DAY 3: Resmetirom Shows Promising Results in Patients with Cirrhosis

Patients with well compensated cirrhosis related to metabolic dysfunction-associated steatohepatitis (MASH) achieved significant reductions in liver stiffness, fibrosis biomarkers and scores, and portal hypertension over 52 weeks of treatment with resmetirom, according to data from a 2-year open-label trial. Naim Alkhouri, MD, chief academic officer at Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology in Cleveland, Ohio, shared results from the trial at the 2025 Annual Scientific Meeting of the American College of Gastroenterology in Phoenix, Arizona. 

Resmetirom, an oral selective agonist of thyroid hormone receptor beta (THR-β), was the first therapy to gain approval for the treatment of MASH in the United States. While this therapy is indicated for adults with moderate-to-advanced fibrosis, it is not yet approved for the treatment of cirrhosis resulting from MASH. Cirrhosis is associated with a high risk of adverse outcomes, including liver failure, need for liver transplantation, and mortality. “Patients with MASH cirrhosis have a high unmet need given the poor clinical outcomes, the risk for decompensation, and potentially the need for liver transplantation,” Alkhouri remarked during a plenary session. “There is evidence that restoring thyroid hormone receptor beta signaling in the liver, which is the mechanism of action for resmetirom, may actually lead to fibrosis regression by inducing mitogenesis, decreasing oxidative stress, and potentially [by] direct effects on hepatic stellate cells.” 

In the MAESTRO-NAFLD-1 open label clinical trial, 161 patients with well compensated MASH cirrhosis (classified as Child Pugh A) were treated with resmetirom 80 mg once daily over 52 weeks. The 122 participants who completed the first phase of the trial continued treatment with resmetirom 80 mg once daily for an additional period of 52 weeks in the open-label extension phase of the trial. A few participants discontinued treatment during the extension phase due to adverse events or other reasons, leaving 113 patients to complete the entire 2-year treatment period. 

The results showed that, after being treated with resmetirom for up to 2 years, more than half of the participants achieved sustained reductions in liver stiffness (at least 25% compared to baseline), measured by vibration-controlled transient elastography (VCTE). Moreover, up to 35% of patients showed signs of cirrhosis reversal, which was defined by a decrease in liver stiffness of at least 25% compared to baseline along with a VCTE value of less than 15 kPa. 

Resmetirom also decreased the risk of clinically significant portal hypertension, which predisposes patients to ascites, variceal hemorrhage, and encephalopathy. By the end of the 2-year treatment period, patients had moved to lower risk categories, regardless of their baseline risk for portal hypertension. Alkhouri cautioned that, although overall the study showed a positive signal in portal hypertension for patients with well compensated cirrhosis, individuals with more severe thrombocytopenia or different spleen and liver volumes may follow different trajectories. 

Magnetic resonance imaging proton density fat fraction (MRI-PDFF) and MR elastography showed significant reductions in liver fat and liver stiffness after 2 years of treatment with resmetirom. Reductions in liver enzymes, specifically alanine transaminase and gamma-glutamyl transferase, were also documented, along with reductions in liver fibrosis and liver injury biomarkers after 2 years. Levels of atherogenic lipids also decreased, independently of liver fat content, which was consistent with the previously documented effects of resmetirom on lipid profiles. The investigators observed an increase in adiponectin, a favorable metabolic biomarker of liver health with powerful anti-inflammatory and insulin-sensitizing effects. 

“We also showed reduction in liver volume on MRI, and we showed that patients with MASH cirrhosis have increased liver volumes, by up to 40%, and with treatment with resmetirom for 2 years, there was a reduction of up to 25% in liver volume,” Alkhouri said. “We also utilized MRI to measure spleen volume and see the correlation with platelet count. We showed that, in patients with platelet counts over 100,000 mcL at baseline, there was a significant reduction in spleen volumes. There was also correlation between improvement in spleen volumes and transient elastography [values].” 
Safety data showed that patients with cirrhosis generally tolerated resmetirom well over 2 years of treatment, with diarrhea and nausea being the most common adverse events. No serious adverse events were related to resmetirom. 

While the preliminary results support the potential clinical benefit of resmetirom in MASH cirrhosis, the long-term safety and efficacy of resmetirom for this population are being evaluated in the ongoing phase 3 MAESTRO-NASH-OUTCOMES trial, which has enrolled 845 patients with MASH cirrhosis.MASH cirrhosis.