Safety and Efficacy of Novel Incretin Co-agonist Cotadutide in Biopsy-proven Non-cirrhotic MASH with Fibrosis

BACKGROUND & AIMS: Cotadutide, a peptide co-agonist at the glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors, has demonstrated robust improvements in body weight, glycemia, and hepatic fat fraction (HFF) in patients living with obesity and type 2 diabetes mellitus. METHODS: In PROXYMO, a 19-week randomized double-blind placebo-controlled trial, the safety and effi cacy of cotadutide (600 mu g, 300 mu g) or placebo were evaluated in 74 participants with biopsy- proven noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with fi brosis. Analyses were performed using intent-to-treat and modified fi ed intent-to-treat population data. RESULTS: Dose- and time-dependent improvements in HFF, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), markers of liver health, and metabolic parameters were observed with significant fi cant improvements after 19 weeks with 600 mu g mu g ([least squares] mean difference vs placebo, [95% confidence fi dence interval] for absolute HFF: - 5.0% [-8.5 - 8.5 to - 1.5]; ALT: - 23.5 U/L [-47.1 - 47.1 to - 1.8]; AST: - 16.8 U/L [-33.0 - 33.0 to-0.8]). - 0.8]). Incidences of any grade treatment-emergent adverse events (TEAEs) were 91.7%, 76.9%, and 37.5% with cotadutide 600 mu g, 300 mu g, and placebo, respectively. The majority were gastrointestinal, mild to moderate in severity, and generally consistent with other incretins at this stage of development. TEAEs leading to treatment discontinuation were 16.7%, 7.7%, and 4.2% with cotadutide 600 mu g, 300 mu g, and placebo, respectively. CONCLUSIONS: PROXYMO provides preliminary evidence for the safety and efficacy fi cacy of GLP-1/GCG receptor coagonism in biopsy-proven noncirrhotic MASH with fi brosis, supporting further evaluation of this mechanism in MASH. Clinical Trial registration number: NCT04019561.