FDA Approves Rezdiffra, the First Drug for Advanced Liver Disease
By April Hopcroft
The daily pill Rezdiffra is the first treatment for people with a type of liver disease known as MASH, which affects up to 20% of people with type 2 diabetes.
Rezdiffra’s FDA approval marks a historic victory as the first medication for people with moderate to advanced liver disease. In clinical trials, over 80% of participants treated with Rezdiffra halted or reversed liver scarring.
MASH, known in the medical community as metabolic dysfunction-associated steatohepatitis, is an advanced form of liver disease marked by excess fat in the liver. As the condition progresses, liver cells can become inflamed and scarred – this is known as fibrosis.
People with type 2 diabetes are at higher risk for liver disease (and vice versa). That’s because many of the underlying risk factors for both conditions are the same, including high blood pressure, high cholesterol, and overweight or obesity.
“The approval of Rezdiffra should help our field raise awareness among primary care providers, diabetologists, and endocrinologists about the need for diagnosis and treatment of these patients,” said Dr. Fernando Bril, assistant professor in the division of endocrinology, diabetes and metabolism at the University of Alabama at Birmingham who studies MASH.
Bril explained that many people with MASH may be underdiagnosed and undertreated by primary care providers. By the time patients are properly diagnosed by liver specialists, they may have developed advanced liver disease.
What is Rezdiffra?
Rezdiffra (resmetirom) is a once-daily oral medication that is approved for the treatment of adults with advanced MASH – those who also have liver scarring. Rezdiffra works by helping reduce the buildup of fat in the liver to minimize scarring and inflammation.
As noted by the CEO of Madrigal, the company that developed Rezdiffra, people prescribed the medication should expect to take it long-term until all factors contributing to MASH (such as obesity) and all signs of liver disease are gone.
Side effects of Rezdiffra
The most common side effects of Rezdiffra include:
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Diarrhea
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Nausea or vomiting
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Constipation
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Itching
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Stomach pain
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Dizziness
The medication label also contains warnings about liver injury and gallbladder-related adverse reactions.
Using Rezdiffra at the same time as statins (for lowering cholesterol) could increase the risk of side effects from statins. Your healthcare provider may lower your statin dose if you are taking both medications.
What led the FDA to approve this medication?
Rezdiffra is the first medication to have achieved both key goals in liver disease: treating MASH and improving liver scarring.
The FDA based its approval on an analysis of roughly 900 participants with MASH and liver fibrosis enrolled in the MAESTRO-NASH trial. Over 25% of participants treated with Rezdiffra experienced MASH resolution without worsening of fibrosis, compared to 10% of those on placebo.
The MAESTRO-NAFLD-1 trial provided additional safety data, showing that Rezdiffra was safe and well tolerated in participants treated for one year.
The FDA approved Rezdiffra through the accelerated approval pathway, a process that allows for earlier clearance of medications for serious conditions with unmet medical needs.
So far, Rezdiffra has been tested in two clinical trials that enrolled a total of 2,019 participants. Ongoing studies are investigating whether Rezdiffra can improve longer-term outcomes like liver transplants and the development of cirrhosis, a more advanced stage of the disease.
Why is Rezdiffra’s approval so significant?
For many decades, the only treatment available for this type of liver disease was diet and exercise. This was based on the finding that weight loss translates to reductions in liver fat, MASH, and scarring.
More recent studies have shown that GLP-1 receptor agonists can improve symptoms of MASH for those with low-level disease. For instance, 83% of participants treated with the investigational drug survodutide saw significant improvement of MASH compared to those not taking the drug. In another study, tirzepatide (marketed as Mounjaro and Zepbound) led to MASH resolution without worsening of liver scarring in adults with overweight or obesity.
However, GLP-1s do not target inflammation and scarring. Improvements in MASH were likely driven by weight loss, not a direct effect of GLP-1s. Because Rezdiffra targets the liver, it directly reduces liver fat buildup, effectively treating MASH and liver scarring.
The bottom line
Rezdiffra’s approval marks a big step forward for the treatment of liver disease related to metabolic dysfunction. Drug companies have spent decades working to develop medications for MASH and faced many setbacks. For the first time, people with moderate to advanced liver disease have a daily pill option to help resolve MASH and liver scarring.
The long-term effects of Rezdiffra on health outcomes and specific subgroups of MASH patients remain to be seen, added Bril. Healthcare providers and patients will also have to weigh the potentially steep price of Rezdiffra compared to other diabetes and obesity drugs, such as GLP-1s, which have been shown to produce somewhat similar results for MASH with additional benefits like weight loss and reduced risk of heart disease.
“Regardless of the long-term outcome of this medication, the approval of Rezdiffra should be seen as a 'hinge moment' in the history of MASH and a huge step in our fight against this public health problem,” Bril said.
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