Resmetirom Reduces Liver Stiffness in MASH-Compensated Cirrhosis

Patients with compensated metabolic dysfunction–associated steatohepatitis (MASH) cirrhosis who received resmetirom (Rezdiffra; Madrigal Pharmaceuticals) experienced reductions in liver stiffness in the phase 3 MAESTRO-NAFLD-1 trial (NCT04197479), according to 2-year results announced in a press release.¹

In the MAESTRO-NAFLD-1 trial, liver stiffness—a surrogate for fibrosis—was measured by vibration-controlled transient elastography (VCTE). There were 101 participants with VTCE results after 2 years of treatment in the open-label active treatment arm of patients with compensated MASH cirrhosis (stage F4c). At baseline, mean liver stiffness was 25 kPa.

At 2 years, participants in the compensated MASH cirrhosis treatment arm experienced a statistically significant reduction in liver stiffness from baseline. | Image Credit: Peakstock - stock.adobe.com

At 2 years, participants in the compensated MASH cirrhosis treatment arm experienced a statistically significant 6.7 kPa reduction in liver stiffness from baseline. At 1 year, there was a 6.1 kPa reduction in liver stiffness from baseline. Notably, these results show the largest reduction in liver stiffness reported in a population of patients with F4c MASH to date.

“These data demonstrating patients with compensated MASH cirrhosis achieved marked reductions in VCTE are highly encouraging,” Mazen Noureddin, MD, MHSc, professor of medicine and director of Houston Research Institute and chief scientific officer of Summit Clinical Research, said in a statement. “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. The results are particularly meaningful in light of recently published, multicenter, 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.”

Investigators conducted a responder analysis and found that 51% of patients experienced improvement based on a threshold of at least a 25% improvement or worsening of liver stiffness. Research has found this magnitude of liver stiffness improvement to be linked with reduced end-stage liver disease progression.² 

“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,” Becky Taub, MD, chief medical officer and president of research and development at Madrigal, said.¹ “The new 2-year data from MAESTRO-NAFLD-1 reinforce our confidence in the ongoing, fully enrolled MAESTRO-NASH OUTCOMES trial of [resmetirom] in patients with compensated MASH cirrhosis. If our OUTCOMES trial is successful, [resmetirom] has the potential to become the first therapy for F2-F4c MASH. It is important to remember that [resmetirom] should not be used for the treatment of patients with compensated MASH cirrhosis until safety and efficacy are established in our phase 3 trial and the medication receives approval for this indication from regulatory authorities.”

The main outcome measure in MAESTRO-NASH OUTCOMES (NCT05500222) is a composite end point including any event of all-cause mortality, liver transplant, ascites, hepatic encephalopathy, gastroesophageal variceal hemorrhage, and confirmed increase of Mayo End-Stage Liver Disease score from less than 12 to 15 or higher due to liver disease.³ The design of the MAESTRO-NASH OUTCOMES trial was informed by draft FDA guidance recommending the use of outcomes as an end point vs biopsy-based surrogate end points.¹

Regarding safety and tolerability, there was a low rate of discontinuation due to adverse events at 2 years in the MAESTRO-NAFLD-1 trial, which is consistent with other clinical trials examining resmetirom.

Additional results from the compensated MASH cirrhosis arm of the MAESTRO-NAFLD-1 will be presented at a future medical conference.

References

1. 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. News release. Madrigal Pharmaceuticals. 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. Lin H, Lee HW, Yip TC, et al. Vibration-controlled transient elastography ccores to predict liver-related events in steatotic liver disease. JAMA. 2024;331(15):1287-1297. doi:10.1001/jama.2024.1447

3. A phase 3 study to evaluate the effect of resmetirom on clinical outcomes in patients with well-compensated NASH cirrhosis (MAESTRO-NASH-OUTCOMES). Updated March 25, 2024. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT05500222