Resmetirom’s Potential Role in MASH Cirrhosis, With Naim Alkhouri, MD

Just a few years ago, there were no US Food and Drug Administration (FDA)-approved pharmacologic treatments for metabolic dysfunction-associated steatohepatitis (MASH), leaving patients and clinicians to rely solely on lifestyle changes with diet and exercise for disease management. Recently, the field has seen unprecedented progress in the form of 2 FDA-approved treatments, resmetirom (Rezdiffra) and semaglutide (Wegovy), and the success of several other agents in clinical development.

“The data have been very encouraging, and I think these medications have the potential to change the natural history of this disease and prevent the development of major adverse liver outcomes,” Naim Alkhouri, MD, chief academic officer of Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology, explained to HCPLive, describing 2025 as having been “a good year for patients living with MASH.”

Despite the therapeutic progress seen in MASH for patients with moderate to advanced fibrosis, a major unmet need remains for patients with cirrhotic MASH, as neither resmetirom or semaglutide are currently indicated for use in this patient population.

New data presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 assessed resmetirom’s use in a cohort of patients with compensated MASH cirrhosis. Specifically, a total of 122 patients with Child Pugh A MASH cirrhosis, defined based on MASH F4 on historic biopsy >66% or clinical diagnosis, were treated with 80 mg resmetirom for up to 2 years in MAETRO-NAFLD-1 and its open-label extension.

Of note, patients experienced a mean gap of 77 (58) days in resmetirom treatment between years 1 and 2. Investigators analyzed non-invasive biomarkers and imaging at baseline and out to 2 years to assess durability of responses and the impact of treatment interruption.

Among the cohort, the mean age was 61.3 (9.1) years, 56% of patients were female, and 27% were Hispanic. The median VCTE was 20.1 (interquartile range [IQR], 17.1 to 31.3)kPa, ELF was 10.7 (IQR, 10.0-11.5), and MRI-PDFF was 8.6% (IQR, 6.0% to 11.5%). Clinically significant portal hypertension or probable clinically significant portal hypertension was predicted in 49%, 93% with platelets(PLT)<100k; 35%, PLT≥100K. Spleen volume in patients with PLT count <100k (n = 30) and ≥100k (n = 92) were 867 (319) and 487 (220), respectively.

Results showed treatment interruption after year 1 resulted in loss of resmetirom biomarker effects including lipids, MRI-PDFF, VCTE, adiponectin and spleen volume. Treatment with resmetirom restored year 1 biomarker effects except in some with baseline PLT<100K. Of 6 total decompensation events, 5 occurred in patients with PLT<100K and elevated spleen volume.

“This speaks to the fact that when we achieve response to resmetirom, continuation of treatment is key in this very advanced population with cirrhosis,” Alkhouri explained.

Resmetirom effects at year 2 compared to baseline included the following in patients with PLT count <100K and ≥100k, respectively:

• VCTE: -7.9 (95% CI, -14.1 to -1.8) and -6.4 (95% CI, -8.7 to -4.0) kPa
• ALT: 6%(95% CI, -11% to 23%) and -25%(95% CI, -32% to -19%)
• AST: 31% (95% CI, 8% to 54%) and -18% (95% CI, -25% to -11%)
• GGT: -19% (95% CI, -39% to 0) and -40% (95% CI, -47% to -33%) (baseline ALT ≥ 30 IU/L)
• LDL: -9% (95% CI, -19% to 1%) and -17% (95% CI, -23% to -12%)
• ApoB: -12% (95% CI, -19% to -6%) and -22% (95% CI, -25% to -18%)
• TGs: -13% (95% CI, -35% to 9%) and -20% (95% CI, -27% to -14%)
• Adiponectin: 63% (95% CI, 31% to 94%) and 36% (95% CI, 26% to 46%)
• Spleen volume: 5% (95% CI, 1% to 9%) and -6% (95% CI, -9% to -2%).

Investigators additionally noted high Agile shifted to lower Agile (35%) and clinically significant portal hypertension shifted to a lower clinically significant portal hypertension risk score in 65%. The treatment discontinuation rate was 8%, with mild gastrointestinal disorders being the most common adverse events.

Editors’ note: Alkhouri reports relevant disclosures with Altimmune, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Rivus, Takeda, and others.

References

1. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 13, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

2. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed November 13, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash

3. Alkhouri N, Taub R, Lu X, et al. Two-year time course of biomarker and imaging responses in well-compensated MASH cirrhosis patients treated with resmetirom. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.