Metabolic-associated steatolic liver disease (MASLD — previously called non-alcoholic fatty liver disease) affects nearly one in three adults in the United States and worldwide. It is the fastest rising cause of liver transplantation and one of the most common causes of chronic liver disease worldwide. A subgroup of those patients has the more severe form of the disease, called metabolic steatohepatitis (MASH – previously non-alcoholic steatohepatitis), where the disease progresses faster towards end-stage liver disease including cirrhosis and liver cancer.
Until very recently, no treatment options were available for MASLD. “The cornerstone of management for MASLD had been weight loss, which is typically associated with a decrease in the level of fat deposits in the liver,” said Bubu Banini, MD, PhD, assistant professor of medicine (digestive diseases) and translational research director of the Metabolic Health and Weight Loss Program. “However, weight loss is not easy or sustainable for many patients, and they were left without any other treatment options.”
In March 2024, the Food and Drug Administration (FDA) approved resmetirom, sold under the brand name Rezdiffra™, the first therapy for MASH. The drug was approved through FDA’s accelerated approval pathway, and is intended to be used as an adjunct to diet and exercise.
“While the new proprietary drug has the potential to help many patients, there remains a need for a generic, affordable treatment option for patients with MASH,” said Banini. “The drug development process is long and expensive, involving preclinical studies and several phases of clinical study. It can take several decades and cost billions of dollars – which ultimately adds to the final price of the drug. So, even though a drug has been approved, there will be major issues of financial viability for a large percentage of the population.”
Banini was recently awarded a $3.05 million R01 grant by the National Institutes of Health (NIH) for a five-year research project to investigate the feasibility of oral digoxin as a treatment for MASH. Digoxin is a relatively inexpensive and widely available drug that is frequently used to treat patients with certain heart conditions. Banini identified digoxin as a potential therapy option after reviewing extensive preclinical work, including research by Xinshou Ouyang, PhD, assistant professor (digestive diseases) and Wajahat Mehal, MD, PhD, professor (digestive disease), that showed digoxin has the potential to decrease inflammation and fibrosis in the liver caused by both MASH and alcohol-associated liver disease.
“Digoxin has been used in a medicinal capacity for more than a century, which means we have a lot of data on its safety profile when used in the clinical arena. All of this gives us a step ahead. We don’t need to spend years and resources developing a novel agent or learning if the treatment is safe in humans,” said Banini. “This kind of research is not very attractive to industry but has the potential to make a major public health impact in the U.S. and internationally.”
Banini is developing a single-site clinical trial to determine if digoxin reduces steatosis, inflammation, and fibrosis in patients with MASH. Patients will be randomized to one of three arms: one arm will receive a dose slightly lower than the standard dose of digoxin currently used with many cardiovascular patients; a second arm will receive a substantially lower dose of digoxin; and the third arm will receive a placebo. At the end of the 24-week treatment period, patients will have a liver biopsy to assess the effect on inflammation and fibrosis. Banini also aims to conduct translational research examining patient samples to better understand how the treatment works at a molecular level.
Banini credits Yale’s academic environment and commitment to research as key to her pursuit of this field of study.
“There aren’t many places where you can get so much support, mentorship, and resources for research,” said Banini. “Having access to robust research infrastructure helps make it possible to do this kind of work.”
Since forming one of the nation’s first sections of hepatology more than 75 years ago and then gastroenterology nearly 70 years ago, Yale School of Medicine’s Section of Digestive Diseases has had an enduring impact on research and clinical care in gastrointestinal and liver disorders. To learn more about their work, visit Internal Medicine: Digestive Diseases.