MASH 2B TRIALS-A SYSTEMATIC REVIEW

Document Type

Conference Proceeding

Publication Date

10-9-2024

Publication Title

Hepatology

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated fatty liver disease (MAFLD), is the leading cause of chronic liver disease in the U.S., encompassing conditions from simple steatosis to cirrhosis and hepatocellular carcinoma. Early symptoms like fatigue and abdominal pain are non-specific, often delaying diagnosis until advanced stages. Systemic insulin resistance leads to lipid accumulation in the liver, triggering inflammatory responses. The gut microbiome and gut-liver axis also play significant roles. Diagnosis uses the NAFLD Activity Score (NAS) and the NASH Clinical Research Network (CRN) fibrosis score to assess disease activity and progression. Treatments emphasize weight loss and lifestyle changes, with promising pharmacological options targeting insulin sensitivity, lipid metabolism, and inflammation. These include PPAR agonists, SGLT-2 inhibitors, GLP-1 inhibitors, and the recently approved Resmetirom. Current research focuses on phase 2b trials to evaluate the efficacy and safety of these treatments. Methods: This study follows PRISMA-2020 guidelines. Three researchers conducted a literature search across multiple databases for phase 2b trials from the past 5 years. Studies were selected using PICO criteria and data were extracted per the Cochrane Handbook. Quality assessment was done using the Cochrane Risk of Bias Tool (2.0). Results: This study includes 11 randomized control trials (RCTs), all double-blinded, with 10 being placebo-controlled, involving adults with histologically confirmed NASH. The trials ranged from 100 to 392 participants. PPAR agonists were tested in the EMMINENCE and NATIVE trials, with NATIVE showing significant fibrosis and NASH resolution at higher doses. FGF21 and FGF19 pathways were targeted in six trials. The Harmony trial with efruxifermin showed significant fibrosis improvement, while the Enliven trial with pegozafermin also demonstrated significant fibrosis reduction at higher doses. The Falcon trials with pegbelfermin did not achieve significant primary outcomes. Alpine 2/3 and Alpine 4 trials with aldafermin showed mixed results, with significant fibrosis improvement only in specific doses. The TANDEM trial, comparing Tropifexor and Cenicriviroc, focused on safety and efficacy, showing ALT, AST, and GGT reductions. ICONA trial with Icosabutate showed potential in NASH patients with T2DM. Belapectin, a galectin-3 inhibitor, did not significantly reduce portal pressure. Outcomes frequently measured NAS or SAF score improvements, highlighting potential in combined drug mechanisms and specific comorbidities. Conclusion: RCTs in NASH treatment showed mixed outcomes. Lanifibranor and icosabutate showed promise, especially in T2D patients. FGF21 analogues like efruxifermin improved fibrosis, while FGF19 trials had variable results. Further research is needed.

Volume

80

First Page

S1265

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