2156-LB: Superior Hepatoprotective Effects of OPK-88006, a Novel GLP-1/Glucagon Receptor Dual Agonist, to Semaglutide and Survodutide in the GAN Diet-Induced Obese and Biopsy-Confirmed Mouse Model of MASH

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Introduction and Objective: The present study aimed to investigate the hepatoprotective effects of OPK-88006, a novel GLP-1/glucagon receptor agonist, in the GAN diet-induced obese and biopsy-confirmed mouse model of MASH with liver fibrosis. The late-stage clinical candidates semaglutide and survodutide for the treatment of patients with MASH and liver fibrosis, were included for comparison.Methods: Male GAN DIO-MASH mice with NAFLD Activity Score (NAS≥5) and moderate/advanced fibrosis (stage F2-F3) were administered once daily subcutaneous vehicle, semaglutide (30 nmol/kg), survodutide (15) nmol/kg) and OPK-88006 (20 nmol/kg) for 12 weeks. Histopathological scoring was performed. Other terminal endpoints included quantitative liver histology, blood and liver biochemistry in addition to RNAsequencing-Bioinformatic analysis.Results: GAN DIO-MASH mice demonstrated vehicle-corrected weight loss of 12%, 24% and 26% for OPK-88006, semaglutide and survodutide treatment, respectively. All treatments improved hepatomegaly, plasma transaminases and plasma lipids levels, albeit only OPK-88006 induced 2-point statistically significant improvement in NAS. In agreement, OPK-88006 reduced quantitative liver histology on steatosis and inflammation (galectin-3). Treatments reduced markers for fibrosis (TIMP-1 PIIINP) and hepatic stellate activation (α-SMA), indicating effect on fibrogenesis. Finally, all treatments induced significant gene regulation and suppressed genes involved in extracellular matrix and inflammation pathways.Conclusion: OPK-88006 treatment improved metabolic, biochemical and histopathological parameters of MASH, including hepatic transcriptomic profile, in the GAN DIO-MASH mouse model. Notably, OPK-88006 treatment improved NAFLD Activity Score superior to late-stage clinical candidates semaglutide and survodutide, introducing OPK-88006 as a promising treatment for MASH.

Disclosure

J. Hsiao: None. L. Moschcovich: None. M. Gerzon-Zakar: None. A. Rivkin: None. S.E. Pors: None. M.R. Madsen: None. T. Cruz: Employee; OPKO Health. M. Feigh: None.



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