OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes.

OBJECTIVE: Dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. METHODS: The in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). RESULTS: OXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. CONCLUSION: These results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.

The Effects of Dual GLP-1/Glucagon Receptor Agonists with Different Receptor Selectivity in Mouse Models of Obesity and Nonalcoholic Steatohepatitis.

There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. However, dual GLP-1/GCG receptor agonists as a treatment of metabolic diseases need delicate optimization to maximize 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 receptor 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 the levels of the fibrosis marker PRO-C4, and improving glucose control. Similarly, dual GLP-1/GCG receptor agonist OXM-101 with increased relative GCG receptor agonism ameliorated NASH by eliciting dramatic body weight reductions to OXM-104, reflected in the improvement of liver and lipid enzymes and reduced PRO-C4 levels. Optimizing dual 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. SIGNIFICANT STATEMENT: There is an unmet need for nonalcoholic steatohepatitis (NASH) therapeutics, considering the increase in global obesity. Dual GLP-1/glucagon (GCG) receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. Therefore, this study has 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.

Tofacitinib and TPCA-1 exert chondroprotective effects on extracellular matrix turnover in bovine articular cartilage ex vivo.

OBJECTIVE: Currently, there are no disease-modifying osteoarthritis drugs (DMOADs) approved for osteoarthritis. It is hypothesized that a subtype of OA may be driven by inflammation and may benefit from treatment with anti-inflammatory small molecule inhibitors adopted from treatments of rheumatoid arthritis. This study aimed to investigate how small molecule inhibitors of intracellular signaling modulate cartilage degradation and formation as a pre-clinical model for structural effects. DESIGN: Bovine cartilage explants were cultured with oncostatin M (OSM) and tumour necrosis factor α (TNF-α) either alone or combined with the small molecule inhibitors: SB203580 (p38 inhibitor), R406 (Spleen tyrosine kinase (Syk) inhibitor), TPCA-1 (Inhibitor of κB kinase (Ikk) inhibitor), or Tofacitinib (Tofa) (Janus kinases (Jak) inhibitor). Cartilage turnover was assessed with the biomarkers of degradation (AGNx1 and C2M), and type II collagen formation (PRO-C2) using ELISA. Explant proteoglycan content was assessed by Safranin O/Fast Green staining. RESULTS: R406, TPCA-1 and Tofa reduced the cytokine-induced proteoglycan loss and decreased AGNx1 release 3.7-, 43- and 32-fold, respectively. SB203580 showed no effect. All inhibitors suppressed C2M at a concentration of 3 µM. TPCA-1 and Tofa increased the cytokine reduced PRO-C2 3.5 and 3.7-fold, respectively. CONCLUSION: Using a pre-clinical model we found that the inhibitors TPCA-1 and Tofa inhibited cartilage degradation and rescue formation of type II collagen under inflammatory conditions, while R406 and SB203580 only inhibited cartilage degradation, and SB203580 only partially. These pre-clinical data suggest that TPCA-1 and Tofa preserve and help maintain cartilage ECM under inflammatory conditions and could be investigated further as DMOADs for inflammation-driven osteoarthritis.