1718-P: Novel GLP-1RA (GmFc) Greatly Reduces GI Adverse Effects while Exhibiting Glycemic Control and Satiety in Rodents

Introduction and Objective: GmFc is a novel GLP-1 RA, comprising a homodimer fusion protein of GLP-1 peptide analog, linker, and IG4-Fc, that activates GLP-1 receptors to enhance insulin secretion and potentially reduce GI adverse effects. We compared GmFc to dulaglutide and semaglutide in GI adverse effects, glycemic control, and satiety in rodents. Methods: Mice (n=10 per group) were administered intraperitoneally saline, LiCl (0.1 mg/kg, positive control), GmFc (0.9 or 9 mg/kg), or dulaglutide (0.9 mg/kg) and subjected to conditioned taste aversion model. Mice (n=6 per group) were administered sc saline, GmFc (9 mg/kg), or semaglutide (200 μg/kg), then after 4h brain tissue was collected for c-Fos immunostaining of NTS region of medulla oblongata. Streptozotocin (STZ) induced diabetic rats (n=4 per group) were administered sc saline, GmFc (0.45 or 4.5 mg/kg), or dulaglutide (0.45 mg/kg), then measured blood glucose, 24h food consumption, and body weight after 1 week. Results: At equivalent doses in the mice conditioned taste aversion model, GmFc exhibited 3.9-fold lower relative aversion index (RAI) compared dulaglutide, and at 10x dose, 1.6-fold lower RAI. In mice NTS neurons, which integrates nausea and emesis-related inputs, GmFc showed 2.6-fold less c-Fos signal (108±49 to 276±56 c-Fos+, p < 0.001) compared to semaglutide. In STZ rats, GmFc (4.5 mg/kg) reduced 24h blood glucose by 16.2% compared to dulaglutide (0.45 mg/kg) (p < 0.01), and reduced 24h food consumption by 20%. After 1 week, rats treated with GmFc weighed 4.5g less (p < 0.01) than those treated with dulaglutide. Conclusion: Novel GmFc in rodents is as effective as other GLP-1 RAs in glycemic control and satiety, but notably exhibits fewer nausea and emesis indicators. This reduction in GI adverse effects can allow for administration of higher therapeutic doses of GmFc for greater glycemic control compared to current GLP-1 RAs on the market. Disclosure Y. Liu: Employee; Current; RxD Nova Pharmaceuticals, Inc.