Background: Survodutide is a novel glucagon receptor/glucagon-like peptide-1 receptor dual agonist under investigation for treatment in advanced liver disease associated with metabolic dysfunction-associated steatohepatitis (MASH), the most severe form of metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods: In this multinational, double-blind, phase 2 trial (NCT04771273), 295 people aged ≥18 to ≤80 years with biopsy-proven MASH (NAFLD Activity Score [NAS] ≥4), liver fibrosis (stage F1–F3), and BMI ≥25 kg/m² were randomized to once-weekly subcutaneous injections of placebo (PBO) 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. This study reports the efficacy and safety results of a pre-planned interim analysis at week 28.

Results: 138 participants were included in this analysis. The mean age (51.7 years), BMI (35.6 kg/m²), and histological activity score (NAS: 5.1) were similar across treatment groups. Overall, 76 (55%) participants were female, 55 (40%) had type 2 diabetes, 55 (40%) had F2 fibrosis, and 51 (37%) had F3 fibrosis. At week 28, in participants with available magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) at baseline (BL) and week 28 (liver fat content [LFC] data were not available for 23 patients which were imputed as non-responders), ≥30% LFC reduction occurred in up to 90.9% of participants receiving survodutide vs 25.0% with PBO (Figure 1). Mean relative change from BL in LFC in the four treatment arms (survodutide 2.4, 4.8, 6.0 mg, and PBO) was –55.4%, –65.3%, –62.0%, and –13.1%. Mean absolute reduction in alanine aminotransferase was –37.8 U/L for all survodutide doses (BL: 57.2 U/L) vs –10.4 U/L with PBO (BL: 65.0 U/L); mean absolute reduction in aspartate aminotransferase was –30.8 U/L (BL: 47.6 U/L) vs –5.1 U/L (BL: 54.5 U/L), respectively (Figure 2). Mean relative reduction of pro-peptide of type III collagen (Pro-C3) level was –22.6% for all survodutide doses (BL: 48.1 ng/mL) vs 1.6% with PBO (BL: 44.61 ng/mL); mean absolute reduction of enhanced liver fibrosis score was –0.64 (BL: 9.7) vs –0.10 with PBO (BL: 9.5), respectively. Any adverse events (AEs) occurred in 92.3% of participants across all survodutide groups, and 88.2% in the PBO group (most commonly gastrointestinal [GI]). GI AEs leading to discontinuation occurred in 18.3% and 2.9%, respectively. No unexpected safety issues were reported.

Conclusion: Survodutide substantially reduced LFC, transaminases and fibrosis markers and was generally well tolerated in people with MASH and fibrosis. These positive results confirmed survodutide effectiveness and confidence towards proceeding with phase 3 trial.

Elisabetta Bugianesi

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