ESSENCE: Semaglutide Improves Fibrosis, Resolves Steatohepatitis in MASH

Martin Holst Lange, MD, PhD

Credit: Novo Nordisk

Novo Nordisk has announced headline results from the first part of the ongoing phase 3 ESSENCE trial of once-weekly subcutaneous semaglutide 2.4 mg in adults with metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis.¹

According to a press release from Novo Nordisk, the trial achieved its primary endpoints by demonstrating a statistically significant and superior improvement in liver fibrosis with no worsening of steatohepatitis, as well as resolution of steatohepatitis with no worsening of liver fibrosis with semaglutide 2.4 mg compared with placebo.¹

“We are very pleased about the ESSENCE clinical trial results and the potential of semaglutide to help people living with MASH” Martin Holst Lange, MD, PhD, executive vice president and head of development at Novo Nordisk, said in a press release.¹ “Among people with overweight or obesity, 1 in 3 live with MASH. This has a serious impact on their health and represents a significant unmet need.”

A GLP-1 receptor agonist, once-weekly subcutaneous semaglutide 2.4 mg is currently indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults with obesity and overweight as well as pediatric patients ≥ 12 years of age with obesity.¹

Prior to the FDA approval of resmetirom (Rezdiffra) as the first pharmacologic treatment for MASH, weight loss served as a cornerstone of disease management. At the time of the thyroid hormone receptor (THR)-β selective agonist’s accelerated approval, the benefit of GLP-1 RAs on fibrosis had not yet been proven, limiting their utility in MASH now that a liver-directed therapy had become available.²

ESSENCE is a 2-part phase 3 trial evaluating the effect of once-weekly subcutaneous semaglutide 2.4 mg in 1200 planned adult participants with MASH and moderate to advanced fibrosis who were randomly assigned in a 2:1 ratio to receive semaglutide 2.4 mg or placebo in addition to standard of care for 240 weeks. In part 1, the objective was to demonstrate the beneficial impact of treatment with semaglutide 2.4 mg on liver histology at 72 weeks based on biopsy sampling from the first 800 randomized patients. In part 2, the objective is to demonstrate treatment with semaglutide 2.4 mg reduces the risk of liver-related clinical events compared to placebo at 240 weeks.¹

Headline results from part 1 showed that at week 72, 37% of people treated with semaglutide 2.4 mg achieved improvement in liver fibrosis with no worsening of steatohepatitis compared to 22.5% on placebo. Additionally, 62.9% of people treated with semaglutide 2.4 mg achieved resolution of steatohepatitis with no worsening of liver fibrosis compared to 34.1% on placebo. Of note, semaglutide 2.4 mg was well-tolerated with a safety profile similar to previous semaglutide 2.4 mg trials.¹

According to a press release from Novo Nordisk, the company expects to file for regulatory approvals in the US and EU in the first half of 2025. Detailed results from ESSENCE will be presented at a scientific conference in 2024, and a readout from part 2 of the ESSENCE trial is expected in 2029.¹

References

1. ^{Novo Nordisk. Novo Nordisk A/S: Semaglutide 2.4 mg demonstrates superior improvement in both liver fibrosis and MASH resolution in the ESSENCE trial. November 1, 2024. Accessed November 1, 2024. https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=171971}
2. ^{Brooks, A. Stephen Harrison, MD: The Role of Weight Loss, Resmetirom in NASH Management. HCPLive. March 18, 2024. Accessed November 1, 2024. https://www.hcplive.com/view/stephen-harrison-md-weight-loss-resmetirom-nash-management}