title: 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.
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and sgy@nordicbioscience.com.
authors.forename: Sofie
authors.initials: S
authors.lastname: Gydesen
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Kim Vietz
authors.initials: KV
authors.lastname: Andreassen
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Sara Toftegaard
authors.initials: ST
authors.lastname: Hjuler
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Jane Marie
authors.initials: JM
authors.lastname: Christensen
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and KeyBioscience AG, Stans, Switzerland.
authors.forename: Morten Asser
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Nordic Bioscience, Herlev, Denmark; and.
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
mesh_terms: D017667:Adipocytes / Q000187:drug effects*; D052436:Adipose Tissue, White / Q000187:drug effects*; D050154:Adiposity / Q000187:drug effects*; D065091:Amylin Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D059305:Diet, High-Fat; D004435:Eating / Q000187:drug effects*; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism; D006984:Hypertrophy; D007328:Insulin / Q000097:blood; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018003:Receptors, Calcitonin / Q000819:agonists*
chemical_list: D065091:Amylin Receptor Agonists; D007328:Insulin; D010455:Peptides; D018003:Receptors, Calcitonin; C553163:davalintide
keywords: DACRA; adiposity; amylin; obesity; treatment