Survodutide, Dual Glucagon/GLP-1 Mimetic, Improves MASH in 83% of Phase 2 Trial Participants

Survodutide, a novel dual glucagon/glucagon-like peptide-1 (GLP-1) receptor agonist, was associated with significant improvement of metabolic dysfunction-associated steatohepatitis (MASH) in up to 83% of adult participants in phase 2 study findings, according to an announcement from codevelopers Boehringer Ingelheim (BI) and Zealand Pharma.¹

The topline results demonstrated biopsy-proven improvement in MASH after 48 weeks of treatment compared with placebo, without worsening of fibrosis stages F1-F3—the trial’s primary endpoint. All secondary endpoints were satisfied as well, including a statistically significant improvement in liver fibrosis, according to both companies.

The survodutide mechanism of action that mimics both glucagon and GLP-1 is likely the reason for the unprecedented level of benefit seen in the phase 2 MASH trial, said BI in its announcement. The glucagon agonist component drives energy expenditure and also has a direct hepatic effect that “potentially contributes” to the observed improvement in fibrosis. Decreased appetite and increased satiety are results of GLP-1 receptor agonism.

The combined effect, said BI, may have strong clinical potential across a spectrum of chronic diseases.

“In order to bring this potential treatment to the more than 1 billion people affected by interconnected cardiovascular, renal, metabolic diseases, we will move forward as quickly as possible in MASH,” Carinne Brouillon, BI head of human pharma, said in the press statement. “We are also progressing with survodutide in other related conditions, having already initiated our Phase III clinical trial program for obesity.”

MASH phase 2 trial

The phase 2 randomized, double-blind, placebo-controlled, dose-finding MASH trial assessed the safety and efficacy of weekly subcutaneous injections of survodutide 2.4 mg, 4.8 mg, and 6.0 mg relative to placebo. The trial’s primary endpoint was the percentage of participants achieving histologic improvement of MASH without worsening fibrosis at the conclusion of the 48-week treatment period.1 of 295 participants and assessed the efficacy and safety of

Study inclusion required participants to be diagnosed with MASH and have stage F1-F3 fibrosis. Participants with and without type 2 diabetes (T2D) were eligible, according to the news release. Investigators defined histologic improvement of MASH as a decrease of 2 or more points on the Non-alcoholic Fatty Liver Disease Activity Score (NAS, score range 0 – 8), including a 1 point or greater decrease in NASH subscore for lobular inflammation or ballooning, and no increase in fibrosis stage.1

Survodutide doses among participants who were randomly assigned to the active treatment groups were escalated to either 2.4 mg, 4.8 mg, and 6.0 mg over 24 weeks; doses were then maintained for another 24 weeks, according to BI.

FINDINGS

The companies reported that among the 295 MASH trial participants, treatment with survodutide was associated with statistically significant improvements in MASH, with 83.% of the survodutide arm achieving histologic remission compared to 18.2% of the placebo arm (response difference, 64.8%; 95% CI, 51.1-78.6; P < .001). The improvement in the primary outcome was observed across all doses examined in the trial. BI reported that all secondary study endpoints also were met, including relative reduction in liver fat content of 30% or greater after 48 weeks, improvement of fibrosis, and absolute change from baseline in total score for NAS after 48 weeks. Further, the development partners stated that there were no unexpected safety or tolerability issues, including with the highest dose of 6.0 mg. The companies expect to present full data from the MASH phase 2 trial in the coming months.

Survodutide was granted fast track designation by the US Food and Drug Administration in 2021. At the American Diabetes Association annual meeting in June 2023, results of a phase 2 dose-finding study showed the novel agent was associated with weight loss of up to 19% among individuals with overweight or obesity. BI and Zealand Pharma said the compound is currently being evaluated in 5 phase 3 studies in individuals in this population as well as other key subpopulations.

1. Survodutide Phase II trial shows 83% of adults treated achieved groundbreaking results in liver disease due to MASH, with significant improvements in fibrosis. News release. Boehringer Ingelheim. February 26, 2024. Accessed February 27, 2024.

2. Halsey G. Survodutide, novel dual GLP-1/glucagon agonist, achieves s ~19% weight loss in people with overweight, obesity. Patient Care. June 26, 2023. Accessed February 27, 2024. https://www.patientcareonline.com/view/survodutide-novel-dual-glp-1-glucagon-agonist-achieves-19-weight-loss-in-people-with-overweight-obesity