O7 Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: results from a randomised, double-blind, placebo-controlled phase 2 trial

<h3>Background and Aims</h3> We report the findings of survodutide, a novel dual agonist, for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). <h3>Methods</h3> In this multinational, double-blind, phase 2 trial, 295 people aged 18 – 80 years with biopsy-proven MASH (NAS Score ≥4), liver fibrosis (stage F1–F3), and body mass index (BMI) ≥ 25 kg/m2 were randomised to once-weekly subcutaneous injections of placebo (PBO) or survodutide 2.4, 4.8, or 6.0 mg (escalated over up to 24 weeks). The primary endpoint was histological improvement of MASH (≥ 2 point decrease in NAS with ≥ 1 point decrease in inflammation or ballooning sub-scores) without worsening of fibrosis after 48 weeks on actual treatment. Secondary and further endpoints included improvement in fibrosis (≥ 1 stage decrease) without worsening of MASH, absolute change in NAS, and change in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histological endpoints refer to patients with baseline (BL) and end-of-treatment biopsies (paired biopsies; n = 219). <h3>Results</h3> BL characteristics were similar across treatment groups: overall mean age, BMI, and NAS were 50.8 years, 35.81 kg/m2, and 5.2, respectively. 155 (53%) were female, 113 (39%) had type 2 diabetes, 120 (41%) had F2 fibrosis, and 103 (35%) F3 fibrosis. At week 48, the primary endpoint was reached in 64.3% (2.4mg), 83.0% (4.8mg), and 65.9% (6.0mg) of participants receiving survodutide, compared with 18.2% of PBO (p &lt; 0.001, all doses). When treated with 6.0 mg survodutide, 50.0% of participants had ≥ 1 stage improvement in fibrosis without worsening of MASH compared with 21.2% with PBO (p &lt; 0.001; actual treatment); absolute reduction in NAS was 2.80 – 3.30 with survodutide and 0.40 with PBO. Mean reduction in ALT from BL was 37.5 – 38.0 U/L (BL: 54.6 – 59.1 U/L) with survodutide and 6.2 U/L (BL: 57.8 U/L) with PBO; mean reduction in AST from BL was 28.1 – 30.9 U/L (BL: 43.2 – 48.0 U/L) and 2.9 U/L (BL: 51.3 U/L), respectively. Adverse event (AE) incidence was similar between survodutide and PBO groups; only differences observed in gastrointestinal disorders (84.9 – 87.8% and 56.8%, respectively). AEs leading to discontinuation for survodutide and PBO groups were 16.4 – 23.0% and 2.7%, respectively. No unexpected safety issues were reported. <h3>Conclusion</h3> Survodutide in people with MASH and fibrosis substantially improved histological activity of MASH without worsening of fibrosis. The results demonstrated improved fibrosis without worsening of MASH. Overall, survodutide was generally well tolerated.