Association Between Surrogate Endpoints and Patient-Relevant Clinical Outcomes in MASH Patients: Interim Report of an Ongoing Systematic Literature Review

Research Question: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver-related morbidity and mortality. Patient-relevant clinical outcomes, such as progression to cirrhosis, decompensation events, and death, are often impractical to study within the context of a clinical trial. For this reason, recent guidelines from the Food and Drug Administration ([1]) and the European Medicines Agency ([2]) acknowledge that the use of surrogate endpoints in clinical trials, such as changes in liver histology or noninvasive tests (NITs), are acceptable in MASH clinical trials. This systematic literature review (SLR) aims to evaluate the association and predictive ability of surrogate markers with patient-relevant clinical outcomes in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) or MASH.

Methodology: A SLR, with an a-priori search strategy, was conducted across multiple databases to identify relevant studies assessing the relationship between histologic markers (e.g., fibrosis, activity score), NITs (fibrosis 4 [FIB-4] index, NAFLD fibrosis score [NFS], enhanced liver fibrosis [ELF]) and clinical outcomes (e.g., liver-related events, mortality) in MASLD/MASH. Interim results are from a subset of studies selected for priority full-text review and data extraction by keyword searches, which had objectives more closely aligned with the review question. Extracted data describing the association between histologic markers or NITs and clinical outcomes were synthesized.

Results: A total of 2,596 abstracts were screened, with 104 selected for priority full-text review. The interim analysis includes data from four unique clinical trials, one pooled analysis of separate clinical trial data and 15 unique observational studies. Histologic fibrosis stage, FIB-4, NFS, and ELF were the most commonly reported markers. Of studies reporting mortality, 17/19 (83%) reported significant associations with surrogate endpoints. Of studies reporting liver-related events, 10/12 (89%) reported significant associations. Preliminary results suggest a consistent association between more severe histologic features, NITs, and worse clinical outcomes, including higher mortality and liver-related events like hepatocellular carcinoma or hepatic decompensation. Despite variations in methodology and demographics, the direction of associations between surrogate endpoints and important clinical outcomes remained consistent.

Conclusions: Despite heterogeneity among studies, this ongoing review shows that surrogate endpoints, including histological assessments and NITs, are consistently associated with important patient oriented clinical outcomes. Given the association between histologic markers and clinically relevant endpoints reported in the literature, these markers are appropriate for use in MASH trials, aiding the development of new therapeutic strategies in shorter timeframes for this challenging disease.

Publication History

Article published online:
28 May 2025

• Literatur

• 1 U.S. Food and Drug Administration. Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry Draft Guidance. 2018
• 2 European Medicines Agency. Reflection paper on regulatory requirements for the development of medicinal products for non-alcoholic steatohepatitis. (NASH) 2023