1995-P: Optimization of DACRA Dosing Frequency—The Balance between Efficacy and Tolerability

Potent 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. Notably, DACRAs activate the receptors for a prolonged time period resulting in metabolic effects superior to those of amylin. This indicates that a less frequent dosing could be feasible, although the tolerability is a question mark. In this study, we compared daily dosing to dosing every other day to characterize the tolerability and efficacy of these regimens. High fat fed Sprague Dawley rats were treated 9 weeks by s.c. injections of the DACRA KBP in two different dosing intervals corresponding to a daily dose of 1.5 nmol/kg. KBP was dosed either daily (q.d., 1.5 nmol/kg) or every other day (q.a.d, 3 nmol/kg). After 3 and 8 weeks of treatment oral glucose tolerance tests were performed 24 hours post injection of treatment. Both treatments resulted in an initial reduction in food intake. KBP q.d. resulted in a transient reduction in food intake that normalized within the first 10 days of treatment, while KBP q.a.d resulted in fluctuating food intake throughout the study. The fluctuations reflected the dosing intervals resulting in a marked suppression of food intake following dosing, however food intake normalized on non-dosing days. This difference is reflected in the accumulated food intake, where KBP q.a.d tended to have a lower food intake than KBP q.d. Both treatments resulted in sustained and significant weight loss as well as reductions in the overall adiposity. Interestingly, KBP q.a.d tended to induce a larger weight loss than KBP q.d., albeit with fluctuations reflecting the dosing intervals. In addition, KBP dose dependently improved oral glucose tolerance with significant reduced insulin levels both after 3 and 8 weeks of treatment. In conclusion, dosing KBP every other day positively affects the efficacy confirming that less frequent dosing with KBP could be feasible. Disclosure A.T. Larsen: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. N. Sonne: None. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience.