Phase 2 trial results of survodutide in MASH with liver fibrosis
In a dose-finding phase 2 trial among patients with metabolic dysfunction–associated steatohepatitis (MASH) and liver fibrosis, 48 weeks of the dual glucagon/GLP-1 receptor agonist survodutide led to a reduction of MASH without worsening fibrosis, compared with placebo. Gastrointestinal disorders were the most common adverse events.
This summary is based on the publication of Sanyal AJ, Bedossa P, Fraessdorf M, et al. - A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. 2024 Jun 7 [Online ahead of print]. doi: 10.1056/NEJMoa2401755
Introduction and methods
Background
Obesity is a risk factor for and a coexisting condition in metabolic dysfunction–associated steatohepatitis (MASH; previously called nonalcoholic steatohepatitis) [1]. Although the GLP-1 receptor seems to be a plausible therapeutic target in this disease, hepatocytes lack this receptor [2]. Dual agonism of the GLP-1 and glucagon receptors may be more effective for treating MASH, because this combines the extrahepatic benefits of GLP-1 receptor agonism (glucose control, reduced appetite, and weight loss) with the direct hepatic effects associated with glucagon receptor agonism (increased energy expenditure, lipolysis, and mobilization of hepatic fat) [3-9].
In a mouse model, the dual glucagon/GLP-1 receptor agonist G49 ameliorated MASH by reducing inflammation, steatosis, apoptosis, and oxidative stress and increased mitochondrial biogenesis and liver regeneration compared with control [10].
Aim of the study
The authors investigated the efficacy, safety, and side-effect profile of survodutide in patients with MASH and liver fibrosis.
Methods
In an international, multicenter, double-blind, placebo-controlled, parallel-group, dose-finding, phase 2 RCT, 293 patients (aged 18–80 years) with liver biopsy–confirmed MASH, fibrosis stage F1–F3, liver fat content ≥8%, and stable body weight were included. Participants were randomized in a 1:1:1:1 ratio (stratified by T2D status) to subcutaneous survodutide (2.4, 4.8, or 6.0 mg) or placebo once weekly for 48 weeks (comprising a 24-week rapid-dose-escalation phase and 24-week dose-maintenance phase).
Outcomes
The primary efficacy endpoint was improvement in histological findings on liver biopsy, defined as a composite outcome of improvement (reduction) in MASH (i.e., decrease in nonalcoholic fatty liver disease activity score ≥2 points and decrease in either lobular inflammation or hepatocellular ballooning ≥1 point) with no worsening of fibrosis (absence of any increase in fibrosis stage), at 48 weeks. Secondary efficacy endpoints included a decrease in liver fat content ≥30% and biopsy-assessed improvement (reduction) in fibrosis by ≥1 stage, both assessed at 48 weeks. As there were no predefined specific safety endpoints, safety assessment was based on the overall safety results.
Main results
Efficacy
- In the modified intention-to-treat population (i.e., all randomized participants who had received ≥1 study medication dose), the primary endpoint (improvement in MASH with no worsening of fibrosis at 48 weeks) occurred in 47% (95%CI: 36%–58%) of the patients treated with survodutide 2.4 mg, 62% (95%CI: 51%–73%) of those receiving survodutide 4.8 mg, and 43% (95%CI: 33%–55%) of those on survodutide 6.0 mg, compared with 14% (95%CI: 8%–23%) of the placebo-treated patients (P<0.001 for quadratic dose-response curve as best-fitting model).
- The secondary endpoint of a decrease in liver fat content by ≥30% at 48 weeks was met by 63% of the participants in the survodutide 2.4-mg group, 67% of those in the survodutide 4.8-mg group, 57% of those in the survodutide 6.0-mg group, and 14% of those in the placebo group.
- Improvement in fibrosis by ≥1 stage at 48 weeks was observed in 34% of the patients in the survodutide 2.4-mg group, 36% of those in the survodutide 4.8-mg group, 34% of those in the survodutide 6.0-mg group, and 22% of the placebo group patients.
Safety
- The frequency of any adverse event was 95% in patients treated with survodutide (all dose combined) and 92% in placebo-treated patients.
- The most common adverse events were gastrointestinal disorders. All of the gastrointestinal adverse events occurred more frequently in the combined survodutide group than the placebo group, including nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%).
- Adverse events leading to discontinuation of the study drug occurred in 20% of the survodutide-treated patients (16% due to gastrointestinal adverse events, mostly occurring in the rapid-dose-escalation phase), compared with 3% of the placebo-treated patients.
- Serious adverse events was observed in 8% of the patients in the combined survodutide group and 7% of those in the placebo group.
Conclusion
In this dose-finding phase 2 RCT among patients with MASH and liver fibrosis, 48-week treatment with survodutide was associated with improvement (reduction) in MASH with no worsening of fibrosis compared with placebo. As expected, gastrointestinal disorders were the most frequently reported adverse events.
The authors added, “Discontinuation of survodutide mainly occurred during the rapid-dose-escalation phase of the trial and may be mitigated by a slower dose-escalation approach.”
References
1. Povsic M, Wong OY, Perry R, Bottomley J. A structured literature review of the epidemiology and disease burden of nonalcoholic steatohepatitis (NASH). Adv Ther 2019;36:1574-94.
2. Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics: tissue-based map of the human proteome. Science 2015;347:1260419.
3. Cegla J, Troke RC, Jones B, et al. Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake. Diabetes 2014;63:3711-20.
4. Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 2009;5:749-57.
5. Eriksson O, Haack T, Hijazi Y, et al. Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes. Sci Rep 2020;10:16758.
6. Tan TM, Field BCT, McCullough KA, et al. Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes 2013;62:1131-8.
7. Sánchez-Garrido MA, Brandt SJ, Clemmensen C, Müller TD, DiMarchi RD, Tschöp MH. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia 2017;60:1851-61.
8. Seghieri M, Christensen AS, Andersen A, Solini A, Knop FK, Vilsbøll T. Future perspectives on GLP-1 receptor agonists and GLP-1/glucagon Receptor co-agonists in the treatment of NAFLD. Front Endocrinol (Lausanne) 2018;9:649.
9. Spezani R, Mandarim-de-Lacerda CA. The current significance and prospects for the use of dual receptor agonism GLP-1/glucagon. Life Sci 2022;288:120188.
10. Valdecantos MP, Pardo V, Ruiz L, et al. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. Hepatology 2017;65:950-68.
11. Le Roux CW, Steen O, Lucas KJ, Startseva E, Unseld A, Hennige AM. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol 2024;12:162-73.