Dose frequency optimization of the dual amylin and calcitonin receptor agonist KBP-088 --long-lasting improvement of food preference and body weight loss.

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity. DACRAs activate the receptors for a prolonged time period resulting in metabolic effects superior to those of amylin. Pharmacological amylin receptor activation leads to body weight loss and reduced food intake as well as improved food preference, at least short-term. Due to the prolonged receptor activation, different dosing intervals and hence less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing (q.d.) to dosing every other day (q.a.d.) with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA, KBP-088, applying two different dosing intervals: 1.5 nmol/kg q.d. and 3 nmol/kg q.a.d, in order to assess the effects on body weight, food intake, glucose tolerance as well as food preference when given the choice between chow (13% fat) and high fat diet (60% fat). Treatment with KBP-088 induced a significant weight loss, reduction in adiposity, improvement in glucose control and altered food preference towards less calorie-dense food. KBP-088 dosed q.a.d. (3 nmol/kg) was superior to KBP-088 q.d. (1.5 nmol/kg) in terms of body weight loss and improvement in food preference. Hence, dosing KBP-088 q.a.d. positively affects overall efficacy on metabolic parameters, suggesting that less frequent dosing with KBP-088 could be feasible. SIGNIFICANCE STATEMENT: Here we show that food preference can be altered chronically towards less calorie-dense choices by pharmacological treatment. Further, pharmacological dosing regimens affects the efficacy differently, as dosing every other day improved body weight loss and alterations in food preference compared to daily dosing. This suggest that alterations of the dosing regimens could be feasible in the treatment of obesity. The American Society for Pharmacology and Experimental Therapeutics.