2064-LB: Novel Amylin and Calcitonin Receptor Coagonists Reduce Food Intake and Body Weight in Rodents

• Published in: Diabetes (New York, N.Y.) Vol. 73; p. 1
• Main Author: Yagiz, Kader
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2024
• Subjects: Agonists; Amylin; Animal models; Appetite; Arrestin; Body weight; Diabetes mellitus; Food; Food intake; Food selection; Metabolic disorders; Metabolic rate; Metabolism; Obesity; Pharmacokinetics; Receptor mechanisms
• DOI: 10.2337/db24-2064-LB
• ISSN: 0012-1797

Amylin analogs have been shown to significantly reduced body weight and dosage of insulin. Dual amylin and calcitonin receptor agonists (DACRAs) are the most potent amylin receptor agonists. We developed a series of novel long-acting amylin agonists to assess the potency on both calcitonin (CTR) and amylin 3 (AMY3) receptor activation on body weight and other metabolic parameters. We report herein the results from an evaluation of these compounds in rodent models.In vitro screening consisted of measurement of ligand-induced β-arrestin recruitment and assessment of cAMP production on human CTR and AMY3 receptors as an indicator of receptor activity, followed by in vivo evaluation. Acute food intake and pharmacokinetic evaluations in lean rats were determined following single subcutaneous administration of selected analogs. Diet-induced obese (DIO) mice were treated with subcutaneous injections of vehicle or one of a series of amylin agonists for 24 days. Cagrilintide was used as positive control. Cohorts were assessed for changes in BW, food intake and other markers.A series of amylin agonists reduced food intake in rats in the range of 56-93%, compared to vehicle, in the period from 0-72 hr post-dose. In comparison, cagrilintide was able to reduce food intake mostly from 0-48 hr and up to 72 hr only at 30 nmol/kg. Durable appetite suppression was further confirmed in a pharmacokinetic study. Treatment with selected novel amylin agonists resulted in reductions to BW in rats up to 10% compared to vehicle. In DIO mice, BW loss effects were comparable to those observed in cagrilintide-treated animals. Improvements in other metabolic markers were also observed. A novel series of amylin analogs produced significant reductions in BW in rodents, with effect sizes comparable to those observed in an active control group. Dual agonism of CTR and AMY3 receptors represents a promising therapeutic approach to metabolic disorders such as obesity and diabetes. Further evaluation of these compounds is ongoing.