Drugs designed to suppress fat production in the liver could become a major new weapon against one of the world’s fastest-growing liver diseases.
Researchers at the University of California, San Diego School of Medicine reported that an experimental treatment called ION224 showed significant improvement in patients with metabolic dysfunction-associated steatohepatitis (MASH), a progressive fatty liver disease strongly associated with obesity and type 2 diabetes. This condition develops silently over many years and can then lead to cirrhosis, liver failure, or liver cancer.
The survey results are lancet This drug has attracted attention because it attacks biological pathways directly involved in liver fat accumulation. Rather than simply helping patients lose weight or manage symptoms, ION224 targets the disease process itself.
How experimental drugs work
ION224 blocks an enzyme known as DGAT2, which helps the liver produce and store fat. Scientists believe that excess fat within liver cells causes inflammation, tissue damage, and scarring over time.
“This study represents an extremely important advance in the fight against MASH,” said Rohit Loomba, MD, the study’s principal investigator and chief of the Division of Gastroenterology and Hepatology at the University of California, San Diego School of Medicine.
“By blocking DGAT2, we interrupt the disease process at its root cause and stop fat accumulation and inflammation in the liver.”
The researchers say this approach is particularly important because many of the current treatments for fatty liver disease primarily focus on weight loss. ION224 appears to improve liver health even if patients do not lose significant weight, suggesting it may eventually be used in combination with common GLP-1 weight loss drugs and other treatments.
Clinical trial results show promising improvements
The Phase IIb clinical trial enrolled 160 adults in the United States with MASH and mild-to-moderate liver fibrosis. Participants received monthly injections of various doses of ION224 or a placebo for 51 weeks.
Patients who received the highest dose showed the strongest results. Approximately 60% experienced significant improvements in liver health compared to patients treated with placebo. The researchers also reported that the drug was generally well-tolerated and there were no serious drug-related side effects.
This study is considered noteworthy because it is the first to show that blocking DGAT2 with antisense therapy can improve liver inflammation and fibrosis in MASH patients. Researchers said the treatment also avoids some side effects seen with other drugs that target liver fat production, such as dangerous triglyceride increases.
Growing global health threat
MASH, formerly called non-alcoholic steatohepatitis (NASH), is part of a broader spectrum of diseases known as metabolic dysfunction-associated fatty liver disease (MASLD). This disease is becoming increasingly common as obesity and diabetes rates continue to rise around the world.
Researchers estimate that one in four adults worldwide may have some form of fatty liver disease, and more than 100 million people in the United States have fatty liver disease. Many people are completely unaware that they have this disease because symptoms often do not appear until severe liver damage has developed.
In severe cases, liver scarring can progress to cirrhosis and liver failure, making transplantation one of the only remaining treatment options.
Why scientists are excited about DGAT2
Interest in DGAT2 is growing because this enzyme plays a key role in de novo adipogenesis, the process the body uses to produce fat in the liver. Scientists increasingly believe that this pathway is a key driver of inflammation and fibrosis in MASH.
“This is the first drug of its kind to show an actual biological effect on MASH,” Loomba said.
“If these findings are confirmed in phase III trials, we may finally be able to offer patients targeted therapies that have the potential to halt and reverse liver damage before it progresses to a life-threatening stage.”
The researchers also noted that future treatment strategies may include combination therapies that combine liver-targeted drugs like ION224 with drugs that improve weight loss, insulin resistance, or metabolic health.
what happens next
The next step will be a large-scale Phase III clinical trial aimed at confirming the drug’s safety and effectiveness in a broader patient population before regulators consider it for approval.
Study authors included Erin Morgan, Keyvan Yousefi, Dan Li, Richard Geary, and Sanjay Bhanot of Ionis Pharmaceuticals, and Naim Alkhouri of Arizona Liver Health.
Funding for the study was provided by Ionis Pharmaceuticals (ION224-CS2).
