Advancement in Metabolic dysfunction-Associated SteatoHepatitis (MASH) treatment: the first FDA approved drug

The FDA approves Madrigal Pharmaceuticals’ Rezdiffra for Metabolic dysfunction-Associated SteatoHepatitis (MASH), previously known as NASH, marking a milestone in treating fatty liver disease. Rezdiffra targets lipid metabolism and shows promising results in clinical trials.

The first line treatment for fatty liver disease due to Metabolic dysfunction-Associated SteatoHepatitis (MASH) has been approved by the US Food and Drug Administration. Rezdiffra (Resmetirom) by Madrigal Pharmaceuticals gained accelerated approval to address the disease, formerly referred to as non-alcoholic steatohepatitis (NASH). MASH is characterized by progressive liver deterioration resulting from fat accumulation, inflammation, and cellular harm, leading to fibrosis and eventual cirrhosis. Prior to this approval, challenges in drug discovery stemmed from the intricate pathophysiology of the disease and the necessity for long-term safety assurance. Rezdiffra, an oral thyroid hormone receptor-β (THR-β) agonist, enhances lipid metabolism and mitochondrial activity in liver cells.

The FDA’s decision relied partly on a phase 3 trial published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa2309000). Biopsy analysis of over 900 individuals revealed that after 12 months of treatment, the 25% of patients presented reduction in both lipids accumulation and inflammation without worsening fibrosis, in contrast to around 10% on placebo. Additionally, approximately 25% of patients experienced fibrosis improvement without making fatty liver symptoms worse, compared to 14% in the placebo group. Rezdiffra also demonstrated enhancements in low-density lipoprotein cholesterol levels.

Ongoing clinical trials for MASH are exploring various candidates with distinct mechanisms of action, such as survodutide, a peptide agent by Boehringer Ingelheim and Zealand Pharma targeting dual glucagon and glucagon-like peptide 1 receptors. Recent phase 2 outcomes indicated that the drug eradicated liver disease in 83% of patients versus 18% in the placebo group, hinting at potential advancements in MASH treatments.

In conclusion, the approval of Rezdiffra marks a significant milestone in the treatment of Metabolic dysfunction-Associated SteatoHepatitis (MASH), offering hope to patients with this severe progressive liver condition. Additional clinical trials for MASH investigate various candidates with distinct modes of action, such as Survodutide, a dual agonist targeting glucagon and glucagon-like peptide 1 receptors, developed by Boehringer Ingelheim and Zealand Pharma. Recent findings from phase 2 trials indicated an 83% clearance rate of liver disease with the drug, compared to 18% in the placebo group, suggesting the potential emergence of more effective MASH treatments. These promising results underscore the importance of continued research and development efforts in the field of metabolic liver diseases. Furthermore, ongoing exploration into novel therapeutic approaches, coupled with advancements in understanding the underlying mechanisms of MASH, offers hope for improved patient outcomes in the future.

By Gabriele Imperato, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan.