823-P: GLY-200, a Pharmacologic Duodenal Exclusion Therapy, Improved Metabolic Parameters in the DIO Rat

Non-invasive alternatives to metabolic surgery or duodenal exclusion devices for type 2 diabetes (T2D) and obesity are lacking. We developed an orally administered therapeutic polymer, GLY-200, designed to create a barrier in duodenum by complexing with mucin. In healthy subjects, 5 days treatment resulted in significant reductions in postprandial glucose and insulin and increases in bile acids and gut hormones. To evaluate the chronic effects of GLY-200, we conducted an 8-week study in the diet-induced obesity (DIO) rat model. Methods: DIO rats (60% kcal fat diet) were gavaged once daily following a 3-hour fast with GLY-200 (120 mg/rat) or saline (n=12/group). Metabolic assessments included body weight, mesenteric fat mass, skeletal muscle mass (gastrocnemius), glycemic responses to an oral glucose tolerance test (oGTT), and gut hormones from fasted samples at study termination. Results: At 8 weeks, GLY-200 treated rats had a significant reduction in % body weight gain (5%, p < 0.05), lower mesenteric fat mass (p < 0.01), and a significant reduction in incremental glucose AUC0-120 min following the oGTT on Day 51 (p < 0.05) compared to control. These metabolic benefits were associated with a significantly higher fasting active GLP-1 level compared to control (p < 0.01). Trends for increased PYY were also observed as compared to control. There was no difference in skeletal muscle mass. Conclusions: In the DIO rat, chronic (8-weeks) once-daily treatment with GLY-200 resulted in significant improvements in metabolic parameters compared to saline control consistent with a duodenal exclusion MOA. These results support further development of GLY-200 for the treatment of T2D and obesity.