Review Article: Fibrosis Reversal in Metabolic Dysfunction‐Associated Steatohepatitis—The Promise of Emerging Therapeutics

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading indication for liver transplantation, and fibrosis stage most strongly predicts clinical outcomes. Pharmacologic treatment is now available with resmetirom and semaglutide holding conditional approval. AIMS: To describe the therapeutic landscape for MASH with a focus on anti-fibrotic impact. METHODS: Narrative review of Phase 2 and 3 trials, meta-analyses, epidemiological data, and trial registries. RESULTS: Historically, drugs targeting downstream fibrogenic or inflammatory pathways have had limited success in advanced development, whereas those improving metabolic dysfunction have had fared better. Fibrosis improvement by at least one stage was seen with resmetirom in up to 26% versus 14% placebo after 52 weeks and with semaglutide in 37% versus 22% after 72 weeks. Several agents in development (e.g., fibroblast growth factor 21 analogues, as well as dual and triple incretin agonists, pan-peroxisome proliferator-activated receptor agonist) report encouraging Phase 2 results, with Phase 3 trials ongoing. Compensated cirrhosis requires a distinct approach related to its fibrosis heterogeneity and burden of portal hypertension. This requires a delicate balance between efficacy and event rates that is further complicated by current regulatory constraints. CONCLUSIONS: Fibrosis improvement in MASH is attainable by available drugs with further promise from emerging therapies. The link between treatment induced histological improvement or improvement in noninvasive tests and reduction in clinical outcomes remains unproven. A rich therapeutic pipeline with the promise of combination regimens and increased focus non-invasive endpoints suggests that the future looks bright for patients living with fibrotic MASH.