KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight

Abstract

This study aims to elucidate the mechanism behind the potent weight loss induced by dual amylin and calcitonin receptor agonists (DACRA) through comparison of the novel DACRA KBP-088 with the amylinomimetic davalintide with regard to in vitro receptor pharmacology and in vivo efficacy on food intake and body weight. KBP-088 and davalintide were tested for their ability to activate the amylin and calcitonin receptors as function of dose and time. Two doses of KBP-088 (1.67 and 5.0 μg/kg) were compared with similar davalintide doses in high-fat diet (HFD)-fed rats receiving subcutaneous dosing once daily for 62 days. Glucose tolerance was assessed after 3 and 7 wk of treatment. KBP-088 demonstrated activation of amylin and calcitonin receptors and prolonged receptor activation compared with davalintide as well as a potent reduction of acute food intake. KBP-088 transiently reduced food intake and induced and notably sustained a significant ∼16% vehicle-corrected weight loss without significant weight loss in the calorie-restricted control groups. Additionally, KBP-088 reduced white adipose tissues and adipocyte hypertrophy. Finally, KBP-088 alleviated hyperinsulinemia and improved oral glucose tolerance even with significantly lower insulin levels after 3 and 7 wk of treatment. KBP-088 is a potent amylin and calcitonin receptor agonist with prolonged receptor activation compared with davalintide. Moreover, KBP-088 induced and sustained significant weight loss and reduced overall adiposity and adipocyte hypertrophy in HFD rats. Finally, KBP-088 improved oral glucose tolerance and alleviated hyperinsulinemia, underscoring the potential of KBP-088 as an antiobesity agent with benefits on glucose control.

A novel dual amylin and calcitonin receptor agonist, KBP‐089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference

“…High‐fat feeding resulted in a phenotype with significantly increased body weight (596 ± 12 vs. 545 ± 8 g, P < 0.05), hyperinsulinaemia (1.9 ± 0.1 vs. 0.9 ± 0.1 ng·mL −1 , P < 0.05), impaired glucose control without hyperglycaemia (OGTT tAUC 1343 ± 18.1 vs. 1259 ± 17.1, P < 0.05) and impaired insulin sensitivity (HOMA‐IR) (11.3 ± 0.3 vs. 4.3 ± 0.3, P < 0.05), compared with the lean age‐matched controls. Thus, the HFD rats resembled an obese and pre‐diabetic phenotype as expected from previous studies (Hjuler et al ., ; Gydesen et al ., ).…”

“…To investigate the anti‐obesity potential of KBP‐089 in vivo , we treated HFD rats for 8 weeks. Previously, DACRAs have been shown to induce hypophagia (Hjuler et al ., ; Gydesen et al ., ); therefore, a pair‐fed group to the highest concentration of KBP‐089 was included to explore the impact of food restriction on body weight. KBP‐089 was s.c. administered in three doses (0.625, 1.25 and 2.5 μg·kg −1 ) for 56 days.…”

“…Synthetic KBP‐089 (American Peptide Company, CA, USA) was dissolved in saline for s.c. delivery. The doses chosen for peptide administration in the current investigations were based on previous comparable DACRA studies in animal models of obesity using potent DACRAs, KBP‐042 and KBP‐088 (Gydesen et al ., ; Hjuler et al ., ).…”

“…Dual amylin and calcitonin receptor agonists (DACRAs) elicit activation not only of the amylin receptor but also of the calcitonin receptor and have been shown to possess superior activity in terms of activation of the amylin receptor, when compared with classical amylin receptor agonists (Andreassen et al ., ). Interestingly, they also activate the receptors for an extended period of time, when compared with the classical agonists, which appears to increase the in vivo efficacy as well as reducing the dosing frequency (Gydesen et al ., ).…”

“…In vivo studies of DACRAs have recently demonstrated a protection against diet‐induced weight gain, a reduction in overall adiposity, as well as adipocyte hypertrophy (Gydesen et al ., ). Furthermore, DACRAs have been shown to improve glucose homeostasis in the diabetic Zucker Diabetic Fatty ZDF‐Lepr fa /Crl (ZDF) rats, a phenomenon not observed with selective and less potent amylin receptor agonists (Mack et al ., , ; Andreassen et al ., ; Hjuler et al ., ), while alleviating obesity‐derived insulin resistance (Hjuler et al ., ).…”