Phase 3 MAESTRO-NAFLD-1 Data for Resmetirom in MASH Cirrhosis, with Naim Alkhouri, MD

In 2024, the US Food and Drug Administration granted accelerated approval to Madrigal Pharmaceuticals’ resmetirom (Rezdiffra) for the treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) in patients with moderate to advanced fibrosis.1

However, as MASH progresses and cirrhosis develops, therapeutic options become increasingly limited, as the selective thyroid hormone receptor-β agonist is not yet approved for MASH cirrhosis. New positive 2-year results from the open-label compensated MASH cirrhosis (F4c) arm of the phase 3 MAESTRO-NAFLD-1 trial suggest a new, much-needed indication may be on its way.2

The trial included an open-label active treatment arm of patients with compensated MASH cirrhosis. After one year, patients were given the option to enroll in an open-label extension trial; 122 patients enrolled and 113 completed 2 years of treatment.2

“The most exciting finding was what we saw with changes in liver stiffness,” Naim Alkhouri, MD, Chief Academic Officer at Summit Clinical Research and the Director of the Steatotic Liver Disease Program at the Clinical Research Institute of Ohio, explained to HCPLive. “After 2 years of treatment, we show reduction in liver stiffness measurement with FibroScan by 6.7 kilopascals. In my mind, this is very clinically meaningful, because if you reduce your liver stiffness by 25% or more from baseline, this has been shown to predict less progression to liver outcomes, and we were able to do this in over 50% of patients after 2 years of treatment.”

Further analysis revealed patients achieved significant improvements from baseline in liver fat, fibrosis biomarkers, liver volume, and risk scores for clinically significant portal hypertension (CSPH).2

At baseline, 35% of patients met Baveno criteria for CSPH, 14% for probable CSPH and 51% for no/low CSPH. Among those with CSPH at baseline, 65% moved into lower risk categories by year 2, including 42% to no/low CSPH and 23% to probable CSPH. Among patients with probable CSPH at baseline, 57% moved into the no/low CSPH category as compared to 14% who moved into the CSPH category by year 2.2

Of note, similar shifts to lower risk categories were observed in an analysis using a more stringent modified Baveno criteria that incorporates magnetic resonance elastography and the Enhanced Liver Fibrosis test as additional evidence for CSPH risk.2

“Overall, we're very pleased with the results of this open label extension trial, and I hope that this will be solidified when we see the results of the MAESTRO NASH OUTCOMES phase 3 trial. This is fully enrolled, and we expect the results hopefully by the end of 2027,” Alkhouri said.

Editors’ note: Alkhouri has relevant disclosures with Altimmune, Chronwell, Cytodyne, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Rivus, Takeda, and Terns.

References

1. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed June 4, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

2. Madrigal Pharmaceuticals. Madrigal Announces New Clinical Data Demonstrating Rezdiffra™ (resmetirom) Significantly Improved Multiple Noninvasive Tests and Portal Hypertension Risk in Patients with Compensated MASH Cirrhosis. May 10, 2025. Accessed June 4, 2025. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-announces-new-clinical-data-demonstrating-rezdiffratm