Resmetirom Reduces Liver Stiffness in Compensated MASH Cirrhosis

Mazen Noureddin, MD, MHSc

Credit: Houston Methodist

Madrigal Pharmaceuticals has announced positive 2-year results from the open-label compensated metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis (F4c) arm of the phase 3 MAESTRO-NAFLD-1 trial of resmetirom (Rezdiffra).¹

According to a February 26, 2025, press release from the company, patients treated with resmetirom achieved marked reductions in liver stiffness, a surrogate for fibrosis, as measured by vibration-controlled transient elastography (VCTE). Of note, the data represent the largest reduction in liver stiffness reported to date in an F4c MASH population.¹

“These data demonstrating patients with compensated MASH cirrhosis achieved marked reductions in VCTE are highly encouraging. We use the ‘Baveno rule of 5 kPa’ to stratify risk of liver-related events in patients with MASH, so a mean 6.7 kPa reduction suggests that many patients are moving into a lower risk category,” Mazen Noureddin, MD, MHSc, a professor of medicine, director of Houston Research Institute, and CSO of Summit Clinical Research, commented.¹ “The results are particularly meaningful in light of recently published, multi-center, longitudinal studies demonstrating VCTE is a strong predictor of clinical outcomes and may be more predictive of clinical outcomes than fibrosis stage assessed by liver biopsy.”

In March 2024, resmetirom became the first and only US Food and Drug Administration-approved MASH therapeutic when it was granted accelerated approval in conjunction with diet and exercise for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis. The decision followed 18 clinical studies in the oral, thyroid hormone receptor (THR)-β selective agonist’s clinical development program: 12 phase 1 studies, a pair of phase 2 studies, and 4 phase 3 studies.²

At the time of resmetirom’s accelerated approval, it was noted that continued approval may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials.2 Resmetirom is not currently approved for the treatment of patients with MASH cirrhosis, although its use in this population is being explored in the phase 3 MAESTRO-NAFLD-1 trial, which included an open-label active treatment arm of patients with compensated MASH cirrhosis.¹

Following 2 years of treatment, 101 patients from this arm of MAESTRO-NAFLD-1 had VCTE results available for analysis. The mean liver stiffness at baseline was 25 kPa. Results showed patients achieved a mean 6.1 kPa reduction in liver stiffness at 1 year and a mean 6.7 kPa reduction at 2 years, which was statistically significant compared with baseline.¹

In a responder analysis examining ≥25% improvement or worsening of liver stiffness, 51% of patients achieved improvement, which has been associated with reduced progression to end-stage liver disease.¹

Investigators noted the safety and tolerability profile of resmetirom in the compensated MASH cohort of MAESTRO-NAFLD-1 was consistent with other resmetirom clinical trials, with a low rate of discontinuations due to adverse events.¹

Draft FDA guidance recommends that phase 3 clinical trials in MASH cirrhosis use outcomes as an endpoint rather than biopsy-based surrogate endpoints. This guidance, in conjunction with data from the open-label compensated MASH cirrhosis arm of MAESTRO-NAFLD-1, was used to inform the design of the ongoing phase 3 MAESTRO-NASH OUTCOMES trial.¹

“Patients with MASH who progress to cirrhosis face a 42 times higher risk of liver-related mortality, so there is an urgent need to improve care for this underserved population with no approved treatment options,” said Becky Taub, MD, chief medical officer and President of research and development at Madrigal.¹ “The new two-year data from MAESTRO-NAFLD-1 reinforce our confidence in the ongoing, fully enrolled MAESTRO-NASH OUTCOMES trial of Rezdiffra in patients with compensated MASH cirrhosis. If our OUTCOMES trial is successful, Rezdiffra has the potential to become the first therapy for F2-F4c MASH.”

In the press release, Madrigal detailed plans to present additional results from the compensated MASH cirrhosis arm of the MAESTRO-NAFLD-1 trial at a future medical conference.¹

References

1. Magrigal Pharmaceuticals. Madrigal Announces New Two-Year Data from the Compensated MASH Cirrhosis Arm of the MAESTRO-NAFLD-1 Trial Demonstrating Potential Benefit of Rezdiffra™ (resmetirom) in Patients with Compensated MASH Cirrhosis. February 26, 2025. Accessed February 26, 2025. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-announces-new-two-year-data-compensated-mash-cirrhosis

2. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed February 26, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash