Rezdiffra reduces scarring in MASH with compensated cirrhosis: Trial
Two years of treatment cut liver stiffness by 25% or more for 51% of patients
Long-term treatment with Rezdiffra (resmetirom) reduces liver scarring for most people with compensated cirrhosis, or irreversible scarring in a still-functioning liver, due to metabolic dysfunction-associated steatohepatitis (MASH).
That’s according to two-year data from the Phase 3 MAESTRO-NAFLD-1 clinical trial (NCT04197479) recently announced by the therapy’s developer, Madrigal Pharmaceuticals.
“We’re sharing new two-year analyses from an active-treatment open-label extension arm of our Phase 3 … trial that demonstrate Rezdiffra continues to improve key markers of MASH fibrosis [scarring] out to two years in patients with compensated MASH cirrhosis,” Bill Sibold, CEO of Madrigal, said in a company press release.
These findings “add to the growing body of evidence supporting Rezdiffra’s potential benefit in this high-risk patient population, for which there is no approved therapy,” Sibold added.
In cirrhosis, fat buildup in the liver causes irreversible scarring
Madrigal plans to present these and additional trial data from this patient group at a future medical meeting.
MASH, formerly known as nonalcoholic steatohepatitis or NASH, is a form of fatty liver disease in which the buildup of fat in the liver leads to scarring. In some cases, this can progress to cirrhosis, where scarring becomes irreversible.
In people with compensated cirrhosis, the scarring doesn’t stop the liver from working, but the condition can easily progress to decompensated cirrhosis, where the liver can no longer function and a liver transplant is the only viable disease treatment.
A once-daily oral therapy, Rezdiffra works to activate thyroid hormone receptor beta (THR-beta), a protein whose reduced activity has been linked with liver scarring in MASH.
Rezdiffra is approved in the U.S., in combination with diet and exercise, to treat MASH patients with moderate to advanced liver fibrosis but no cirrhosis. It is currently the only approved treatment for this patient population.
The decision was given under the accelerated approval pathway of the U.S. Food and Drug Administration (FDA), which allows promising therapies to be marketed based on early clinical evidence of likely effectiveness. To gain full approval, drug developers have to conduct further testing to prove the therapy provides clinical benefits as expected.
Its accelerated approval was partly based on data from the Phase 3 MAESTRO-NAFLD-1 study, which tested the therapy against a placebo in 972 adults with presumed MASH. One-year trial data showed that the therapy was generally safe, and its use resulted in significant and clinically relevant reductions in liver fat relative to a placebo.
Rezdiffra being evaluated in large MASH group with compensated cirrhosis
MAESTRO-NAFLD-1 includes an open-label extension group of patients with compensated cirrhosis who are being treated with Rezdiffra for a long period. Newly announced data cover outcomes in 101 of these adults.
After two years of daily treatment, significant reductions in average liver stiffness relative to the study’s start were reported. Because scar tissue is stiffer than healthy tissue, a reduction in liver stiffness implies that there’s less fibrosis.
According to Madrigal, 51% of the patients experienced a liver stiffness reduction of at least 25% — a magnitude of reduction that’s been linked to a lower likelihood of progressing to liver failure.
Long-term safety data were consistent with findings from other Rezdiffra trials, the company added, with a low rate of treatment discontinuation due to adverse events.
Madrigal is running a Phase 3 trial called MAESTRO-NASH OUTCOMES (NCT05500222) that is evaluating the effects of Rezdiffra against a placebo on liver decompensation events in up to 700 MASH patients with compensated cirrhosis.
If top-line trial data, expected in 2027, are positive, the company hopes to use these findings as a basis to apply for an expansion of Rezdiffra’s label to cover MASH patients with compensated cirrhosis.
“A positive read out in our fully enrolled Phase 3 MAESTRO-NASH OUTCOMES trial could make Rezdiffra the first and only treatment for F2 to F4c [moderate liver fibrosis to compensated cirrhosis] MASH, and the only therapy with outcomes data this decade,” Sibold said.
According to Madrigal, nearly 12,000 people in the U.S. were taking Rezdiffra by the end of 2024.
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