FDA Approves Madrigal’s Rezdiffra as First MASH Therapy

Pictured: A fatty liver over a cell/Taylor Tieden for BioSpace

This story was originally published March 14.

In one of the year’s most highly anticipated decisions, the FDA approved Madrigal Pharmaceuticals’ resmetirom Thursday as the first-ever therapy for metabolic dysfunction-associated steatohepatitis.

Resmetirom, which will be marketed as Rezdiffra, is indicated for the treatment of patients with metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis, along with diet and exercise, according to the FDA’s press release.

Speaking with BioSpace ahead of the decision, experts said the approval could signal a sea-change in the diagnosis and treatment of MASH.

Resmetirom met its two primary endpoints in the MAESTRO-NASH Phase III trial, significantly improving disease resolution and liver fibrosis. The data, published last month in The New England Journal of Medicine, show that NASH resolved in 25.9% of patients who received an 80-mg dose of resmetirom and 29.9% of those taking 100 mg, with no worsening of fibrosis. This was compared to 9.7% of patients in the placebo group.

Resmetirom targets thyroid hormone receptor beta (THR-β), which helps maintain liver homeostasis. THR-β agonists have been shown to improve lipid metabolism. “This is a huge area and affects millions of patients,” Rajarshi Banerjee, CEO of Perspectum, which supported Madrigal’s clinical trials, told BioSpace prior to the decision.

“There are no effective approved therapies, and so Madrigal’s resmetirom, even though it has limited efficacy, would be an important first.”

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), affects 5.3 out of every 1000 people worldwide, according to a 2021 article published in MDPI. In the U.S., the disease accounts for 18% of all hepatocellular carcinoma cases.

Rohan Palekar, CEO of the biotech 89bio, which is developing therapies for the treatment of liver and cardiometabolic diseases, told BioSpace that this is likely an underestimate. “Right now, if someone walks into the clinic who is obese and diabetic, physicians counsel them on diet and lifestyle but don’t necessarily work them up for MASH, because they don’t have a medication to give them,” Palekar explained. “Once we have one approved drug, I believe the diagnosis of MASH will increase.”

The same is true for the MASH precursor, fatty liver or MAFLD (metabolic dysfunction-associated fatty liver disease), he said. “There is a greater unmet need than we know.”

89bio is developing pegozafermin, which aims to prolong the biological activity of fibroblast growth factor 21 (FGF21), for MASH. FGF21 regulates multiple metabolic pathways and cellular processes. The company earlier this week initiated its Phase III clinical trial program with the ENLIGHTEN-Fibrosis study, which will evaluate pegozafermin in non-cirrhotic MASH patients with fibrosis stage F2-F3. A second trial, ENLIGHTEN-Cirrhosis, which will assess the drug in patients with compensated cirrhosis (F4), is expected to begin in the second quarter of 2024.

“We think a pretty dramatic change is on the way for the recognition and treatment of MASH,” Palekar said. “People may remember when the first lipid-lowering agents came out, it took time for awareness and education to catch up. Now everybody gets their LDL [cholesterol] checked and gets on a statin if it’s elevated.” He sees a similar trajectory for MASH and MAFLD.

Already, some of the unmet need in MASH can be met by GLP-1 anti-obesity drugs, said Mayank Mamtani, head of healthcare research at B. Riley Securities. “The unmet need is simply not the same as it was before the weight loss drugs came along,” he told BioSpace. “I would argue that the anti-obesity drugs have the same benefit as resmetirom [in MASH].” Moreover, Mamtani said, weight loss drugs such as Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound, might be less expensive. While a weight loss drug can cost $15,000 per year, Madrigal’s drug may cost between $30,000 and $40,000 annually.

Still, there are “multiple molecules out there” with potential to treat MASH specifically, Mazen Noureddin, who recently established the Houston Research Institute, told BioSpace. “I hope this will be the first in a series of approvals,” he said of resmetirom.

As more drugs hit the market, Noureddin envisions that different pharmaceuticals will be combined to treat MASH. “In a perfect world, resmetirom will be combined with other molecules, such as those targeting semaglutide,” the GLP-1 analog that forms the basis of Wegovy and Zepbound, he said. Anti-obesity drugs can be effective in earlier stages of MASLD, he added, but because some of them have “little antifibrotic effect, they will be combined with strong antifibrotics.”

Mamtani said he hopes the greenlight of resmetirom will lead the way for other approvals that act directly on fibrosis. He specifically cited pegozafermin and Akero Therapeutics’ exfruxifermin, both FGF21 analogs, as examples. “That’s the holy grail to help people who are very close to liver failure,” he said. “It will just take a lot of time and capital to generate that data.”

Ultimately, treatment of MASH may have a huge impact on patients’ health and physicians’ treatment practices because of the ways it can overlap with cardiovascular medicine, Banerjee predicted. “Liver disease can cause liver failure, but it is more likely to cause heart disease, including heart failure, atrial fibrillation and heart attacks,” he said. However, he added, “Liver disease is a modifiable cardiovascular risk factor, like high cholesterol, diabetes and smoking. It can be reversed. This is why MASH matters to cardiologists and internists, even if it is asymptomatic—treat it, and you could potentially stop heart attacks like statins do.”

One of the biggest challenges facing the MASH field is how to identify, define and measure the disease and improvements in it, including primary endpoints to be met in clinical trials. In a paper published in Nature on March 9, Noureddin and colleagues address both the challenges and opportunities in MASH diagnosis and treatment.

Currently, liver biopsy is the gold standard, but it has drawbacks. At 89bio, Palekar said, liver biopsies were performed at the start of the Phase IIb ENLIVEN 48-week clinical trial, then again at week 24. Because pathologist interpretations on the degree of fibrosis can vary, each biopsy was sent to three separate pathologists. “At least two out of three had to agree,” he explained.

Another problem with biopsies is that the liver is a large organ, Palekar noted, and a biopsy can only capture a small slice of it. In addition, “patients don’t like biopsies, and they present risks, such as bleeding.” Moreover, once medications are approved and available, liver biopsy would be impractical and too expensive for routine clinical use, Palekar said.

Currently, two large consortiums, the U.S.-based Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) and the European Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS), are working to establish noninvasive markers and clinical endpoints for MASH and non-alcoholic fatty liver disease. These can include MRI imaging to quantify the amount of fat and fibrosis in the liver, ultrasound and blood biomarkers such as liver enzyme levels. In addition, Banerjee said, Perspectum is working on a proprietary marker called cT1, which the company hopes will predict clinical outcomes even better than liver biopsy.

For now, those in the field appear to be optimistic. “2024 is going to be a happy year for MASH,” Noureddin said. “I think we’re going to see the movement to replace liver biopsy with noninvasive markers. I’m excited we are going to be able to give our patients options.”

Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at jillneimark.com.