Survodutide Improves MASH Without Worsening of Fibrosis, Reduces Liver Fat (2024)

Survodutide, a glucagon/GLP-1 receptor dual agonist, improved MASH with no worsening of fibrosis, reduced liver fat content, and improved fibrosis by ≥ 1 stage in a phase 2 trial.

Arun Sanyal, MD

Credit: VCU

“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:

^{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}
^{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}
^{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}
^{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}
^{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}