Noninvasive surrogate endpoints in MASH trials: current perspectives and challenges

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of cirrhosis and liver-related morbidity. Current regulatory pathways rely on histology and long-term clinical outcomes, but repeated liver biopsy is noninvasive and poorly reproducible; regulators have signaled interest in noninvasive tests (NITs) as surrogate endpoints.

This review synthesizes contemporary regulatory perspectives, the evidentiary framework for biomarker qualification, and the published performance of leading noninvasive tests (vibration-controlled transient elastography [VCTE], magnetic resonance elastography [MRE], and the enhanced liver fibrosis [ELF] test). We summarize diagnostic, prognostic, monitoring and response assessment data from cohort studies, meta-analyses and trial datasets, and outline the analytical and clinical validation steps required for reasonably likely surrogate endpoint (RLSE) qualification.

Evidence shows that baseline values and longitudinal changes in liver stiffness measurement (LSM by VCTE and MRE) and ELF correlate with histological stage and predict liver-related events. VCTE offers broad accessibility and a mature outcome linkage; MRE provides superior accuracy and repeatability; ELF supplies a scalable prognostic blood signal. However, variability in measurement, limited trial-level surrogacy data, and low-event rates in pre-cirrhotic cohorts constrain definitive qualification. Composite or tiered strategies and prospective trial datasets linking on-treatment NIT changes to major adverse liver outcomes are needed.

NITs show promise as surrogate endpoints for MASH trials, but full qualification as RLSE requires standardized assays, robust prospective evidence that treatment‑induced biomarker changes predict hard clinical outcomes, and close collaboration among academia, industry, and regulators.