GLP-1 Receptor Agonists and FGF21 Analogs May Be Key Treatments for MASH-Related Cirrhosis

Metabolic dysfunction–associated steatohepatitis (MASH)–related cirrhosis is increasingly prevalent among patients with metabolic dysfunction–associated steatotic liver disease (MASLD) and is associated with substantial morbidity and mortality because of hepatic decompensation, hepatocellular carcinoma, major adverse cardiovascular events, and all-cause mortality, wrote authors of a review published in Journal of Translational Gastroenterology.

In the review, they evaluated notable clinical trials while addressing the unique challenges of this patient population, who require novel, differentiated approaches to drug development and support to develop an independent regulatory framework for clinical trial end points that are “rational” for them.¹

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MASLD has emerged as a leading cause of chronic liver disease and cirrhosis in the Western world, according to the investigators. As obesity rates continue to grow, so does the prevalence of MASH-related liver damage or cirrhosis. Additionally, MASH is associated with chronic hepatic inflammation and progressive liver fibrosis, and a significant amount of MASH-related research is focused on developing pharmacological therapies to reverse these adverse complications.¹

Although the authors analyze multiple clinical trials, one notable trial is the ESSENCE trial (NCT04822181)², an ongoing multicenter, randomized, double-blind, placebo-controlled phase 3 trial evaluating the effects of 2.4 mg of the glucagon-like peptide-1 (GLP-1) receptor agonist, semaglutide (Ozempic, Wegovy; Novo Nordisk), once per day in patients with biopsy-defined MASH and stage 2 or 3 fibrosis. The trial enrolled 1197 patients with the end goal of resolving steatohepatitis without worsening liver fibrosis and reducing liver fibrosis without worsening steatohepatitis.^1-3

Although semaglutide did not appear to show a benefit in earlier-stage MASH¹, findings from May 2025 demonstrated that the resolution of steatohepatitis without worsening of fibrosis occurred in approximately 62.9% (n = 534) of patients in the semaglutide group and in 34.3% (n = 266) of patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI [21.1 to 36.2]; P < .001). Additionally, a reduction in liver fibrosis without worsening of steatohepatitis was reported in about 36.8% and 22.4% of patients in the semaglutide and placebo groups, respectively (estimated difference, 14.4 percentage points; 95% CI [7.5 to 21.3]; P < .001).¹ The mean change in body weight was about −10.5% with semaglutide and −2.0% with placebo (estimated difference, −8.5 percentage points; [95% CI −9.6 to −7.4]; P < .001); however, the investigators of this trial wrote that mean changes in bodily pain scores did not differ significantly between the groups.³

Generally, adverse events (AEs) were more frequently reported by patients receiving semaglutide (86.3%) than those receiving placebo (79.7%), with the most common AEs being nausea, diarrhea, constipation, and vomiting.³

Outside of GLP-1 receptor agonists, farsenoid X receptor (FXR) agonists, galectin-3 inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, and fibroblast growth factor (FGF)21 analogs are also undergoing clinical evaluation for their efficacy in treating patients with MASH. Regardless of the treatment, trial end points (eg, hepatic decompensation events, liver transplantation, death) represent well-validated outcomes that would serve as acceptable characteristics for full FDA approval; however, because of the latency and variability of disease progression in patients with MASH-related fibrosis or cirrhosis, establishing clinical end points can represent unique challenges, including the potential need for larger sample sizes to ensure an adequate number of clinical events, a long timeframe that surpasses 1 year, and careful patient selection that is properly implemented and practiced throughout the trial’s duration.¹

In their review, the investigators suggest that, at the time of publication, FGF21 analogs appear to be the best positioned in demonstrating efficacy in patients with compensated cirrhosis (reversal of stage 4 fibrosis to stage 3 or lower) because of their direct antifibrotic properties, mediation through inhibition of stellate cell activation, and indirect antifibrotic effects through significant decreases in inflammation, lipotoxicity, and triglycerides.¹

The investigators point to 96-week data from the phase 2 SYMMETRY trial (NCT05039450),⁴ a randomized, double-blind, placebo-controlled study that revealed that approximately 39% of patients receiving 50 mg of efruxifermin (Akero Therapeutics) achieved fibrosis reversal, compared with 15% in the placebo arm. These data marked the first demonstration of histologic cirrhosis reversal in a randomized controlled trial to date, wrote the authors. They noted that future studies with efruxifermin and pegozafermin (89Bio, BiBo Biopharma Engineering), another FGF21 analog, will further clarify the potential role of FGF21 analogs in the stage 4 cirrhosis population.^1,4

Above all, the authors explained that future advances in drug development for MASH-related cirrhosis will require further exploration of novel 2- or 3-agent combination approaches that have metabolic, anti-inflammatory, and antifibrotic mechanisms that could enhance synergy on MASH and fibrosis end points. Further, there will also be a need for further validation of histologic and biomarker end points (eg, elastography or enhanced liver fibrosis), which may serve as surrogate end points for FDA accelerated approval and are considered separate from clinical outcomes.¹

REFERENCES

1. Nasir SA, Mangla A, Taneja V, et al. Advances in novel drug therapy for metabolic dysfunction-associated steatohepatitis cirrhosis. JTG. 2025;3(1):9-17 doi:10.14218/JTG.2024.00040

2. Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH) (ESSENCE). ClinicalTrials.gov identifier: NCT04822181. Updated May 16, 2025. Accessed June 4, 2025. https://clinicaltrials.gov/study/NCT04822181

3. McGovern G. Study demonstrates semaglutide improves liver histologic results in patients with MASH. Pharmacy Times^®. May 6, 2025. Accessed June 4, 2025. https://www.pharmacytimes.com/view/study-demonstrates-semaglutide-improves-liver-histologic-results-in-patients-with-mash

4. A Study of Efruxifermin in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (Symmetry). ClinicalTrials.gov identifier: NCT05039450. Updated April 9, 2025. Accessed June 4, 2025. https://clinicaltrials.gov/study/NCT05039450