Non-alcoholic fatty liver disease (NAFLD) is an umbrella term representing two subtypes: non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH). Non-alcoholic fatty liver is characterized by steatosis almost exclusively, whereas NASH is characterized by steatosis, fibrosis, inflammation, and hepatocyte ballooning (Sanyal, 2019). Although untreated NASH triggers cirrhosis and cancer an incremental healthcare costs, no pharmacological therapy exists for the treatment of NASH.

Projections for obesity and its comorbidities are pointing towards an increase in the coming decade, highlighting the importance of novel therapeutics targeting NASH. Guidelines on NASH treatment are currently focused on lifestyle interventions due to the beneficial effects on liver enzymes, steatosis, and NASH(Chalasani et al., 2018; Koutoukidis et al., 2019). Glucagon-like peptide-1 (GLP-1) is a peptide hormone with both insulinotropic and anorectic effects currently being explored as a potential treatment option for NASH. GLP-1 receptor agonists have been reported to reduce steatosis, metabolic dysfunction, insulin resistance, and inflammation in preclinical studies (Armstrong et al., 2016; Ding et al., 2006; Eguchi et al., 2015; Wang et al., 2014). Resolution of NASH was also confirmed in liver biopsy of NASH patients treated with once-weekly GLP-1 agonist semaglutide over 72 weeks (Newsome et al., 2021a). However, with the apparent lack of GLP-1 receptors in the liver, these effects are most likely weight-mediated (McLean et al., 2020). Unimolecular dual incretins with improved therapeutic potential are currently being investigated as treatments for NASH. The rationale for incretin-based dual agonists lies in the potential synergism between gut hormones to maximize effects on metabolism (Boland et al., 2020; Finan et al., 2013; Klein et al., 2022; Nestor et al., 2022; Parker et al., 2022; Zimmermann et al., 2022).

Dual GLP-1 and glucagon receptor agonists are other types of candidates showing great potential as NASH treatment. Interestingly, a combination of these two peptide hormones not only reduces the hyperglycemic risk linked to glucagon agonism but also provides promising hepatospecific effects (Boland et al., 2020; Day et al., 2012; Nestor et al., 2022; Zimmermann et al., 2022).

Reductions in body weight driven by lifestyle-changes exceeding ≥10% is associated with improved histological features of NASH(Vilar-Gomez et al., 2015). Interestingly, semaglutide and cotadutide have both been shown to elicit clinically meaningful reductions on body weight, which alone improves the overall health status (Ambery et al., 2018; Frias et al., 2018; O'Neil et al., 2018). NASH is a highly complex hepatic manifestation of the metabolic syndrome, which can be considered a culmination of several metabolic abnormalities. For that reason, the focus on the development of pharmacological interventions acting through several receptors has increased. However, there is a need for studies that investigate efficacies of selective GLP-1 receptor agonists and unimolecular dual incretins in head-to-head settings to elucidate the most beneficial modality as a treatment for NASH(Dufour et al., 2020).

Here we describe the in vitro and in vivo effects of a new dual GLP-1/glucagon receptor agonist OXM-104 against a daily dual GLP-1/glucagon receptor agonist, and the well-known GLP-1 receptor agonist semaglutide as treatments for obesity, type 2 diabetes (T2D), and NASH.