Rezdiffra reduces liver scarring in high-risk MASH patients: Trial data
Continuous treatment also shown to lower risk of disease progression
Long-term treatment with Rezdiffra (resmetirom) reduces liver scarring and other signs of advanced disease in adults with high-risk compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH).
That’s according to two-year data from the Phase 3 MAESTRO-NAFLD-1 clinical trial (NCT04197479), which tested Rezdiffra against a placebo in more than 1,300 adults with MASH, and its open-label extension study (NCT04951219), where all participants are receiving the therapy. High-risk compensated cirrhosis refers to irreversible liver scarring with preserved function.
“Rezdiffra reduced multiple imaging and biomarker parameters in these vulnerable patients despite their advanced state of compensated cirrhosis and a period of treatment interruption between the first and second year of treatment,” Naim Alkhouri, MD, director of the steatotic liver disease program at the Clinical Research Institute of Ohio, said in a press release from Madrigal Pharmaceuticals, the therapy’s developer.
The company presented the new findings at The Liver Meeting hosted by the American Association for the Study of Liver Diseases, which was held earlier this month in Washington, D.C.
Other trial analyses were also presented at the meeting, including data suggesting that Rezdiffra can improve life quality for MASH patients, irrespective of cirrhosis (irreversible liver scarring), and that pausing treatment can cause MASH to worsen.
“The breadth of data we are presenting at AASLD reinforces our conviction that Rezdiffra has the potential to benefit patients across the full spectrum of [liver scarring severity in] MASH,” said David Soergel, MD, chief medical officer of Madrigal.
Ongoing trial testing rezdiffra in adults with MASH and compensated cirrhosis
Rezdiffra is approved in the U.S. as a treatment for MASH patients with moderate to advanced liver scarring, or fibrosis, but no cirrhosis. The therapy is intended for use in combination with diet and exercise.
“Madrigal is determined to pioneer treatment in compensated MASH cirrhosis, and we are currently executing a fully enrolled Phase 3 outcomes study in this population,” Soergel said.
The trial, called MAESTRO-NASH OUTCOMES (NCT05500222), is testing the therapy against a placebo in about 700 adults with MASH and compensated cirrhosis. It is expected to end in early 2027.
MASH is a severe form of fatty liver disease in which the buildup of liver fat leads to liver inflammation and fibrosis. This can progress to cirrhosis and life-threatening complications like liver failure and cancer.
Rezdiffra’s approval was based in part on data from the yearlong Phase 3 MAESTRO-NAFLD-1 trial, which showed the therapy was better than a placebo at reducing liver fat in MASH patients with fibrosis but no cirrhosis. The study also included a group of MASH patients with compensated cirrhosis.
Those completing the trial had the option to continue or start Rezdiffra treatment for up to a year in the open-label extension study.
New two-year data from more than 100 participants with compensated cirrhosis showed significant reductions in liver stiffness, indicating reduced liver fibrosis. A total of 30 of these patients had low counts of platelets, or cell fragments that help blood clot, which is associated with more severe disease in this setting.
In these patients, Rezdiffra led to reductions in liver stiffness on par with what was seen in patients with higher platelet levels. Data also indicated that two-thirds of them experienced a reduction in the risk of having portal hypertension, or high blood pressure in the main vessel that delivers blood to the liver. Portal hypertension increases the risk of progression to decompensated cirrhosis, where the liver can no longer work properly.
“Patients with [low platelet counts] have been excluded from other trials in [MASH with compensated cirrhosis], so these new data from MAESTRO-NAFLD-1 offer unique insights about a population that is on the cusp of progressing to liver decompensation events,” Alkhouri said.
Analysis shows sustained gains in health-related quality of life after treatment
An analysis of pooled data from more than 1,300 MASH patients across the MAESTRO-NAFLD clinical program showed significant and sustained gains in health-related quality of life after Rezdiffra treatment, irrespective of whether patients had compensated cirrhosis.
Madrigal also presented data from the more than 500 participants who had a gap between the first and second year of treatment while transitioning from MAESTRO-NAFLD-1 to its extension study.
During this gap, which lasted a mean of more than three months, patients tended to experience signs of disease progression, such as increases in liver damage markers and liver stiffness. Once patients resumed Rezdiffra treatment, these signs of progression generally reversed.
These data … help answer an important question that many clinicians and patients ask about pausing treatment after a positive early treatment response to Rezdiffra. We now have compelling evidence that continuous treatment with Rezdiffra maintained benefit and prevented progression; stopping therapy at one year resulted in an immediate return of disease activity in this analysis.
Liver health markers remained stable over time in Rezdiffra-treated patients who successfully transitioned to the extension study without a treatment gap. In patients who were originally on the placebo, liver health markers improved after starting Rezdiffra in the extension study.
“These data … help answer an important question that many clinicians and patients ask about pausing treatment after a positive early treatment response to Rezdiffra,” Soergel said. “We now have compelling evidence that continuous treatment with Rezdiffra maintained benefit and prevented progression; stopping therapy at one year resulted in an immediate return of disease activity in this analysis. In most cases, patients with MASH will require continuous treatment, similar to other chronic diseases like diabetes.”
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