Breakthrough Drug Targets Enzymes to Reverse Fatty Liver Damage

For millions of people worldwide, a serious condition called Metabolic dysfunction-associated Steatohepatitis, or MASH (formerly known as NASH), represents a major threat to their health.³ This advanced form of fatty liver disease is silent for years but can lead to severe scarring, liver failure, and the need for a liver transplant.⁴

Now, a new investigational drug is bringing a wave of optimism. This treatment works by directly targeting a specific enzyme in the liver to fight the disease at its very source.⁵

MASH is a progressive, life-threatening liver disease.⁶ It is part of a larger group of conditions now called Metabolic dysfunction-associated Steatotic Liver Disease (MASLD).⁷

• It is often called a “silent disease” because it can progress for years without showing any clear symptoms.⁸
• The main problem is a dangerous buildup of fat in the liver cells, which then causes inflammation and damage.⁹
• This chronic damage leads to fibrosis, which is the medical term for scar tissue in the liver.¹⁰
• Over time, fibrosis can worsen into cirrhosis, a severe form of scarring that greatly limits liver function and can lead to liver failure or cancer.¹¹
• MASH is strongly linked to other common metabolic health issues, such as obesity, high blood pressure, and type 2 diabetes.¹²
• It is a widespread global health crisis, affecting as many as 1 in 4 adults worldwide.¹³

For many years, the main way to manage MASH has been through intense lifestyle changes such as diet and exercise, to achieve significant weight loss.¹⁴ However, these changes are often not enough to halt or reverse the damage in more advanced cases, highlighting an urgent need for effective medical treatments.¹⁵

The new investigational drug, named ION224, represents an exciting step forward because it is designed to address one of the root causes of the disease.¹⁶ Instead of just treating the symptoms, this drug stops the process that creates excessive fat in the liver in the first place.¹⁷

• The Target: ION224 works by blocking a key liver enzyme called DGAT2 (Diacylglycerol O-Acyltransferase 2).¹⁸
• The Role of the Enzyme: DGAT2 is a major enzyme in the liver responsible for the production and storage of fat.¹⁹
• The Drug’s Action: By stopping or “inhibiting” DGAT2, the drug effectively puts a brake on the liver’s fat production.²⁰ This helps to reduce the harmful fat buildup that drives the disease.²¹

Dr. Rohit Loomba, the lead investigator on the Phase IIb clinical trial, noted that this drug is “the first drug of its kind to show real biological impact in MASH,” by interrupting the disease process at its root cause.²²

The positive results for ION224 came from a Phase IIb clinical trial involving adults with biopsy-confirmed MASH and early to moderate liver scarring (fibrosis).²³

• Study Size and Duration: The trial included 160 participants who received monthly injections of ION224 at various doses or a placebo over the course of one year.²⁴
• Key Finding: At the highest dose of the drug, a significant 60% of participants showed a notable improvement in their overall liver health compared to the placebo group.²⁵
• Fighting Fat and Inflammation: The drug successfully helped to reduce both the fat accumulation and the inflammation in the liver, which are the two main drivers of liver damage in MASH.²⁶
• Weight Loss Independent: Crucially, these positive effects on the liver happened regardless of whether the participants lost weight or not.²⁷ This suggests that the drug is targeting the disease directly in the liver and could be used alongside other treatments.²⁸
• Safety Profile: No serious side effects were reported that were directly linked to the drug.²⁹

If these strong results are confirmed in larger, future Phase III trials, ION224 could become a vital, targeted therapy to halt and potentially reverse liver damage before it reaches life-threatening stages.

While ION224 represents a cutting-edge, enzyme-targeting approach, the field of MASH treatment is rapidly advancing with other new therapies that target different pathways of the disease.

In a major milestone for patients, Resmetirom was the first drug to receive conditional approval from the U.S. Food and Drug Administration (FDA) for the treatment of MASH with moderate to advanced fibrosis (scarring) in non-cirrhotic adults.³¹

• Drug Type: It is a selective Thyroid Hormone Receptor-Beta (THR$\beta$) agonist.
• Mechanism: It works by activating the THR$\beta$ protein in the liver, which helps to regulate fat metabolism, reduce liver fat, decrease inflammation, and improve liver function.³²
• Clinical Impact: In clinical trials, it led to both the resolution of MASH and an improvement in liver scarring without the disease getting worse.
• Administration: It is a once-daily pill.
• Limitation: It is not currently approved for patients who already have cirrhosis (severe liver scarring).

Another class of drugs, originally developed for diabetes and weight loss, has also shown remarkable success in treating MASH.³³ These include well-known medications like semaglutide and tirzepatide.³⁴

• Drug Type: These are agonists that target receptors like Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP).³⁵
• Mechanism: These drugs help with weight loss, improve insulin sensitivity, and are also showing direct benefits in the liver by reducing fat and inflammation.
• Clinical Impact: Trials have shown high rates of MASH resolution and improvement in liver fibrosis.

Drugs that mimic natural signaling proteins in the body, such as efruxifermin (an FGF21 analog), are also showing strong results in late-stage clinical trials.³⁶

• Mechanism: These drugs help control metabolism and energy balance, leading to reduced liver fat and inflammation.
• Potential for Cirrhosis: Some studies suggest that these types of drugs may be the first to show a significant reversal of MASH-related cirrhosis itself, which would be a monumental achievement.³⁷

The emergence of these new drug classes marks the end of an era where lifestyle changes were the only viable treatment for MASH. The future of care is moving toward a more targeted, multi-drug approach.

• Targeted Therapies: The latest drugs, like ION224, Rezdiffra, and others in development, offer the ability to treat the disease at a molecular level, interrupting the damage process directly in the liver.³⁸
• Combination Treatment: Doctors expect to use combinations of drugs to tackle MASH from different angles; for example, pairing a drug that targets fat metabolism (like ION224 or Rezdiffra) with a drug that promotes weight loss (like a GLP-1 agonist).
• Focus on Early Intervention: With effective treatments becoming available, the push for earlier diagnosis and treatment for MASLD and MASH will become even more critical to prevent the progression to end-stage liver disease.³⁹

This new enzyme-targeting approach, along with other promising drugs, brings a powerful message of hope: for millions of people at risk of liver failure, the future of treatment is looking brighter than ever.