Survodutide Improves MASH Without Worsening of Fibrosis, Reduces Liver Fat

Arun Sanyal, MD

Credit: VCU

New phase 2 data for survodutide are showcasing the dual glucagon and glucagon-like peptide-1 (GLP-1) receptor agonist’s ability to improve metabolic dysfunction-associated steatohepatitis (MASH) without worsening fibrosis.¹

Findings were presented at the European Association for the Study of the Liver (EASL) Congress in Milan, Italy, and published in the New England Journal of Medicine. Compared to placebo, survodutide was superior for histologic improvement with no worsening of fibrosis, and a greater percentage of patients taking survodutide achieved reduction in liver fat content by ≥ 30% and improvement in fibrosis by ≥ 1 stage.¹

“I am particularly excited about the findings of the Phase II trial in survodutide, which demonstrate the potential for glucagon agonism, in addition to GLP-1, to both improve MASH and shift the needle on fibrosis,” said principal investigator Arun Sanyal, MD, professor of Medicine, Physiology and Molecular Pathology at Virginia Commonwealth University School of Medicine.² “These data position survodutide as a leading glucagon/GLP-1 receptor dual agonist that could be a game-changer for people living with MASH and clinically significant fibrosis.”

Currently, resmetirom (Rezdiffra) is the only US Food and Drug Administration (FDA)-approved treatment for noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis. The oral, thyroid hormone receptor (THR)-β selective agonist received accelerated approval on March 14, 2024, following 18 studies in its clinical development program.^1,3

In the absence of an FDA-approved therapeutic prior to this decision, weight loss served as the cornerstone of MASH management. Although GLP-1 RAs have emerged as prominent weight loss tools, their lack of direct impact on fibrosis limits their utility in MASH.4

“Dual agonism of glucagon receptor and GLP-1 receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction–associated steatohepatitis,” Arun Sanyal, MD, professor of Medicine, Physiology and Molecular Pathology at Virginia Commonwealth University School of Medicine, and colleagues wrote.¹

A glucagon/GLP-1 receptor dual agonist, survodutide activates the glucagon and GLP-1 receptors, both of which are critical for controlling metabolic functions. Co-invented by Boehringer Ingelheim and Zealand Pharma, survodutide received a Fast Track Designation from the FDA in 2021 for the treatment of MASH and fibrosis and is also being examined in 5 phase 3 trials among people with overweight and obesity.^1,5

In a 48-week phase 2 trial of adults with biopsy-confirmed MASH and fibrosis stage F1 through F3, participants were randomly assigned in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4 mg, 4.8 mg, or 6.0 mg or placebo. The trial included a 24-week rapid-dose-escalation phase followed by a 24-week maintenance phase.¹

The primary endpoint was a composite of improvement in MASH, defined as a ≥2-point decrease in the NAFLD activity score with a ≥1-point decrease in either lobular inflammation or hepatocellular ballooning, and no worsening of fibrosis, defined as the absence of any increase in fibrosis stage. Secondary endpoints included a decrease in liver fat content by ≥ 30% and biopsy-assessed improvement in fibrosis by ≥ 1 stage.¹

A total of 293 participants received ≥ 1 dose of survodutide or placebo. Investigators noted improvement in MASH with no worsening of fibrosis occurred in 47% of participants in the survodutide 2.4 mg group; 62% of those in the 4.8 mg group; and 43% of those in the 6.0 mg group as compared with 14% of those in the placebo group (P <.001 for the quadratic dose-response curve as best-fitting model).¹

Regarding secondary endpoints, a decrease in liver fat content by ≥ 30% occurred in 63% of participants in the survodutide 2.4 mg group; 67% of those in the 4.8 mg group; 57% of those in the 6.0 mg group; and 14% of those in the placebo group. The percentage change from baseline in liver fat content after 48 weeks was −62.0% in the survodutide 6.0 mg group, as compared with −5.7% in the placebo group. Investigators also observed improvement in fibrosis by ≥ 1 stage in 34% of participants in the survodutide 2.4 mg group; 36% of those in the 4.8 mg group, 34% of those in the 6.0 mg group; and 22% of those in the placebo group.1¹

Overall, 95% of participants receiving survodutide and 92% of those receiving placebo reported an adverse event. Of note, nausea (66% vs 23%), diarrhea (49% vs 23%), and vomiting (41% vs. 4%) all occurred more frequently with survodutide than with placebo. Serious adverse events occurred in 8% with survodutide and 7% with placebo.¹

“Survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials,” investigators concluded.¹

References:

1. ^{Sanyal AJ, Bedossa P, Fraessdorf M, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. doi:10.1056/NEJMoa2401755}
2. ^{Boehringer Ingelheim. Boehringer Ingelheim’s survodutide shows breakthrough improvement in liver fibrosis with no worsening of MASH in 64.5% of patients with F2 and F3 fibrosis. Boehringer Ingelheim. June 7, 2024. Accessed June 7, 2024. https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/breakthrough-phase-2-survodutide-data-liver-fibrosis-mash}
3. ^{Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed June 6, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}
4. ^{Brooks, A. Stephen Harrison, MD: The Role of Weight Loss, Resmetirom in NASH Management. HCPLive. March 18, 2024. Accessed June 6, 2024. https://www.hcplive.com/view/stephen-harrison-md-weight-loss-resmetirom-nash-management}
5. ^{Campbell, P. Survodutide, a Glucagon/GLP-1 RA, Reduces MASH in Phase 2 Trial. HCPLive. February 26, 2024. Accessed June 6, 2024. https://www.hcplive.com/view/survodutide-a-glucagon-glp-1-ra-reduces-mash-in-phase-2-trial}