MASH Drug Efficacy Varied Widely Across Fibrosis, Resolution Outcomes

Targeted therapies showed uneven but measurable progress in reshaping the treatment landscape for people living with metabolic dysfunction–associated steatohepatitis (MASH), as new comparative evidence highlights which drug classes were most consistently associated with fibrosis improvement and disease resolution.¹

As drug development for MASH accelerated, clinicians and payers faced a growing challenge: Multiple late-phase therapies were advancing simultaneously, but few head-to-head trials existed to guide treatment prioritization.² With fibrosis regression and MASH resolution serving as regulatory end points for approval, comparative effectiveness data became increasingly important for clinical decision-making and trial design.³

The investigators of the current study evaluated the relative efficacy of pharmacologic therapies in people with biopsy-proven MASH.¹ The systematic review and network meta-analysis, published in Hepatology, synthesized data from 29 randomized controlled trials (RCTs) involving 9324 participants and compared treatments across 2 coprimary end points: fibrosis improvement of at least 1 stage without worsening MASH and MASH resolution without worsening fibrosis.

The investigators searched PubMed and Embase for RCTs published between January 1, 2020, and December 1, 2024. Eligible studies enrolled adults with biopsy-confirmed MASH, included at least 6 months of follow-up, and reported FDA-recognized histologic endpoints. Observational studies, lifestyle-only interventions, trials involving cirrhosis, and studies with fewer than 40 participants were excluded.

Most trials were multicenter and placebo-controlled, with durations ranging from 24 to 72 weeks. Participants were drawn from North America, Europe, Asia, and multinational sites. Across trials, populations generally reflected typical MASH demographics, including high prevalence of obesity, type 2 diabetes, and metabolic comorbidities, although baseline characteristics varied between studies.

Using Bayesian network meta-analysis and surface under the cumulative ranking curve (SUCRA) methodology, the authors ranked therapies according to their probability of achieving each endpoint.

Fibrosis Regression Outcomes

For fibrosis improvement of at least 1 stage without worsening MASH, 24 RCTs involving 8708 participants were analyzed. Several agents demonstrated statistically significant benefit compared with placebo.

Pegozafermin showed the strongest relative effect (RR, 3.46; credible interval [CrI], 1.54-11.15), followed by cilofexor plus firsocostat (RR, 2.67; CrI, 1.05-8.13), denifanstat (RR, 1.94; CrI, 1.04-4.04), survodutide (RR, 1.86; CrI, 1.18-3.28), obeticholic acid (RR, 1.85; CrI, 1.30-2.75), tirzepatide (RR, 1.77; CrI, 1.17-2.94), resmetirom (RR, 1.64; CrI, 1.27-2.20), and semaglutide (RR, 1.51; CrI, 1.23-1.90).

Based on SUCRA rankings, pegozafermin ranked highest for fibrosis regression (79.92%), followed by cilofexor plus firsocostat (71.38%) and cilofexor plus selonsertib (69.11%).

MASH Resolution Outcomes

For MASH resolution without worsening fibrosis, 28 RCTs including 9277 participants were evaluated. Pegozafermin again demonstrated the strongest effect (RR, 8.65; CrI, 2.63-59.42), followed by survodutide (RR, 6.62; CrI, 3.13-17.97), tirzepatide (RR, 4.65; CrI, 2.31-10.66), efruxifermin (RR, 3.51; CrI, 1.83-8.17), liraglutide (RR, 3.23; CrI, 1.11-14.17), vitamin E plus pioglitazone (RR, 3.03; CrI, 1.31-9.04), resmetirom (RR, 2.54; CrI, 1.86-3.55), pioglitazone (RR, 2.29; CrI, 1.41-4.03), semaglutide (RR, 1.87; CrI, 1.60-2.24), and lanifibranor (RR, 1.93; CrI, 1.30-3.02).

SUCRA rankings placed pegozafermin highest for MASH resolution (91.75%), followed by survodutide (90.87%) and tirzepatide (84.70%).

Interpretation and Limitations

The authors emphasized that while several therapies demonstrated statistically significant benefits, most comparisons were indirect due to limited head-to-head trials. Variability in trial design, treatment duration, dosing regimens, and patient populations limited direct comparability. Some therapies included in the analysis are no longer under development for MASH, and many agents remain in early- or mid-phase trials.

Liver biopsy, while the regulatory gold standard, also introduced measurement variability, and most trials were not powered to assess long-term clinical outcomes such as progression to cirrhosis or liver-related mortality.

“This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution,” the authors wrote, adding that “these data are helpful to inform practice and clinical trial design.”

They further noted that treatment selection in the future would likely depend not only on liver outcomes but also on extrahepatic effects and metabolic comorbidities, rather than small differences in histologic efficacy alone.

The findings provide an early comparative framework for evaluating a crowded therapeutic pipeline. The analysis supports the emerging role of FGF21 analogs and incretin-based therapies while reinforcing the need for long-term outcomes data and direct comparative trials.

As combination regimens and precision approaches evolve, the authors suggested that these rankings may help guide trial design and payer evaluation strategies in a rapidly expanding MASH treatment landscape.

References

1. Souza M, Al-Sharif L, Antunes VLJ, Huang DQ, Loomba R. Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: systematic review and network meta-analysis. Hepatology. 2025;82(6):1523-1533. doi:10.1097/HEP.0000000000001254
2. Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000
3. Rinella ME, Tacke F, Sanyal AJ, Anstee QM. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD. J Hepatol. 2019;71(4):823-833. doi:10.1016/j.jhep.2019.04.019