The U.S. Food and Drug Administration (FDA) has recently approved a groundbreaking drug for treating a liver disease associated with obesity.
As reported by Nature, the drug named resmetirom has been shown to reduce fibrotic tissue in the liver and other features of metabolic dysfunction associated with nonalcoholic steatohepatitis (NASH). NASH is typically linked to metabolic disturbances accompanying obesity and diabetes, and in severe cases can lead to liver failure or cancer.
Liver tissue of individuals with excess fat in organs. Image source: IKELOS GmbH
This condition is on the rise globally, estimated to affect 5% of adults worldwide, emerging as a primary cause of liver function failure and liver transplantation. "It's a massive cohort," said Dr. Lina Li, a hepatologist at the Wexner Medical Center of Ohio State University. "I think we've taken a big step forward in improving care for this population."
This step has been a long time coming, with pharmaceutical companies striving to develop a successful treatment for MASH. Last year, U.S.-based Intercept Pharmaceuticals abandoned a highly anticipated drug—obeticholic acid—due to concerns from the FDA about the drug's efficacy not outweighing safety risks.
"For years, many trials have failed, even those that initially seemed promising," Dr. Li said. "It's been a tragic journey we've been through."
MASH, characterized by the accumulation of toxic fat molecules in the liver, leads to inflammation and tissue damage over time. As the liver begins to accumulate scar tissue—a process known as fibrosis—its function declines. MASH was formerly known as non-alcoholic fatty liver disease or NASH until a new naming convention was adopted by professional associations last year.
The drug works by enhancing the liver's response to thyroid hormones, which in turn stimulates the organ's fatty acid metabolism. In a year-long multinational clinical trial involving 966 MASH patients, researchers found that participants receiving the highest dose of resmetirom experienced a 30% reduction in inflammation and fat accumulation, compared to around 10% in the placebo group. Additionally, the former showed an improvement rate of approximately 26% in fibrosis, compared to 14% in the latter, making resmetirom the first candidate drug to reduce fibrosis in MASH, to be marketed under the name Rezdiffra.
"The efficacy of this drug along with its relatively mild side effects is exciting, indicating that we may finally be on track to finding a treatment for MASH," said Dr. Maya Balakrishnan, a gastroenterologist at Baylor College of Medicine. The FDA, however, emphasized that to keep the drug on the market, its developer—U.S.-based Madrigal Pharmaceuticals—ultimately needs to provide long-term evidence demonstrating meaningful benefits.
"Only time will tell," Balakrishnan said. "The key question is whether this drug improves survival rates."
Meanwhile, researchers are eagerly awaiting the results of studies on semaglutide, a popular weight loss drug being investigated for MASH. Weight loss has been associated with a reduction in the severity of MASH, but the results of early clinical trials of semaglutide in MASH patients have been mixed: some features of the disease improved, but liver fibrosis did not. Dr. Li said that despite this, researchers remain hopeful that semaglutide could be helpful, with ongoing larger-scale trials expected to provide clearer results.
Resmetirom may emerge as the top choice for MASH patients, Balakrishnan said, but doctors must be clear about the limitations of data when discussing resmetirom with patients.
Access to the drug in other countries is still pending. Dr. Claudia Oliveira, a pathologist at the University of São Paulo in Brazil, noted that clinical trials of resmetirom by Madrigal Pharmaceuticals have been mainly focused in the U.S. "We haven't had the opportunity to see the efficacy of this drug in Latin American patients," she said. "But we all hold hope for this drug because the trial results are very interesting."
Dr. Norberto Chavez Tapia, a hepatologist in Mexico, predicts that resmetirom will soon be studied in clinical trials worldwide. Following that, depending on the drug's price and its impact on transplantation and survival, resmetirom may become popular in many healthcare systems. "It's a very attractive drug, globally," Tapia said.
