the benefits on liver histology. Specific drug therapy for MASLD appears to be difficult because of the complicated pathophysiology. According to the guidelines for MASLD prevention and treatment, basic pharmaceutical therapies are recommended, especially for comorbidities, including lowering weight, blood glucose, blood pressure, and blood lipids.^[3]

Vitamin E

Oxidative stress plays a pivotal role in the occurrence and development of MASLD. Vitamin E supplementation has the antioxidative properties and has proven efficacy on MASLD and has the ability to improve hepatic histology, especially in non-diabetic patients with non-cirrhotic steatohepatitis.^[10] However, appropriate dosage should be considered, high-dose vitamin E has the potential risk of hemorrhagic stroke and prostate cancer which limits its clinical application.

PPAR agonist

Clinical research has confirmed that the PPAR-γ agonist pioglitazone, could improve hepatic steatosis and inflammation,^[11,12] especially for MASH patients with type 2 diabetes or glucose and lipid metabolism disorder. Clinical trials using pioglitazone (30 mg or 45 mg) showed that it could significantly improve the histological components of MASH (steatosis, ballooning, and lobular inflammation), 2 points in NAFLD activity score, or MASH resolution without worsening liver fibrosis.^{[12,13,14,15]} However, patients should be vigilant for side effects of pioglitazone, such as weight gain, fluid retention, cardiac decompensation, an increased risk of bone fractures, and bladder cancer.^[13,14,16]

Saroglitazar, a double PPAR-α/γ agonist (4 mg), can significantly decrease serum alanine aminotransferase, reduce liver fat content, and improve insulin resistance and atherogenic dyslipidemia in patients with MASLD.^[17] Elafibranor, an agonist of PPAR-α/δ (120 mg/day for 1 year), resolved MASH without worsening fibrosis, based on a post hoc analysis using a modified definition of treatment endpoint. However, in the intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in resolution of MASH without worsening fibrosis.^[18] Because of these unsatisfactory results, the clinical application of saroglitazar or elafibranor is not approved for MASLD.

Metformin

Metformin, as a first-line medication for the prevention and treatment of type 2 diabetes in overweight or obese patients, may not alleviate the pathology of MASH, but may decrease the occurrence of HCC in MASLD patients.^[19,20] Besides, clinical researches exhibited that metformin intervention could regulate the gut microbiota, reduce serum transaminases, improve body insulin resistance, and help to lose weight.^[21,22] However, a randomized controlled trial published in 2011 found that neither metformin nor vitamin E demonstrated significant improvements in histological features and serum alanine aminotransferase level compared with placebo.^[23]

GLP-1 agonists

GLP-1 is a gut-derived hormone, secreted by intestinal endocrine L-cells. The biological functions of GLP-1 are mainly regulating insulin secretion and reducing food intake, which are beneficial for glucose homeostasis and weight loss.^[24] GLP-1 receptor agonists, including liraglutide, semaglutide, dulaglutide, and exenatide, are commonly used in type 2 diabetes. A multicenter, double-blind, randomized, placebo-controlled phase 2 study published in 2016 showed that 9 of 23 patients who received liraglutide had resolution of definite MASH compared with 2 of 22 in the placebo group. However, the sample size of the above research was too small, warranting extensive, longer-term studies to evaluate the therapeutic effect of GLP-1 receptor agonists.^[25] Another clinical trial published in 2021 showed that treatment with semaglutide resulted in a significantly higher percentage of MASH resolution with no worsening of fibrosis, compared with placebo. However, in a randomized, placebo-controlled phase 2 trial, semaglutide (2.4 mg once weekly) was used to treat patients with MASH-related cirrhosis. After 48 weeks, there was no significant improvement in liver fibrosis by one stage or more without worsening of MASH, and there was also no significant improvement in MASH resolution. The results suggested that semaglutide had no effect on liver histology in patients with compensated MASH cirrhosis.^[26] The side effects of semaglutide, such as gastrointestinal reactions and the occurrence of neoplasms, need more attention.^[26,27] Larger studies should be conducted to confirm the therapeutic efficacy and safety for future applications in MASH patients, and the therapeutic mechanism of GLP-1 receptor agonists in MASH should be further explored, especially for metabolic and cardiac benefits.

Recently, pemvidutide, a GLP-1/glucagon dual receptor agonist, was used to treat patients with MASLD in a newly published randomized, double-blind, placebo-controlled study. Weekly pemvidutide treatment significantly reduced the liver fat content, alanine aminotransferase, and body weight, without serious adverse events. This showed the potential application of pemvidutide in patients with MASLD or obesity.^[28]

Glucose-dependent insulinotropic peptide (GIP) and GLP-1 agonist

Tirzepatide is a newly discovered glucose-lowering agent that acts on the GIP and GLP-1 receptor.^[29] Clinical trials have found that tirzepatide had a beneficial effect on metabolism, including substantial weight loss and improvements in serum hemoglobin A1c, hyperglycemia, and hyperlipidemia, which could help to alleviate MASLD.^[30,31] A clinical study published in 2020 showed that higher tirzepatide doses significantly decreased MASH-related biomarkers such as serum alanine aminotransferase and aspartate aminotransferase.^[32] Another clinical study focused on the effect of tirzepatide on liver fat content and abdominal adipose tissue in patients with type 2 diabetes. This showed that liver fat content and volume of visceral and abdominal subcutaneous adipose tissue were significantly decreased after tirzepatide treatment compared with insulin degludec.^[33] A randomized clinical trial showed that once-weekly tirzepatide (10 mg or 15 mg) in Chinese adults with obesity or overweight resulted in significant and clinically meaningful weight reduction with an acceptable safety profile, and weight loss is beneficial for attenuation of MASLD.^[34] New clinical research about tirzepatide for MASH with liver fibrosis published in 2024 showed that treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis.^[35] All these positive results show the potential therapeutic value of tirzepatide in MASH; however, larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. More reliable data about the effects of tirzepatide on the improvement of liver histology such as inflammation and fibrosis are needed and liver biopsy evaluation should be chosen in future clinical trials.

Retatrutide is an agonist of the glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors. A phase 2 placebo-controlled trial noted that higher doses of retatrutide resulted in a reduction of multiple risk factors for MASLD, such as waist circumference, systolic and diastolic blood pressure, and levels of serum glycated hemoglobin, fasting glucose, and triglycerides.^[36]

The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) was recently assessed in patients with MASH and liver fibrosis. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4 mg group, 62% of those in the 4.8 mg group, and 43% of those in the 6.0 mg group. The results indicated that survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials.^[37] However, the side effects, such as nausea, diarrhea, and vomiting, happened more frequently and treatment should proceed with attention.

Sodium-glucose cotransport protein 2 (SGLT-2) inhibitors

SGLT-2 inhibitors are a new drug class approved as antidiabetic drugs. SGLT-2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, have been confirmed to have metabolic and cardiac benefits.^[38,39] Several clinical trials conducted in different countries showed that SGLT-2 inhibitors reduced serum aminotransferase levels and liver fat content detected by magnetic resonance imaging, and promoted weight loss, which is beneficial for the improvement of MASLD.^{[40,41,42,43]} In a recent phase 2a study, 107 patients with phenotypic or histological MASH were randomized (1:2:2) to receive oral placebo or licogliflozin (30 mg or 150 mg) once daily for 12 weeks. Licogliflozin (150 mg) showed a significant decrease in alanine aminotransferase and 39% reduction in liver steatosis.^[44] Two-thirds of the patients treated with licogliflozin (150 mg) achieved ≥30% reduction in liver fat content. Despite the considerable variability in research design, the SGLT-2 inhibitors resulted in improvements in non-invasive markers of steatosis or even fibrosis in patients with type 2 diabetes. However, more data about the therapeutic effect of SGLT-2 inhibitors on liver histology are needed.^[45]

Dipeptidyl peptidase-4 (DPP-4) inhibitors

DPP-4 expressed on the surface of cells can cause degradation of GLP-1 and GIP. DPP-4 inhibition results in enhanced endogenous insulin secretion with suppression of glucagon and reduction of glucose.^[46] DPP-4 inhibitors, including anagliptin, gemigliptin, teneliptin, sitagliptin, linagliptin, vildagliptin, saxagliptin, and alogliptin, are widely available globally and mainly used in patients with type 2 diabetes. In a clinical trial, 15 diabetic patients with MASH were treated with sitagliptin (100 mg) once daily. Sitagliptin treatment attenuated ballooning and MASH scores, accompanied by a significant reduction in body mass index, aspartate aminotransferase, and alanine aminotransferase.^[47] A prospective comparative study enrolled 68 Chinese MASLD patients with type 2 diabetes and showed that sitagliptin improved abnormalities in glucose metabolism. However, sitagliptin did not reduce the intrahepatic lipid content in type 2 diabetes patients with MASLD, indicating that sitagliptin might be a therapeutic option for indirect treatment of MASLD.^[48] Other clinical trials showed that sitagliptin was not better than placebo in reducing liver fat and did not improve fibrosis score or NAFLD activity score after 24 weeks in patients with biopsy-proven MASH.^[49,50,51] The above results show that the application of DPP-4 inhibitors in MASLD is still disputed.

Statin drugs

MASLD often coexists with hyperlipidemia or cardiovascular disease. Statins are mostly used in patients with hyperlipidemia. In a clinical study, 437 patients with moderately abnormal liver tests at baseline, which were possibly caused by MASLD, were divided into two groups, 227 patients who were treated with a statin (mainly atorvastatin 24 mg/day) had substantial improvement in liver tests, whereas the liver enzymes were elevated in 210 patients not treated with a statin.^[52] Another study also showed that both the combined ezetimibe/simvastatin treatment and the simvastatin monotherapy proved to be effective and safe in patients with MASLD, and the liver enzyme was significantly decreased in the treatment group.^[53] A long-time follow-up study showed that treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of MASLD and reduced the odds of having hepatic steatosis.^[54] Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in MASLD patients. Larger population sample size and large-scale investigations are needed to explore the application of statins in MASH/MASLD.

Pentoxifylline

Pentoxifylline is a methylxanthine derivative. Studies have shown that pentoxifylline, as a non-specific phosphodiesterase inhibitor, has various physiological functions. It could increase the cyclic adenosine monophosphate level and decrease tumor necrosis factor-α level. The latter plays a pivotal role in the progression of MASLD. A meta-analysis including five randomized trials of 147 patients with MASLD/MASH found that compared to the placebo, pentoxifylline therapy resulted in a significant decrease in body weight, aspartate aminotransferase, alanine aminotransferase, glucose, and tumor necrosis factor-α, but had no influence on body mass index and blood lipids. As for the liver histology, pentoxifylline treatment could reduce the NAFLD activity score and improve lobular inflammation, but the effect on steatosis grade, ballooning, and fibrosis were insignificant.^[55]

Potential Therapeutic Drugs

FXR agonist

FXR is a member of the nuclear receptor superfamily and is mainly expressed in the liver and intestinal villi. FXR plays a key role in reducing bile acid synthesis and regulating enterohepatic circulatory homeostasis. Activation of FXR can regulate lipid metabolism, increase fatty acid synthesis and uptake, decrease fatty acid oxidation, and be a potential therapeutic target for MASLD. Obeticholic acid, a ligand of FXR, is a synthetic chenodeoxycholic acid. FXR activation has been demonstrated to reduce hepatic glucogenesis, lipogenesis, and steatosis in animal models. A randomized clinical trial conducted in patients with non-cirrhotic MASH showed that 50 of 110 patients in the obeticholic acid group had improved liver histology (including hepatocellular ballooning, steatosis, and lobular inflammation) compared with 23 of 109 patients in the placebo group.^[56] However, the potential side effects of obeticholic acid such as causing pruritus, influencing the mitochondrial function of hepatocytes, and promoting cell apoptosis should be considered.^[56,57] Until now, obeticholic acid has not been approved for MASLD treatment by the US Food & Drug Administration (FDA). The long-term benefits and safety need further clarification.

THR-β agonists

Thyroid hormone-mediated regulation of lipid metabolism and mitochondrial activity are associated with the development of MASLD. The activation of THR-β (mainly in the liver) can promote lipophagy, increase hepatic fatty acid β-oxidation, and decrease the burden of lipotoxic lipids.^[58] Sobetirome and eprotirome were the first-generation THR-β agonists that could reduce intrahepatic lipid content in animal models,^[59,60] but their clinical application is limited due to their side effects.^[61] Another THR-β agonist for treating MASH is resmetirom, which was approved by the FDA for the treatment of adults with MASH. Resmetirom resulted in a significant reduction in hepatic fat after 12 weeks or 36 weeks in patients with MASH in a phase 2 clinical trial conducted in the USA.^[62] A phase 3, randomized controlled trial of resmetirom in MASH with liver fibrosis was published at the beginning of the year. The results showed that both 80 mg and 100 mg of resmetirom were superior to placebo in alleviating MASH and improving liver fibrosis by at least one stage. MASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80 mg resmetirom group and 29.9% of those in the 100 mg resmetirom group. Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80 mg resmetirom group and 25.9% of those in the 100 mg group. Resmetirom treatment reduced low-density lipoprotein cholesterol and triglycerides. Although diarrhea and nausea were more frequent with resmetirom than with placebo, their degree and incidence were acceptable.^[63] In another non-invasive assessment study, the results confirmed the lipid-lowering effect of resmetirom on MASLD.^[64] These results have made resmetirom the world’s first approved drug for MASH. There are still some unresolved issues, such as the safety and effectiveness of resmetirom in chronic hepatitis B patients with MASLD or in patients with cirrhosis.

Fibroblast growth factor 21 (FGF21)

FGF21 is an endocrine messenger that activates the co-receptor complex of β-klotho and FGF receptors.^[65] Many in vitro and in vivo studies have demonstrated that FGF21 regulates energy homeostasis and lipid metabolism and improves insulin sensitivity.^[66] Efruxifermin is a long-acting Fc-FGF21 fusion protein that was used to treat patients with MASH in a phase 2a trial. Eighty patients were randomly assigned to receive placebo or efruxifermin (28 mg, 50 mg, or 70 mg) via weekly subcutaneous injection for 16 weeks. Treatment with efruxifermin significantly reduced hepatic fat fraction in patients with fibrotic-MASH.^[67] In a phase 2b trial, 128 patients with biopsy-confirmed MASH were randomly assigned to placebo or efruxifermin (28 mg or 50 mg). Efruxifermin improved liver fibrosis and resolved MASH over 24 weeks in patients with F2 or F3 fibrosis with acceptable side effects.^[68] In a phase 2a trial, efruxifermin was used to treat patients with compensated MASH-associated cirrhosis. Patients with MASH and stage 4 fibrosis were randomized to 50 mg efruxifermin or placebo once weekly for 16 weeks. Although the sample size was small, significant improvements were found in key markers of liver injury (alanine aminotransferase), glucose, and lipid metabolism. Non-invasive markers of fibrosis, including Pro-C3 and enhanced liver fibrosis score, were reduced in the efruxifermin group. Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 patients achieved fibrosis improvement of at least one stage without worsening of MASH, while an additional 3 patients achieved resolution of MASH.^[69] The most frequent adverse events of efruxifermin treatment were gastrointestinal, including transient, mild to moderate diarrhea, and nausea. Efruxifermin presented an acceptable safety profile. Longer-duration studies with large samples are warranted to evaluate the safety and efficacy of efruxifermin in MASH patients.

Pegbelfermin, a PEGylated FGF21 analog, was evaluated in MASH patients in a phase 2a study. Seventy-five patients were randomly assigned to groups, received at least one dose of treatment (25 received 10 mg pegbelfermin once daily; 24 received 20 mg pegbelfermin once weekly, and 26 received placebo). There was a significant decrease in hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (−6.8% vs. −1.3%) and 20 mg pegbelfermin weekly (−5.2% vs. −1.3%) compared with the placebo group.^[70] In another phase 2 trial, pegozafermin was used in patients with severe hypertriglyceridemia. Pegbelfermin-treated patients showed a significant reduction in median triglyceride level, as well as a significant decrease in liver fat fraction, assessed by magnetic resonance imaging.^[71] Surprisingly, most adverse events associated with pegbelfermin treatment were mild. In the FALCON 1 phase 2b study, patients with biopsy-confirmed MASH and stage 3 fibrosis received weekly subcutaneous pegbelfermin (10 mg, 20 mg, or 40 mg) or placebo injections for 48 weeks. The study failed to meet its primary endpoint (a ≥1-point decrease in fibrosis score without MASH worsening or MASH improvement without fibrosis worsening assessed via biopsy), although it was well tolerated during the study.^[72] In the FALCON 2 phase 2b study, pegbelfermin (10 mg, 20 mg, or 40 mg) or placebo was injected subcutaneously once weekly in biopsy-confirmed MASH and stage 4 fibrosis. Unfortunately, FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the MASH Clinical Research Network fibrosis without MASH worsening assessed via liver biopsy.^[73] The above results indicated that pegbelfermin failed to show clinical efficacy for MASH or fibrosis resolution. It is hoped that FGF21 analogs will be used for therapy of MASLD, but clinical trials with long duration and larger sample sizes are needed to obtain convincing evidence.

Other potential chemical products

Aramchol, an inhibitor of hepatic stearoyl-CoA desaturase (SCD1), improved steatohepatitis and fibrosis in animal models.^[74] In a phase 2 trial, 3 months’ administration of aramchol was safe, and tolerable, and liver fat content in patients with MASLD was significantly reduced in a dose-dependent manner and was associated with body metabolic improvements.^[75] In another phase 2b trial, 247 patients with MASH were enrolled. MASH resolution without worsening fibrosis was achieved in 16.7% (13 of 78) of the aramchol (600 mg) group vs. 5% (2 of 40) of the placebo group, and fibrosis improvement by ≥1 stage without worsening MASH was seen in 29.5% vs. 17.5%, respectively. Aramchol treatment was safe and well tolerated. The observed safety and improvements in liver histology and serum enzymes provide a rationale for SCD1 modulation as a promising therapy for MASH and fibrosis. A phase 3 trial of aramchol for the treatment of MASH is currently being conducted by Galmed Pharmaceuticals (Tel Aviv, Israel) (NCT04104321).

Selonsertib, an apoptosis signal-regulating kinase-1 (ASK1) inhibitor, was assessed in patients with bridging fibrosis or compensated cirrhosis due to MASH in the phase 3 STELLAR trial. Forty-eight weeks of selonsertib intervention had no antifibrotic effect.^[76] However, a combination with other agents might be a good direction of therapy. In a clinical study, three therapeutic approaches FXR agonism (cilofexor), acetyl-CoA carboxylase (ACC) inhibition (firsocostat), and ASK1 inhibition (selonsertib) were used alone or in two-drug combinations in patients with bridging fibrosis and cirrhosis attributable to MASH. The primary endpoint (a ≥1-stage improvement in fibrosis without worsening of MASH) was achieved in 11% of placebo-treated patients vs. cilofexor/firsocostat (21%), cilofexor/selonsertib (19%), firsocostat/selonsertib (15%), firsocostat (12%), and cilofexor (12%). Cilofexor/firsocostat caused a significant decrease in machine learning MASH Clinical Research Network fibrosis score and a shift in biopsy area from F3/F4 to ≤F2 fibrosis patterns, and had a ≥2-point NAFLD activity score reduction. This combination offers a potential therapy for patients with advanced fibrosis attributable to MASH.^[77]

Non-coding ribonucleic acids (RNAs), especially miRNAs are involved in the pathophysiology and progression of MASLD and are potential therapeutic targets for MASH.^[78] Abul-Husn et al^[79] found that hydroxysteroid dehydrogenase 17B13 (HSD17B13) mutation was associated with progression from hepatic steatosis to steatohepatitis in a human genetics study. In a phase 1/2 study, an RNA interference therapeutic was used to treat MASH. An RNA interference oligonucleotide-hydroxysteroid dehydrogenase (ARO-HSD) was an RNA interference therapeutic designed to selectively reduce expression of HSD17β13 mRNA in hepatocytes. Hepatic HSD17β13 protein levels were significantly reduced as well as alanine aminotransferase. However, there were no clinically meaningful effects on lipids or other metabolic parameters, and no significant change in liver fat fraction or liver stiffness following ARO-HSD administration at all dose levels. ARO-HSD treatment was well tolerated with no serious adverse events or drug discontinuations, and indicated the potential application of ARO-HSD in the future, but more research is needed to evaluate its safety and efficacy.^[80]

There are still many drugs under preclinical development or in ongoing phase 2 clinical trials, such as fatty acid synthase inhibitor,^[81] diacylglycerol acyltransferase 2 antisense inhibitor,^[82] and transglutaminase 2 inhibitor,^[83] and further research results are eagerly anticipated.

Conclusion, research agenda, and prospects

At present, the research and development of new drugs for MASH is ongoing and has made much progress. A more comprehensive understanding of the molecular mechanisms of MASH has laid the foundation for the exploration of new therapeutic agents. The molecular targets for the development of new drugs for MASLD mainly include three categories: regulating hepatic lipid metabolism, regulating liver fibrosis, and regulating hepatic inflammatory response and apoptosis.^[84] Despite the many drugs currently being studied, resmetirom is the only and first drug approved by the FDA for treating MASH with fibrosis, and this has become a huge milestone in this new research field. However, the limited clinical efficacy and high treatment costs of resmetirom are challenges in real-world applications.

Although many new drugs have been tried in MASH treatment, the results are not satisfactory.^[85] First of all, the heterogeneity of MASLD might be the main reason for the pessimistic outcome, resulting in many clinical trials not being able to achieve the primary study endpoint. Patients with MASLD usually have multiple comorbidities, such as hyperlipidemia, hyperuricemia, type 2 diabetes, and obesity, making treatment strategies more complex. Similarly, the pathogenesis of MASLD is complicated and not driven by a single factor. In order to achieve better therapeutic effects in the future, combination therapy with different targets will be the clinical trial direction for MASH. Changing behavior or lifestyle, enhancing compliance of patients, and strengthening patient stratification management are also important during the research period.

To rationalize clinical research, the selection of MASLD/MASH patients should consider several points. First of all, the natural history and subtypes should be taken into consideration, even though accurate classification and identification of patient subgroups are still challenging. Comorbidities such as obesity, type 2 diabetes, metabolic syndrome, and cardiovascular diseases are potentially worthy of consideration in clinical trial design, depending on the mechanism of action of any new drugs. Alcohol consumption may modify treatment outcome, and the influence of the quantity, duration, and pattern of alcohol consumption needs to be taken seriously, especially for long-duration trials. At present, the appropriate duration of clinical trials is still not standardized, and mainly depends on the drug properties and research objective or endpoint. We suggest that better design and longer follow-up should be used to evaluate the effects on hepatic histological endpoints or liver-related events in future studies, and longer duration is also better for the observation of adverse drug reactions.^[86] The evaluation system of clinical trials is also an important factor affecting research results. The evaluation criteria for MASH clinical trials are based on liver histological improvement. The commonly used clinical endpoints are: MASH relief without worsening liver fibrosis, liver fibrosis improvement without worsening MASH, or simultaneous improvement of MASH and liver fibrosis.^[86] Liver biopsy is an invasive evaluation method, and sampling error and histological review processes by different experts can have a significant impact on the results of clinical trials. To improve this, it is crucial to seek more accurate non-invasive evaluation methods. In recent years, various non-invasive methods have been used in MASH clinical trials, such as magnetic resonance imaging, Fibroscan, or serological markers. The therapeutic benefits and safety profiles are critical for every new drug for treating MASLD, as well as the real economic cost.

The incidence of MASLD is constantly increasing worldwide; therefore, it is urgent to develop new drugs for treating MASLD. Currently, THR-β agonists, FXR agonists, PPAR agonists, GLP-1 analogs, and FGF21 analogs exhibit great potential, and merit further investigation [Table 1]. In the future, healthy lifestyle and propriety athletics are always the cornerstone of MASLD treatment, and combination therapies targeting different pathways should be taken into consideration. Truly effective treatment of MASLD is not restricted to the liver, and systemic treatment will reduce hepatic and extrahepatic complications and improve quality of life.

Table 1.

Summary of ongoing pharmacotherapeutic agents in phase 3 trials for MASH/MASLD.

Drug	NCT number	Inclusion criteria	Mechanism	Sponsor	Study type	Start	Completion
Resmetirom	NCT03900429	MASH and fibrosis	THR-β agonist	Madrigal Pharmaceuticals	Interventional	2019-03	2028-01
Resmetirom	NCT05500222	Well-compensated (Child-Pugh A) MASH cirrhosis	THR-β agonist	Madrigal Pharmaceuticals	Interventional	2022-08	2027-01
Resmetirom	NCT04951219	MASLD	THR-β agonist	Madrigal Pharmaceuticals	Interventional	2021-07	2026-04
IVA337 (Lanifibranor)	NCT04849728	Non-cirrhotic MASH and fibrosis stages F2 and F3	PPAR agonist	Inventiva Pharma	Interventional	2021-08	2026-09
Namodenoson	NCT04697810	MASH and F1-3 fibrosis	A3 adenosine receptor agonist	Can-Fite BioPharma	Interventional	2021-12	2025-10
Belapectin (GR MD-02)	NCT04365868	MASH cirrhosis	Galactin-3 inhibitor	Galectin Therapeutics	Interventional	2020-06	2024-12
Survodutide	NCT06309992	Overweight or obesity with MASH	GCGR/GLP-1R agonist	Boehringer Ingelheim	Interventional	2024-03	2026-02
Aramchol	NCT04104321	MASH	SCD1 inhibitor	Galmed Research and Development	Interventional	2019-09	2027-06
Efruxifermin	NCT06161571	MASH/MASLD	FGF21 analog	Akero Therapeutics	Interventional	2023-11	2026-10
Efruxifermin	NCT06215716	Non-cirrhotic MASH and fibrosis	FGF21 analog	Akero Therapeutics	Interventional	2023-12	2027-03
Pegozafermin	NCT06318169	MASH with fibrosis	Long-acting glycopegylated FGF21 analog	89bio	Interventional	2024-03	2029-02
Pegozafermin	NCT06419374	MASH with compensated cirrhosis	Long-acting glycopegylated FGF21 analog	89bio	Interventional	2024-05	2031-08

FGF: Fibroblast growth factor; FGF21: Fibroblast growth factor 21; MASH: Metabolic dysfunction associated steatohepatitis; MASLD: Metabolic dysfunction-associated steatotic liver disease; PPAR: Peroxisome proliferator-activated receptor; GCGR: Glucagon receptor; SCD1: Stearoyl CoA desaturase-1; THR-β: Thyroid hormone receptor-β.

Funding

This work was supported by grants from the National Science and Technology Major Project of China (No. 2023ZD0508700) and the National Natural Science Foundation of China (No. 82170593).

Conflicts of interest

None.