Amylin improves glucose homeostasis through at least three distinct mechanisms of action, including prevention of the postprandial rise in plasma glucagon, slowing of gastric emptying, and increased satiety, leading to decreased caloric intake and potential weight loss. Clinical efficacy has been demonstrated with short-acting amylin analogue pramlintide. ZP8396, currently in phase 1 clinical testing, is a long-acting, amylin analogue designed to improve solubility, stability and allow for co-formulation with other relevant peptides. We previously reported that ZP8396 provides body weight reduction in DIO rats alone and in combination with semaglutide, a once-weekly GLP-1 agonist (Skarbaliene et al, Obesity Week 2021) . Here we investigated the antidiabetes potential of ZP8396 in Zucker Diabetic Fatty (ZDF) rats. The antidiabetes potential after a single subcutaneous (s.c.) injection of ZP8396 (nmol/kg) or vehicle was measured in ZDF rats (aged 12-13 weeks, n=10) , an animal model of type 2 diabetes, and continuously monitored for 168 h after dosing.ZP8396 induced a significant body weight loss in ZDF rats vs. vehicle group. A significant decrease in body weight was observed in rats treated with ZP8396 from initiation of the dosing and up to 96 h post-dose. In addition, single s.c. injection of ZP8396 showed a significant reduction in blood glucose levels at 24 h post-dose, reaching a 20 % difference in blood glucose levels vs. vehicle group (14,97±0,39 and 18,60±1,18 mmol/L, respectively; p <0.05) . Also, ZP8396 significantly reduced plasma glucagon levels, reaching a 55% difference in ZP8396-treated diabetic rats vs. vehicle group at 24 h post-dose (p <0.05) .
In conclusion, in diabetic rat ZP8396 improved glycaemic status, supporting that long-acting amylin analogues may provide future valuable therapeutic options to manage diabetes. Further preclinical characterization of the antidiabetes effects of long-term treatment with ZP8396 is ongoing.
J.Skarbaliene: Employee; Zealand Pharma A/S, Stock/Shareholder; Zealand Pharma A/S. T.Baader-pagler: Employee; Boehringer Ingelheim International GmbH. P.Eriksson: Employee; Zealand Pharma A/S.