The Food and Drug Administration (FDA) of the United States has recently granted approval for a medication aimed at treating a liver condition associated with obesity.
As reported by Nature, the drug named resmetirom has been shown to reduce fibrotic tissue in the liver as well as other features of metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD is typically linked with metabolic disturbances accompanying obesity and diabetes and can lead to liver failure or cancer in severe cases.
Liver tissue of individuals with excess fat in their organs. Image source: IKELOS GmbH
This disease is on the rise globally, estimated to affect 5% of adults worldwide, and is becoming a leading cause of liver failure and liver transplants. "We're talking about a huge population here," says Lina Lee, a hepatologist at The Ohio State University Wexner Medical Center in the USA, "and I think we've made significant strides in improving care for this group."
It's been a long road, with pharmaceutical companies striving to develop a successful treatment for MASH. Last year, Intercept Pharmaceuticals had to abandon an eagerly awaited drug, obeticholic acid, due to FDA concerns that its effectiveness did not outweigh safety risks.
"For years, many trials have failed, even those that initially looked promising," Lee remarks. "That's the tragedy we've been facing."
MASH is caused by the accumulation of toxic fat molecules in the liver. Over time, this can lead to inflammation and tissue damage. As the liver starts to accumulate scar tissue—a process known as fibrosis—its function declines. MASH, previously known as non-alcoholic steatohepatitis or NASH, was renamed last year by professional societies.
The drug boosts the liver's responsiveness to thyroid hormones, which in turn stimulate the organ's fatty acid metabolism. In a year-long multinational clinical trial involving 966 MASH patients, researchers found that 30% of participants treated with the highest dose of resmetirom showed a reduction in inflammation and fat accumulation, compared to about 10% in the placebo group. Additionally, about 26% of the former saw an improvement in fibrosis, compared to 14% improvement in the latter, making resmetirom the first MASH candidate drug to reduce fibrosis, set to be marketed as Rezdiffra.
"The effectiveness of this drug and its relatively mild side effects are exciting, indicating that we might finally have a way to treat MASH," says Maya Balakrishnan, a gastroenterologist at Baylor College of Medicine, USA. The FDA emphasizes that for the drug to remain on the market, its developers—Madrigal Pharmaceuticals in the USA—must ultimately provide long-term evidence of meaningful benefits.
"Only time will tell," Balakrishnan says. "The important question is, can this drug improve survival rates?"
Meanwhile, researchers are eagerly awaiting results for semaglutide, a popular weight-loss drug being studied for MASH. Weight loss is associated with reduced severity of MASH, but early clinical trials of semaglutide in MASH patients have had mixed results: some disease characteristics improved, but there was no improvement in liver fibrosis. Despite this, researchers like Lee hope that semaglutide will prove helpful, with larger ongoing trials expected to provide clearer outcomes.
"Resmetirom might be the best shot for MASH patients," Balakrishnan says, but doctors must be clear about the limitations of the data when discussing resmetirom with patients.
The drug's availability in other countries is still pending. "Madrigal Pharmaceuticals' clinical trials for resmetirom were primarily conducted in the USA," says Claudia Oliveira, a pathologist at the University of São Paulo, Brazil. "We haven't had the chance to see the drug's efficacy in patients in Latin America. However, we are all hopeful because the trial results are very interesting."
Norberto Chavez Tapia, a hepatologist in Mexico, predicts that resmetirom will soon be studied in clinical trials worldwide. After that, depending on the drug's cost and its impact on transplants and survival, resmetirom could become popular in many healthcare systems. "It's a very attractive drug, globally speaking," says Tapia.
