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The effects of dual GLP-1/GCG receptor agonists with different receptor selectivity in mouse models of obesity and NASH.

There is an unmet need for NASH therapeutics, considering the increase in global obesity. Dual GLP-1/GCG receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. However, dual GLP-1/GCG receptor agonists as a treatment for metabolic diseases need delicate optimisation to maximise metabolism effects. The impacts of increased relative GLP-1/GCG receptor activity in NASH settings must be addressed to unleash the full potential. In this study, we investigated the potential of OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists with different selectivity in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions. We developed dual GLP-1/GCG receptor agonists with selective agonism. Despite the improved metabolic effects of OXM-101, we explored a hyperglycemic risk attached to increased relative GCG receptor agonism. Thirty-eight days of treatment with a dual GLP-1/GCG receptor agonist OXM-104 with increased GLP-1 receptor agonism in obese NASH mice was found to ameliorate the development of NASH by lowering body weight, improving liver and lipid-profiles, reducing levels of the fibrosis marker PRO-C4, and improve glucose control. Similarly, dual GLP-1/GCG receptor agonist OXM-101 with increased relative GCG receptor agonism ameliorated NASH by eliciting dramatic bodyweight reductions to OXM-104, reflected in the improvement of liver and lipid enzymes and reduced PRO-C4 levels. Optimising GLP-1/GCG agonists with increased relative GCG receptor agonism can provide the setting for future agonists to treat obesity, type 2 diabetes, and NASH without having a hyperglycemic risk. Significance Statement There is an unmet need for NASH therapeutics considering the increase in global obesity. Dual GLP-1/GCG receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. Therefore, we have examined OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions.