MILAN, ITA. Survodutide, an investigational dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, produced “exceptional improvement in disease activity and fibrosis” in patients with steatohepatitis associated with metabolic dysfunction ( MASH), according to the results of phase 2 presented at the Congress of the European Association for the Study of the Liver (EASL) of 2024 and published simultaneously in The New England Journal of Medicine.[1]
Primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants who received survodutide showed a statistically significant improvement in steatohepatitis associated with metabolic dysfunction compared to those who received placebo (18.2%) according to the results of paired biopsies.[3]
Additionally, 75% of survodutide-treated participants experienced resolution of steatohepatitis associated with metabolic dysfunction without worsening fibrosis compared with 15% of placebo patients, and of patients with F2-F3 fibrosis, 64.5% achieved resolution. improved fibrosis without worsening steatohepatitis associated with metabolic dysfunction, reported Dr. Arun Sanyal, principal investigator of the study and director of the Stravitz-Sanyal Institute for Liver Diseases and Metabolic Health at VCU School of Medicine – Virginia Commonwealth University ( VCU), in Richmond, United States.
What’s amazing is that this “exceptional improvement” occurs after 48 weeks of treatment with a class of molecule that also has cardiometabolic benefits, Dr. Sanyal told Medscape Medical News.
“With the highest dose of survodutide [6,0 mg]two-thirds of the patients for whom we have biopsy data, both at baseline and at the end, actually showed regression of fibrosis at 48 weeks,” he said. “This is pretty dramatic.”
Efficacy and adverse effects of survodutide
A total of 293 participants with steatohepatitis associated with biopsy-confirmed metabolic dysfunction and fibrosis stages F1-F3 were randomized (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4 mg (n = 73), 4.8 mg (n = 72) or 6.0 mg (n = 74) or placebo (n = 74).
About half of the people participating in the study were women, with an average age of around 50 years and a body mass index of 35 kg/m2. Overall, 26% to 30% lived with type 2 diabetes; between 24% and 36% presented F2 fibrosis; and between 23% and 30%, F3 fibrosis. The total nonalcoholic steatohepatitis activity score was 5.2.
After completing a 24-week rapid dose escalation phase, participants followed a 24-week maintenance phase. The primary endpoint was histological improvement (reduction) in steatohepatitis associated with metabolic dysfunction without worsening fibrosis after 48 weeks of treatment, while the secondary endpoints were reduction in liver fat content by at least 30%. and reduction of fibrosis assessed by biopsy in at least one stage.
The main analyzes of the trial were based on two sets of treatments: actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal primarily reported results based on actual treatment, which were used for the primary analysis.
Overall primary endpoint data, including non-responders, showed a 47% improvement in steatohepatitis associated with metabolic dysfunction in the 2.4 mg group, 62% in the 4.8 mg group, and 43% in the 4.8 mg group. in the group receiving 6.0 mg, compared with 13.5% in the group receiving placebo (p
Additionally, 50% of patients receiving doses of 2.4 and 6 mg experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of steatohepatitis associated with metabolic dysfunction. In patients with F2-F3 fibrosis, 64.5% of people in the 6 mg survodutide group showed improvement versus 25.9% in the placebo group.
Reduction of liver fat by at least 30% was achieved by up to 87% in the 6 mg group based on proton density fat fraction estimated by MRI; when nonresponders were included, the percentage was 76.9% of the 6 mg group. Other results were weight loss and reduction in glycated hemoglobin (A1c).
The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said. Patients who cannot tolerate the higher dose can switch to a lower dose without much loss of efficacy, he said, adding that even the low dose was enough to obtain a near-maximal effect of glucagon.
Adverse effects were similar between survodutide and placebo, except for digestive effects, such as nausea, diarrhea, and vomiting. The occurrence of serious adverse events was also similar between survodutide and placebo.
Discontinuations due to adverse effects were 20% in all survodutide groups (with 16% due to digestive adverse effects) compared to 3% in the placebo group.
Dual agonist versus single agonist treatment
The dual-agonist approach may confer clinical advantages over glucagon-like peptide-1 receptor agonist monoagonist pharmacotherapy for steatohepatitis associated with metabolic dysfunction.
“Glucagon-like peptide has no receptors in the liver, so all of its effects are mediated outside of it, especially with regard to weight loss and improved metabolic status, increased secretion and insulin sensitivity and overall systemic blood glucose,” explained Dr. Sanyal.
“People with established fibrosis take longer to respond in terms of subsequent liver healing with just extrahepatic changes,” he added.
Because “glucagon targets the liver directly, we believe it reduces oxidative injury and possibly stimulates the secretion of fibroblast growth factor 21 (FGF-21). [factor derivado del hígado que regula el metabolismo de los lípidos y la glucosa] in the liver, so the antifibrogenic benefits are likely due to multiple mechanisms,” Dr. Sanyal said.
In comparison, the study authors highlighted that data on the glucagon-like peptide 1 (GLP-1) receptor monoagonist semaglutide indicate that a significantly higher proportion of patients on semaglutide achieve resolution of steatohepatitis associated with metabolic dysfunction than those who receive placebo, but that this does not translate into “a significantly higher percentage of patients with improved fibrosis stage.”
“It could be that semaglutide took longer to take effect in the liver,” Dr. Sanyal said.
By the end of the year, we will know how the single glucagon-like peptide-1 agonist approach (e.g., semaglutide) and the dual-agonist approach work, and eventually we will have data on triple agonists, Dr. Sanyal added. .
The morbidity and mortality burden of liver diseases
Co-moderator Debbie Shawcross, PhD, professor of hepatology and chronic liver disease at King’s College London, England, highlighted the importance of new drugs, including survodutide, in reducing the burden of morbidity and mortality from steatotic liver disease. .
Approximately one-third of the world’s population and 7% to 9% of children suffer from steatotic liver disease, he noted. Fat accumulation causes inflammation and scarring of the liver, which can progress to liver cirrhosis and primary liver cancers.
Survodutide offers a lot of hope “as a drug that will reduce both liver inflammation and fibrosis, while providing the benefit of better diabetes control,” Dr. Shawcross said.
Reflecting on dual agonism, he stated that both glucagon and glucagon-like peptide-1 receptors are essential for controlling metabolic functions.
Survodutide is currently being investigated in five Phase 3 studies for overweight and obese people, both related to steatohepatitis associated with metabolic dysfunction. According to a company press release, there is also a trial studying overweight-obese people with a confirmed or suspected diagnosis of steatohepatitis associated with metabolic dysfunction.[4]
Dr. Sanyal disclosed receipt of fellowships, consulting fees, and speaking fees from a wide range of companies working in the field of liver medicine. Shawcross has declared no conflicts of interest related to this medication and is a member of the advisory board or advisor to EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
This content was originally published in the English edition of Medscape.
