title: Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog.
abstract: Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P< 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance (P< 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.
authors.affiliation: Nordic Bioscience, Herlev, Denmark; sgy@nordicbio.com.|Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark; and.
authors.forename: Sofie
authors.initials: S
authors.lastname: Gydesen
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Kim Vietz
authors.initials: KV
authors.lastname: Andreassen
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Sara Toftegaard
authors.initials: ST
authors.lastname: Hjuler
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark; and.
authors.forename: Lars I
authors.identifier: 0000-0001-9215-4880
authors.initials: LI
authors.lastname: Hellgren
authors.affiliation: Nordic Bioscience, Herlev, Denmark.|KeyBioscience, Stans, Switzerland.
authors.forename: Morten Asser
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Nordic Bioscience, Herlev, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
mesh_terms: D065091:Amylin Receptor Agonists / Q000008:administration & dosage*; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D004763:Glucagon-Like Peptides; D006801:Humans; D000069450:Liraglutide / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018003:Receptors, Calcitonin / Q000819:agonists; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
chemical_list: D065091:Amylin Receptor Agonists; D019440:Anti-Obesity Agents; C000625695:KBP-089; D018003:Receptors, Calcitonin; D004763:Glucagon-Like Peptides; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1
keywords: DACRA; GLP-1; adiposity; amylin; insulin sensitivity; obesity; tolerance; treatment