Two-Year Time Course of Biomarker and Imaging Responses in Patients With Well-Compensated MASH Cirrhosis Treated With Resmetirom

The thyroid hormone receptor b (THR-b) agonist resmetirom has been approved by the US Food and Drug Administration (FDA) for adults with metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver scarring without cirrhosis. There are currently no FDA-approved therapies for MASH with compensated cirrhosis, and stage F4 fibrosis is associated with an increased risk of adverse outcomes, including liver-related complications, need for transplantation, and death.¹

Through its binding to THR-b, resmetirom may affect multiple biologic processes in the liver, regulating gene expression, reducing inflammation, indirectly blocking stellate cell activation, and reducing fibrosis production.² Alkhouri and colleagues presented results from the MAESTRO-NAFLD-1 trial evaluating the safety and efficacy of resmetirom in an open-label cohort of patients with well compensated MASH cirrhosis (Child-Pugh A).³ Patients were required to have at least 3 metabolic risk factors and a platelet count of 70,000/mL or higher.

Patients in the cohort received resmetirom 80 mg for 52 weeks. After a variable gap off treatment ranging from 1 month to 1 year (median treatment gap, 77 days), patients could enter a 1-year open-label extension (OLE). Of the 161 patients who completed 52 weeks of treatment, 122 enrolled in the OLE and 113 completed the 2-year study.

Outcomes were presented based on baseline platelet count of 100,000/mL or higher (n=92; high-platelet group) or less than 100,000/mL (n=30; low-platelet group). Median spleen volume was substantially higher in the low-platelet group than the high-platelet group (906.5 mL vs 424.7 mL), which the investigators noted was attributed to advanced portal hypertension. Conversely, multiple measures of fibrosis and liver stiffness were higher in the low-platelet group, including median Agile-4 (0.85 vs 0.56), magnetic resonance elastography (MRE) (5.9 vs 5.1 kPa), vibration-controlled transient elastography (VCTE) (26.4 vs 19.3 kPa), and Fibrosis-4 (3.9 vs 2.0).

In the efficacy analysis, resmetirom was associated with significant reductions in liver stiffness measurement (LSM) as assessed by VCTE after 1 year and 2 years in both groups. In the low-platelet group, the mean change from baseline was -6.2 kPa at year 1 and -7.9 kPa at year 2; in the high-platelet group, the mean changes were -6.5 kPa and -6.4 kPa, respectively (Figure 1). After 2 years, 59% of patients in the low-platelet group and 49% of patients in the high-platelet group were considered LSM responders, with a 25% change in LSM.

Figure 1.

Change from baseline in liver stiffness measurement by VCTE (FibroScan) (kPa) and in MRI-PDFF in the open-label 52-week cirrhosis arm of MAESTRO-NAFLD-1 followed by a 52-week extension trial.

kPa, kilopascal; MRI-PDFF, magnetic resonance imaging–proton density fat fraction; VCTE, vibration-controlled transient elastography.

Adapted from Alkhouri N, et al. AASLD abstract 0167. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.3

At baseline, clinically significant portal hypertension (CSPH) or probable CSPH as assessed by the Baveno CSPH risk score was present in 93% of patients with a platelet count less than 100,000/mL and 36% of patients with a platelet count 100,000/mL or higher. Resmetirom was associated with a shift to a lower CSPH risk score in approximately two-thirds of patients and to a lower Agile-4 score, indicating a lower risk of cirrhosis. During the median 77-day treatment gap between years 1 and 2, there were transient increases in magnetic resonance imaging–proton density fat fraction (MRI-PDFF), apolipoprotein B, and VCTE; however, the reintroduction of resmetirom resulted in restoration of these values to the levels observed at the end of year 1.

It was striking that resmetirom treatment shifted two-thirds of individuals with CSPH to a lower Baveno risk score. This shift is important when it comes to treating a higher risk population, and therapy was safe. A concern in patients with more advanced disease, like those with portal hypertension, is always that side effects may limit treatment. Irrespective of how fibrosis was measured, there was an improvement with resmetirom in patients with compensated cirrhosis, especially in patients at high risk for CSPH, which is exciting news for individuals with more advanced MASLD.

—Nancy S. Reau, MD

Spleen volume decreased at year 1 of resmetirom in both the low-platelet group (median change, -2.4%) and in the high-platelet group (median change, -7.7%) and increased during the treatment gap. The increase was particularly notable in the low-platelet group. During year 2, spleen volume stabilized in the low-platelet group and decreased in the high-platelet group.

There were significant improvements in multiple imaging measures after 2 years, including in MRI-PDFF, controlled attenuation parameter, and MRE, and these improvements occurred across baseline platelet count groups. Liver enzyme levels also reduced significantly with resmetirom treatment, particularly in patients with a high baseline platelet count, as did biomarkers associated with fibrosis, liver injury, and atherogenic lipids.

In the safety analysis, no serious adverse events (AEs) were study drug–related. The most common AEs were diarrhea (37.7%), COVID-19 (31.1%), nausea (31.1%), and urinary tract infection (25.4%). Over 2 years of treatment, no changes in bone mineral density or fracture risk were noted; there were 6 hepatic decompensation events, 5 of which occurred in patients with a baseline platelet count less than 100,000/mL.