For years, the management of liver fibrosis centered on addressing the underlying causes, such as viral hepatitis, alcohol abuse, or non-alcoholic fatty liver disease (NAFLD). With the rise of the obesity and diabetes epidemics, NAFLD's more severe form, MASH (metabolic dysfunction-associated steatohepatitis), has become a leading cause of liver damage. The recent approval of the first-ever medications specifically targeting MASH-related fibrosis represents a new era for patients. These breakthroughs offer the first pharmacological options to potentially reverse or halt the progression of liver scarring, a condition that can otherwise lead to cirrhosis, liver failure, and liver cancer.
Resmetirom (Rezdiffra): The First-of-its-Kind Approval
In March 2024, the FDA granted accelerated approval to resmetirom (Rezdiffra™) for treating adults with noncirrhotic MASH and moderate to advanced liver fibrosis (stage 2 or 3). This makes Rezdiffra a "first-in-class" therapy for this specific condition.
Mechanism of Action
Rezdiffra is a selective thyroid hormone receptor-beta (THR-β) agonist, primarily acting in the liver to regulate lipid and energy metabolism. By activating THR-β receptors, Rezdiffra aims to reduce liver fat, inflammation, and scarring.
Clinical Efficacy and Safety
The FDA approval was based on the Phase III MAESTRO-NASH trial. After one year, Rezdiffra showed improvement in MASH and fibrosis compared to placebo. Common side effects include diarrhea and nausea, and it's not for those with decompensated cirrhosis. Ongoing studies are required due to the accelerated approval.
Semaglutide (Wegovy): A New Indication for a Familiar Drug
In August 2025, Wegovy (semaglutide) also received FDA approval for treating MASH with moderate-to-advanced fibrosis in adults. This GLP-1 receptor agonist, known for diabetes and weight management, shows promise for liver health.
Mechanism of Action
Semaglutide improves metabolic health through glycemic control, appetite reduction, and weight loss, which indirectly benefits the liver by reducing inflammation and scarring.
Clinical Efficacy and Safety
An interim analysis of a Phase III trial supported Wegovy's approval, showing improvements in MASH resolution and liver scarring compared to placebo. Common side effects are gastrointestinal. Accelerated approval requires further clinical outcome confirmation.
Standard of Care vs. Emerging Pharmacotherapies
Historically, liver fibrosis treatment focused on managing the underlying cause.
Standard Lifestyle and Etiology Management
Key strategies include weight loss, alcohol abstinence (for alcohol-related disease), antiviral treatment (for viral hepatitis), and managing comorbidities like diabetes.
The Rise of Targeted Therapies
Rezdiffra and Wegovy offer targeted treatment for MASH-related fibrosis, complementing lifestyle changes.
Comparison of Recent MASH Approvals
| Feature | Resmetirom (Rezdiffra) | Semaglutide (Wegovy) |
|---|---|---|
| Mechanism of Action | Selective THR-β agonist targeting liver fat metabolism. | GLP-1 receptor agonist affecting appetite, weight, and metabolic health. |
| FDA Approval | Accelerated approval in March 2024 for noncirrhotic MASH with F2/F3 fibrosis. | Accelerated approval in August 2025 for MASH with moderate-to-advanced fibrosis. |
| Target Population | Adults with noncirrhotic MASH and moderate to advanced fibrosis. | Adults with MASH and moderate-to-advanced fibrosis. |
| Common Side Effects | Nausea, diarrhea. | Nausea, vomiting, diarrhea, constipation. |
| Administration | Once-daily oral pill. | Once-weekly subcutaneous injection. |
Promising Treatments in Clinical Trials
The development pipeline for liver fibrosis treatments is active. Several candidates are in clinical trials:
- FGF21 Analogs: Mimic FGF21 hormone to regulate metabolism. Efruxifermin and pegozafermin are in Phase III for MASH fibrosis.
- Dual Agonists: Survodutide (GLP-1/glucagon agonist) is in Phase III for MASH with fibrosis, combining metabolic and liver effects.
- Cell Therapies: Investigating engineered macrophages for advanced cirrhosis.
- Other Approaches: Epigenetic modulators (like BRD4 inhibitors) and targeted delivery systems are also being explored.
Conclusion: A New Era for Liver Fibrosis Treatment
The approvals of Rezdiffra and Wegovy mark a significant advance for MASH-related liver fibrosis, providing the first drug options to target inflammation and scarring. While lifestyle changes remain vital, these medications offer a crucial pharmacological intervention. The ongoing research into other therapies indicates a promising future for better outcomes and potentially reducing the need for liver transplantation.
Visit the official Rezdiffra website for more detailed prescribing information.
