OR09-04 A novel Melanocortin and Gut-peptide Multiple Agonist for Obesity and Diabetes Treatment

Abstract

Disclosure: C.L. Roth: None. C. Elfers: None. K. Chichura: None. E. Ashlaw: None. G. Mullins: None. I. Chavez Miranda: None. L. den Hartigh: None. M.R. Hayes: None. R. Doyle: None.Background: Successful pharmacological treatment of obesity has been achieved using single agonists of the glucagon-like peptide-1 receptor (GLP-1R). However, monomeric dual or triple agonists, such as those based on GLP-1 with glucagon and/or glucose-dependent insulinotropic peptide (GIP), have exhibited improved efficacy through the synergistic effects on energy intake, appetite, and metabolic function. While there is evidence that GIPR agonism reduces GLP-1 induced nausea, the rate of gastrointestinal adverse events remains a limiting factor despite the multi-agonist approach using incretins. Based on this, we hypothesized that a more effective obesity and type-2 diabetes intervention could be produced by targeting the GLP-1, GIP, and MC4 receptors (MC4R) with a monomeric peptide utilizing the synergistic effects of GLP-1R and MC4R co-agonism to allow for dosing that is sub-threshold for adverse effects. Methods: We created KCEM1, a monomeric peptide, which is an agonist for GLP-1R, GIPR, and MC4R. After 7 weeks of once daily subcutaneous (sc) KCEM1 injections, changes in food intake and body weight, glucose tolerance, and gene expression in skeletal muscle (SM), white adipose tissue (WAT), and liver were measured in diet-induced obese (DIO) rats vs. vehicle, with semaglutide (SEMA) and tirzepatide (TIRZ) as standard of care positive controls. Emesis was tested in Asian musk shrews. Results: While KCEM1 is a weaker GLP-1R agonist compared to SEMA or TIRZ, it offered superior glycemic control (IPGTT 7 min peak glucose: KCEM1 208±19, SEMA 301±32, TIRZ 339±23, vehicle 357±43 mg/dL, one-way ANOVA p=0.0011), despite comparable weight loss (KCEM1: -14.5%; SEMA: -14.1%; TIRZ: -12.7%; relative to vehicle). Reductions in calorie intake (KCEM1: -26.5±3.9%; SEMA: -19.9±2.4%; TIRZ: -17.0±2.6%; relative to vehicle) were consistent with weight loss. KCEM1 treatment resulted in no observable emetic episodes at therapeutic doses in musk shrews. In gene expression analyses, KCEM1, but not SEMA or TIRZ, significantly increased SM expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1. In sc inguinal WAT (IWAT), adipogenic gene Lpl mRNA was reduced in response to KCEM1. In visceral epididymal WAT (EWAT), Cd68 (macrophage marker) was reduced, and GLUT4 was increased in response to KCEM1, but not to TIRZ or SEMA. In the liver, inflammatory markers IL-6 and TNF-α were reduced, and Fasn, a gene involved in lipogenesis, was increased by KCEM1, with no such changes observed in response to SEMA. Conclusion: The specific balance of agonism of KCEM1 at the GLP-1R, GIPR, and MC4R allows for anorectic effects comparable to current benchmark GLP-1R agonists while improving upon tolerability and glucose homeostasis, potentially due to the synergistic effects of GLP-1R and MC4R co-agonism. The beneficial metabolic effects of KCEM1 are novel compared to SEMA and TIRZ.Presentation: Saturday, July 12, 2025