220-OR: First-in-Human Study of a Pharmacological Duodenal Exclusion Therapy Mimics a Roux-en-Y Gastric Bypass Biomarker Signature

To address the need for non-invasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity, we designed an orally administered therapeutic polymer, GLY-200, that binds to and enhances the barrier function of mucus in the gastrointestinal tract. Methods: A Phase 1, randomized, double-blind, placebo (PBO)-controlled, multiple ascending dose study was conducted in healthy volunteers. Four cohorts (N=32, 19-61 yrs, BMI 26.2 ± 3.20 kg/m2) received 5 days of BID or TID dosing (total daily dose between 2.0 g and 6.0 g GLY-200 or PBO). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics (PD), including serum glucose, insulin, bile acids, and gut hormones. Results: No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. On Day 5, reductions in glucose and insulin and increases in bile acids, GLP-1, PYY, and glicentin were observed following a non-standardized meal in subjects receiving 2.0 g BID GLY-200 (N=9) vs PBO (N=8). Conclusions: GLY-200 is safe and generally well tolerated. PD results mimic the biomarker signature observed following RYGB and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine.