Background and 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 efficacy of cotadutide (600 μg, 300 μg) or placebo were evaluated in 74 participants with biopsy-proven non-cirrhotic MASH with fibrosis. Analyses were performed using intent-to-treat and modified intent-to-treat population data.
Results: Dose- and time-dependent improvements in HFF, alanine (ALT) and aspartate aminotransferase (AST), markers of liver health, and metabolic parameters were observed with significant improvements after 19 weeks with 600 μg ([LS] mean difference vs placebo [95%CI] for absolute HFF: -5.0% [-8.5,-1.5]; ALT: -23.5 U/L [-47.1,-1.8]; AST: -16.8 U/L [-33.0,-0.8]). Incidences of any grade treatment-emergent adverse events (TEAE) were 91.7%, 76.9% and 37.5% with cotadutide 600 μg, 300 μg, and placebo respectively. The majority were gastrointestinal (GI), mild to moderate in severity and generally consistent with other incretins at this stage of development. TEAE leading to treatment discontinuation were 16.7%, 7.7% and 4.2% with cotadutide 600 μg, 300 μg, and placebo respectively.
Conclusion: PROXYMO provides preliminary evidence for the safety and efficacy of GLP-1/GCG receptor co-agonism in biopsy-proven non-cirrhotic MASH with fibrosis, supporting further evaluation of this mechanism in MASH.
Keywords: cotadutide; hepatic fat; liver toxicity; metabolic dysfunction-associated steatohepatitis.
Copyright © 2024. Published by Elsevier Inc.