The FDA approved the first drug to treat a severe form of liver disease earlier this year, which was developed through research conducted by a Duke professor.
The drug, resmetirom, is a novel treatment for metabolic dysfunction-associated steatohepatitis (MASH), a common nonalcoholic liver disease linked to obesity that causes damaging fat buildup in the liver. MASH is estimated to affect 115 million people worldwide.
Paul Yen, professor at the Duke-NUS Medical School and professor of medicine at the Duke School of Medicine, led research that aided in the development of the treatment.
According to Yen, severe MASH usually leads to cirrhosis and subsequent liver transplant, as well as severe cardiovascular and kidney disease. He added that these issues are all also driven by obesity and diabetes, falling under the “metabolic syndrome” umbrella.
When Yen joined Duke at the National University of Singapore in 2009, he hoped to pursue work in metabolism research and build on his existing work in thyroid hormone research.
“In 2010 I went to … the International Thyroid Congress in Paris, and there was a speaker there that talked about looking at patients that were really severely obese,” Yen said. “They also had some liver biopsies done. What was very interesting was these people had fatty liver disease.”
By conducting microarray studies, which allow for simultaneous analysis of thousands of genes, the researchers discovered that a thyroid hormone gene appeared to be the most changed in fatty liver disease patients.
In addition, Yen found through his group’s research that autophagy — a cellular process critical for fat breakdown in the liver — was stimulated by thyroxine and triiodothyronine, the two main hormones produced by the thyroid. Together with Christopher Newgard, W. David and Sarah W. Stedman distinguished professor of nutrition in the School of Medicine, Yen found that the thyroid hormones did drive an increase in autophagy in the liver.
Moreover, collaboration with Newgard revealed that the thyroid hormones were actually defective in patients with nonalcoholic liver disease.
Newgard stated that Yen’s discovery of fatty acid degradation by thyroid hormone mimetics was critical to combatting MASH and other connected liver disorders, which he considers a “pandemic in modern society.”
Yen continued to use thyroid hormones in models of MASH to conduct early clinical trials, and pharmaceutical companies eventually picked up on his work. One particular company, Madrigal Pharmaceuticals, ended up developing resmetirom — an oral drug based on Yen’s thyroid mimetic that goes directly to the liver.
“From a health economic perspective, if people are not treated, the country will have a big health burden because a lot of people end up with end-stage liver disease or heart problems [or] kidney problems,” Yen said. “If we can attack the disease earlier, maybe we can prevent people getting more severe disease, and then that will actually alleviate some of the health burdens.”
Yen did qualify that only 30% of trial participants benefited from the treatment after one year, adding that it costs around $50,000 a year. Still, he believes continued research will expand the number of drugs and treatments available for the disease, lowering costs and offering patients more options for treatment.
Yen noted that an interest in MASH has been on the rise in endocrinology.
“I would say, five years ago, if we went to the Endocrine Society, we might be one of two people that even had anything related to MASH,” he said. “At the last meeting I went to, there were five symposia dedicated to this topic.”
Yen believes resmetirom and its analogs will come to the market and work concurrently to “other types of pharmacological therapies.”
He acknowledged that further work is still necessary to analyze the benefits of the drug at different stages of disease, but expressed a personal satisfaction that his research has contributed to a critical step forward in combating MASH.
“We understand the disease, we understand the consequences of the disease on people's lives, and then to realize that something that we're doing actually is part of the whole process that can lead to a therapy — it’s a very satisfying feeling that you can have from doing medical research,” Yen said.
Get The Chronicle straight to your inbox
Signup for our weekly newsletter. Cancel at any time.
Ahilan Eraniyan is a Trinity sophomore and a staff reporter for the news department.