A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis

In this Journal Club Video Module, Lisa Richards, NP, a hepatology specialist with over 20 years of experience at UC San Diego Health, presents the pivotal findings of the Phase 3 randomized controlled trial of Resmetirom for the treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) with liver fibrosis. Published in The New England Journal of Medicine in February 2024, this study provided the data that led to FDA approval of Resmetirom in March 2024 for adults with moderate to advanced fibrosis (F2-F3) due to MASH.

MASH, formerly known as Non-Alcoholic Steatohepatitis (NASH), is a progressive liver disease characterized by hepatic steatosis, hepatocellular damage, and inflammation. Once fibrosis reaches Stage 2 or 3, the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC) significantly increases. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta (THR-β) selective agonist designed to improve mitochondrial function, enhance fatty acid oxidation, and reduce fibrosis progression. The MAESTRO-NASH trial assessed its safety and efficacy in adults with biopsy-confirmed MASH and liver fibrosis.

The 52-week results from 966 patients demonstrated that Resmetirom at both 80 mg and 100 mg doses significantly improved MASH resolution and fibrosis reduction compared to placebo. In the study, MASH resolution without worsening fibrosis was achieved in 25.9% of patients in the 80 mg group and 29.9% in the 100 mg group, compared to just 9.7% in the placebo group. Similarly, fibrosis improvement by at least one stage without worsening MASH was observed in 24.2% of the 80 mg group and 25.9% of the 100 mg group, whereas only 14.2% of placebo patients showed fibrosis improvement. Both primary endpoints were statistically significant, confirming the therapeutic potential of Resmetirom.

In addition to its effects on liver health, Resmetirom also demonstrated benefits in lipid metabolism. LDL cholesterol levels decreased by 13.6% in the 80 mg group and by 16.3% in the 100 mg group, compared to a 0.1% increase in the placebo group, indicating a potential cardiometabolic advantage of this treatment.

The overall safety profile of Resmetirom was favorable, with the incidence of serious adverse events comparable across treatment groups: 10.9% (80 mg group), 12.7% (100 mg group), and 11.5% (placebo group). The most commonly reported side effects were diarrhea and nausea, though they were generally well tolerated and did not lead to treatment discontinuation in most cases.

These findings led to the FDA approval of Resmetirom on March 14, 2024, making it the first approved therapy for non-cirrhotic MASH with moderate to advanced fibrosis. The MAESTRO-NASH trial is ongoing for up to 54 months to further assess long-term liver outcomes, including the progression to cirrhosis.

The approval of Resmetirom represents a major breakthrough in MASH treatment, providing the first targeted therapy that directly addresses liver fat accumulation, inflammation, and fibrosis progression. With MASH being a leading cause of liver failure, cirrhosis, and liver transplantation, this approval marks a significant advancement in the management of the disease.

For more expert discussions on MASH and liver disease management, visit the GHAPP website or download the GHAPP ACE mobile app.