Madrigal wins FDA approval of first drug for MASH

The Food and Drug Administration has approved the first medicine for a common liver disease that’s been a top target of drugmakers over the last decade.

The drug, known as Rezdiffra and developed by biotechnology company Madrigal Pharmaceuticals, was given an accelerated clearance on Thursday for use in adults with metabolic dysfunction-associated steatohepatitis, or MASH. The approval is specifically for people with the disease and moderate to advanced liver fibrosis, alongside diet and exercise. It’ll only be upheld if the drug’s benefits are confirmed in an ongoing trial.  

In testing, treatment with Rezdiffra resolved MASH and helped improve the liver scarring that is typically associated with the condition.

“Previously, patients with [MASH] who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, the acting director of the FDA office that evaluates immunology and inflammation drugs. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.” 

The therapy’s labeling includes a safety warning for physicians to monitor for the elevation of liver enzymes or the development of liver-related side effects. The agency also recommends limiting use in cholesterol-lowering statins in people receiving Rezdiffra. The prescribing information doesn’t, however, require patients to undergo a liver biopsy before treatment, something that’s been seen as a potential barrier to use.

The approval is a turning point against a disease that, by one estimate, affects anywhere from 6 million to 8 million people. Previously known as NASH, the condition often develops alongside metabolic diseases like diabetes and obesity. It’s characterized by an accumulation of fat in the liver, causing progressive inflammation and scarring. In recent years, MASH has become one of the leading causes of liver transplants. 

For about a decade, large and small companies have targeted MASH, only to see their prospects fail in clinical testing. The first company to succeed, Intercept Pharmaceuticals, had its drug rejected twice by the FDA due to questions about its effectiveness and safety. Intercept abandoned MASH research altogether last year.

Madrigal has fared better in testing, though. Its drug activates a type of thyroid hormone that’s important to liver function but doesn’t work properly in people with MASH. Stimulating that hormone is supposed to reverse the buildup of fat and damage to the liver.

Phase 3 results published in The New England Journal of Medicine earlier this year detailed how the drug hit its two main trial goals, resolving symptoms of the disease and improving liver fibrosis without making the condition worse. Rezdiffra also lowered markers of heart disease, suggesting a broader benefit. Notably, the rate of serious adverse events was comparable among placebo and drug recipients.

The most common side effects related to treatment were diarrhea, nausea and vomiting. Rezdiffra was also associated with an increase in sex hormones, though the significance of that elevation over long-term use isn’t known.

“These results are encouraging to the field,” wrote Kenneth Cusi, a professor of medicine at the University of Florida’s endocrinology, diabetes and metabolism division, in an editorial also published in NEJM. Cusi argued the findings might even “boost guideline recommendations” for primary care physicians to screen people at high risk of developing MASH.

Still, Madrigal faces challenges, as the sales potential for MASH drugs have long been debated. The disease usually goes undiagnosed for years and some of its symptoms can be addressed with diet and exercise. 

More recently, drugmakers have pushed their new weight loss drugs into testing for MASH. Two, Eli Lilly’s Zepbound and Boehringer and Zealand Pharma’s survodutide, have delivered early study results that compare favorably to Rezdiffra and other experimental MASH medicines, pressuring the shares of Madrigal and others in the field. Additionally, a drug developed by Akero Therapeutics and currently in late-stage testing may have a more pronounced impact on liver scarring, making it a potential future threat to Rezdiffra.

In the NEJM editorial, Cusi noted that, while Rezdiffra was successful in testing, its benefit was “modest.” Most patients will need combination therapy with other drugs for obesity and Type 2 diabetes, he wrote, raising questions about who should receive Rezdiffra and for how long.

“The large number of persons needing treatment will open a debate about treatment access and about how to best monitor treatment response and when to discontinue [Rezdiffra] in patients who do not have a response in order to avoid futile long-term therapy,” Cusi wrote.

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