Naim Alkhouri, MD: Interim Analysis of Phase 2 Survodutide Data Show Promise for MASH, Fibrosis

New phase 2 data are underscoring survodutide’s potential for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), highlighting its effect on liver fat content, transaminases, and markers of fibrosis.¹

Findings from an interim analysis of the multinational, double-blind, phase 2 trial for the novel glucagon receptor/glucagon-like peptide (GLP)-1 receptor dual agonist were presented at Digestive Disease Week (DDW) 2024 in Washington, DC, during a late-breaking abstract session.¹

On March 14, 2024, resmetirom (Rezdiffra), an oral thyroid hormone receptor (THR)-β selective agonist, became the first and only treatment to receive US Food and Drug Administration (FDA) approval for noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis.² However, other pathways are also being explored for their therapeutic potential in the progressive liver disease.

“We've known that GLP-1 agonists, such as semaglutide, may have beneficial effects on MASH, but their effects are indirect through weight loss…they do not have direct effects on the liver,” Naim Alkouri, MD, chief medical officer, chief of transplant hepatology, and director of the Fatty Liver Program at Arizona Liver Health, explained to HCPLive. “Glucagon targeting, on the other hand, has direct effects on the liver. It can enhance the utilization of fatty acids and it can also increase what we call your resting energy expenditure, and that may help with weight loss.”

A glucagon/GLP-1 receptor dual agonist, survodutide is being investigated in a phase 2 trial among 295 patients 18-80 years of age with biopsy-proven MASH, liver fibrosis (stage F1–F3), and BMI ≥ 25 kg/m2. Participants were randomly assigned to receive once-weekly subcutaneous injections of placebo or survodutide 2.4, 4.8, or 6.0 mg escalated over up to 24 weeks from a starting dose of 0.3 mg for 48 weeks.¹

At DDW, Alkhouri presented efficacy and safety results of a pre-planned interim analysis at week 28. Among 138 participants included in the analysis, the mean age was 51.7 years, BMI was 35.6 kg/m2, and histological activity score was 5.1, all of which investigators noted were similar across treatment groups. The majority (55%) of participants were female and many had type 2 diabetes (40%), F2 fibrosis (40%), and F3 fibrosis (37%).¹

At week 28, in participants with available magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) at baseline and week 28, ≥30% liver fat content reduction was observed in up to 90.9% of participants receiving survodutide compared to 25.0% with placebo. The mean relative change from baseline in liver fat content was –55.4% in the survodutide 2.4 mg treatment group –65.3% in the survodutide 4.8 mg treatment group, and –62.0% in the survodutide 6.0 mg treatment group versus –13.1% with placebo.¹

The mean absolute reduction in alanine aminotransferase was –37.8 U/L for all survodutide doses (57.2 U/L at baseline) versus –10.4 U/L with placebo (65.0 U/L at baseline) and the mean absolute reduction in aspartate aminotransferase was –30.8 U/L (47.6 U/L at baseline) versus –5.1 U/L (54.5 U/L at baseline), respectively. Investigators also pointed out the mean relative reduction of pro-peptide of type III collagen (Pro-C3) level was –22.6% for all survodutide doses (48.1 ng/mL at baseline) compared to 1.6% with placebo (44.61 ng/mL at baseline) and the mean absolute reduction of enhanced liver fibrosis score was greater with survodutide ( –0.64; 9.7 at baseline) than placebo ( –0.10; 9.5 at baseline).¹

Of note, adverse events occurred in 92.3% of participants across all survodutide groups and 88.2% of participants in the placebo group, most commonly gastrointestinal in nature and leading to discontinuation in 18.3% of patients in the survodutide groups versus 2.9% of patients in the placebo group.¹

“These data are very encouraging and we will present the final histology data at 48 weeks of treatment at the upcoming International Liver Congress in Milan,” Alkhouri concluded.

References:

1. ^{Alkhouri N, Fraessdorf M, Neff G, et al. SURVODUTIDE REDUCES LIVER FAT CONTENT, TRANSAMINASES, AND FIBROSIS MARKERS WITH GOOD SAFETY PROFILE IN PEOPLE WITH METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS (MASH): AN INTERIM ANALYSIS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2 TRIAL. Abstract presented at Digestive Disease Week (DDW) 2024 Annual Meeting. Washington, DC. May 17-21, 2024.}
2. ^{Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed May 21, 2024. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash}