Novo Nordisk's Phase 3 ESSENCE trial has revealed promising results for semaglutide 2.4 mg in treating metabolic dysfunction-associated steatohepatitis (MASH). The trial demonstrated statistically significant and superior improvements in liver fibrosis and resolution of steatohepatitis compared to placebo. These findings, presented at The Liver Meeting® during the 75th American Association for the Study of Liver Diseases (AASLD), suggest that semaglutide 2.4 mg could become a valuable therapeutic option for patients with MASH.
Primary Endpoint Achievement
The ESSENCE trial met both its primary endpoints. Specifically, 62.9% of participants treated with semaglutide 2.4 mg achieved resolution of steatohepatitis without worsening of liver fibrosis, compared to only 34.1% in the placebo group. Furthermore, 37.0% of those on semaglutide 2.4 mg experienced improvements in liver fibrosis without worsening of steatohepatitis, versus 22.5% on placebo. These results indicate a significant impact on both key histological features of MASH.
Secondary Endpoint Success
Beyond the primary endpoints, the trial also showed positive results in several supportive secondary endpoints. These included improvements in liver enzymes such as alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyl transferase (GGT), as well as the Enhanced Liver Fibrosis (ELF) test. Overall, 32.8% of patients treated with semaglutide 2.4 mg achieved both resolution of steatohepatitis and improvements in liver fibrosis, compared to 16.2% of patients on placebo.
Expert Commentary
"These initial data shared at The Liver Meeting® demonstrated that semaglutide 2.4 mg slowed MASH progression and reversed existing liver damage," said Arun Sanyal, MD, principal investigator of the study, and Director, Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University. "The ESSENCE data may represent key findings for patients in the treatment of MASH, which is estimated to affect about one in 20 adults in the US."
Trial Design and Patient Population
The ESSENCE trial is a Phase 3 study involving adults with MASH and moderate to advanced liver fibrosis (stage 2 or 3). Participants were randomized in a 2:1 ratio to receive either semaglutide 2.4 mg or placebo, in addition to standard of care, for 240 weeks. Part 1 of the trial, which provided the data presented at AASLD, focused on demonstrating improvements in liver histology at 72 weeks based on biopsy samples from the first 800 randomized patients. Part 2 aims to assess the impact of semaglutide 2.4 mg on reducing the risk of liver-related clinical events compared to placebo over 240 weeks.
MASH Disease Burden
MASH affects approximately one in 20 adults in the United States, with about 20% of cases progressing to cirrhosis. It is a leading cause of cirrhosis in adults in the US and the second most common indication for liver transplants in the country. The lack of specific symptoms in the early stages often leads to delayed diagnosis, highlighting the need for effective treatments to prevent disease progression.
Regulatory Plans
Semaglutide 2.4 mg is currently not approved in the US for the treatment of MASH. However, Novo Nordisk anticipates filing for regulatory approvals in the US in the first half of 2025, potentially bringing a new therapeutic option to patients suffering from this chronic liver disease.
