A groundbreaking Phase 2 clinical trial has demonstrated that survodutide, an experimental dual-agonist drug combining GLP-1 and glucagon receptor targeting, achieved significant improvements in fatty liver disease markers among 83% of treated patients. The results, published in the New England Journal of Medicine and presented at the European Association for the Study of Liver conference in Milan, represent a potential paradigm shift in treating metabolic dysfunction-associated steatohepatitis (MASH).
Trial Results Show Remarkable Efficacy
The 48-week study involving 293 adults from 25 countries with MASH and varying stages of fibrosis revealed unprecedented treatment outcomes. After receiving weekly injections of survodutide, 75% of patients experienced disease resolution, characterized by significantly reduced liver inflammation, fat content, and scarring. Additionally, up to 50% of treated patients showed improved fibrosis and liver enzymes with no disease progression.
"These data demonstrate that direct liver targeting with glucagon agonism in addition to GLP-1 effects helps resolves nonalcoholic fatty liver disease and improve fibrosis while maintaining the benefits of GLP-1 agonism," said principal investigator Dr. Arun Sanyal, director of the VCU Stravitz-Sanyal Institute for Liver Disease and Metabolic Health.
Addressing Critical Unmet Medical Need
MASH affects approximately one in four people globally and is closely linked to obesity. The condition occurs when liver fat content exceeds 5% of the organ's weight, potentially leading to serious complications including cirrhosis, liver cancer, or liver transplant requirements. Currently, only resmetirom has FDA approval for treating fatty liver disease, and it is not suitable for all patients.
The trial's dual-agonist approach represents a significant advancement over existing GLP-1 medications like Ozempic and Wegovy. While these drugs contain only GLP-1 agonists that mimic glucagon-like peptide 1 hormone, survodutide combines GLP-1 agonism with glucagon receptor targeting to directly address liver fat accumulation and energy metabolism.
Study Design and Patient Outcomes
The randomized trial enrolled 282 patients who completed the 48-week treatment protocol, representing a 96% completion rate. Participants received weekly injections starting at doses of 2.4 mg, 4.8 mg, or 6 mg, with gradual dose escalation to 6 mg over the first 24 weeks, followed by maintenance therapy for an additional 24 weeks.
Mouse studies had previously suggested that enhancing GLP-1 agonists with glucagon targeting could improve liver-specific effects by directly increasing energy utilization and reducing hepatic fat levels. The human trial results confirmed these preclinical findings.
Safety Profile and Side Effects
Consistent with other GLP-1 medications, survodutide treatment was associated with gastrointestinal side effects including nausea, diarrhea, and vomiting. The safety profile appeared manageable, as evidenced by the high trial completion rate.
Clinical Significance and Future Directions
"These findings are remarkable and exciting and open a new chapter in drug development for MASH with fibrosis, where a single agent could potentially target both the liver disease and related medical conditions may provide hope for millions who have both MASH with fibrosis and multiple obesity-related ailments," Sanyal stated.
The research addresses a significant public health challenge, as obesity affects more than 33 million Americans with type 2 diabetes, and between 5% and 7% of these individuals develop clinically significant liver disease. Several Phase 3 clinical trials of survodutide are currently underway, including studies examining the drug's effects on weight loss and liver fat reduction in overweight or obese patients with fatty liver disease.
The trial was funded by Boehringer Ingelheim, the pharmaceutical company developing survodutide. The promising Phase 2 results position the drug as a potential game-changer in treating a condition that currently has limited therapeutic options and affects millions of patients worldwide.
