Network Meta-Analysis Reveals Pegozafermin Leads MASH Treatment Rankings for Fibrosis Regression and Disease Resolution
核心洞察
Pegozafermin demonstrated the strongest efficacy for both fibrosis (搜索) improvement (RR 3.46) and MASH (搜索) resolution (RR 8.65) compared to placebo in a comprehensive network meta-analysis of 29 randomized controlled trials.
The analysis of 9,324 participants revealed significant variability in treatment effectiveness, with incretin-based therapies like survodutide and tirzepatide also showing substantial benefits for disease resolution.
FGF21 (搜索) analogs including aldafermin and pegozafermin ranked highest for reducing liver fat content measured by MRI-PDFF, providing noninvasive markers that may predict histologic response.
A comprehensive network meta-analysis has identified pegozafermin as the most effective therapy for achieving both fibrosis (搜索) regression and disease resolution in metabolic dysfunction-associated steatohepatitis (搜索) (MASH (搜索)), providing crucial comparative effectiveness data as multiple treatments advance through late-phase development.
The systematic review, published in Hepatology, synthesized data from 29 randomized controlled trials involving 9,324 participants with biopsy-proven MASH (搜索). The analysis compared treatments across two FDA-recognized coprimary endpoints: fibrosis (搜索) improvement of at least one stage without worsening MASH, and MASH resolution without worsening fibrosis.
Pegozafermin Demonstrates Superior Efficacy Across Key Endpoints
For fibrosis (搜索) improvement, pegozafermin showed the strongest relative effect compared to placebo (RR 3.46; credible interval 1.54-11.15), followed by the combination of cilofexor plus firsocostat (RR 2.67; CrI 1.05-8.13). Other agents demonstrating statistically significant benefits included denifanstat (RR 1.94), survodutide (RR 1.86), obeticholic acid (RR 1.85), tirzepatide (RR 1.77), resmetirom (RR 1.64), and semaglutide (RR 1.51).
The surface under the cumulative ranking curve (SUCRA) methodology placed pegozafermin highest for fibrosis (搜索) regression with a 79.92% probability ranking, followed by cilofexor plus firsocostat (71.38%) and cilofexor plus selonsertib (69.11%).
For MASH (搜索) resolution without worsening fibrosis (搜索), pegozafermin again demonstrated the strongest effect (RR 8.65; CrI 2.63-59.42). Survodutide ranked second (RR 6.62; CrI 3.13-17.97), followed by tirzepatide (RR 4.65; CrI 2.31-10.66) and efruxifermin (RR 3.51; CrI 1.83-8.17).
Liver Fat Reduction Patterns Align with Histologic Benefits
A separate network meta-analysis of 39 trials enrolling 3,311 participants examined liver fat reduction using MRI proton-density fat fraction (MRI-PDFF), a validated noninvasive marker increasingly used in MASH (搜索) trials. The analysis revealed that aldafermin demonstrated the largest absolute reduction in MRI-PDFF compared with placebo (log mean difference -6.64; CrI -8.64 to -4.64), followed closely by pegozafermin (-6.60; CrI -8.53 to -4.65).
When the outcome was defined as achieving at least a 30% decline in MRI-PDFF at 24 weeks—a threshold associated with MASH (搜索) resolution in prior studies—efinopegdutide ranked highest, followed by semaglutide combined with firsocostat and pegbelfermin.
Treatment Landscape Reflects Diverse Mechanisms
The analysis encompassed multiple drug classes targeting different pathways in MASH (搜索) pathogenesis. FGF21 (搜索) analogs, including pegozafermin and aldafermin, consistently ranked highly across both histologic and imaging endpoints. Incretin-based therapies such as survodutide and tirzepatide showed particular strength for MASH resolution, while combination regimens pairing metabolic and antifibrotic mechanisms demonstrated favorable performance in longer-term analyses.
The investigators noted that most comparisons were indirect due to limited head-to-head trials, and variability in trial design, treatment duration, and patient populations limited direct comparability. Participants across trials generally reflected typical MASH (搜索) demographics, including high prevalence of obesity, type 2 diabetes, and metabolic comorbidities.
Clinical Implications and Future Directions
"This study provides updated rank-order efficacy of MASH (搜索) pharmacological therapies for fibrosis (搜索) regression and MASH resolution," the authors wrote, adding that "these data are helpful to inform practice and clinical trial design."
The findings provide an early comparative framework for evaluating a crowded therapeutic pipeline as drug development for MASH (搜索) has accelerated. The analysis supports the emerging role of FGF21 (搜索) analogs and incretin-based therapies while reinforcing the need for long-term outcomes data and direct comparative trials.
The authors emphasized 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. They also cautioned that improvements in MRI-PDFF do not always translate directly into fibrosis (搜索) regression or long-term clinical benefit.
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 (搜索) treatment landscape. The comparative effectiveness data addresses a growing challenge faced by clinicians and payers as multiple late-phase therapies advance simultaneously with few head-to-head trials to guide treatment prioritization.