Oxyntomodulin has proven to be very promising with regards to weight loss and improved glucose control, however it has a very short half-life. There is a need of more potent and longer-lived molecules and therefore, we have identified a novel Oxyntomodulin analog known as OXM-001, with a better pharmacological efficacy. In vitro potency of OXM-001 was determined in both GLP-1/Glucagon receptor cell lines using β-Arrestin readout. Zucker Diabetic Sprague Dawley male rats (ZDSD) were treated with vehicle and OXM-001 (100 nmol/kg) every third day (n=6/group). The OXM-001 effects on body weight, food intake, FBG, fasting insulin and HbA1C were examined for three-weeks. HFD female C57BL/6J mice were administrated vehicle, OXM-001 (10 and 30 nmol/kg) and pair-fed to OXM-001 (50 nmol/kg) every third day and MEDI0382 (10 and 30 nmol/kg) everyday (n=8/group). Body weight, food intake and oral glucose tolerance test (OGTT) were assessed during the one-month study. OXM-001 showed to be more potent than stabilized Oxyntomodulin, both over a short 3h stimulation and a long 24h potency test. In ZDSD rats, OXM-001 significantly reduced FBG and HbA1C compared to vehicle group. Furthermore, OXM-001 improved fasting insulin due to the weight loss effect. In C57BL/6J mice, OXM-001 (30 and 50 nmol/kg) significantly reduced weight in a dose-depended manner (12.4% and 23.5% compared to vehicle) and was associated with a decreased energy intake. Both OXM-001 doses showed superiority in weight loss compared to MEDI0382. Interestingly, the pair-fed to OXM-001 lost 16.2 % of its body weight compared to vehicle, showing a superiority of the OXM-001 (50 nmol/kg) to the pair-fed group. Both OXM-001 doses improved glucose control compared to MEDI0382 during the OGTT.
In conclusion, OXM-001 significantly lowered the body weight and improved glucose tolerance in prediabetic rats and fat mice, more potent than MEDI0382, and may therefore represent a possible treatment opportunity for obesity-related co-morbidities.
A. Kayed: None. A. Katri: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Stock/Shareholder; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience.