First‐in‐human study of a pharmacological duodenal exclusion therapy shows reduced postprandial glucose and insulin and increased bile acid and gut hormone concentrations

Aims To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing an orally administered therapeutic polymer, GLY‐200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively. Materials and Methods A Phase 1, randomized, double‐blind, placebo‐controlled, single‐ (SAD) and multiple‐ascending‐dose (MAD) healthy volunteer study was conducted. In the SAD arm, four cohorts received a single dose of 0.5 g up to 6.0 g GLY‐200 or placebo, while in the MAD arm, four cohorts received 5 days of twice‐daily or three‐times‐daily dosing (total daily dose 2.0 g up to 6.0 g GLY‐200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, 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. In the MAD arm (Day 5), reductions in glucose and insulin and increases in bile acids, glucagon‐like peptide‐1, peptide YY and glicentin, were observed following a nonstandardized meal in subjects receiving twice‐daily dosing of 2.0 g GLY‐200 (N = 9) versus those receiving placebo (N = 8). Conclusions GLY‐200 is safe and generally well tolerated at doses of ≤2.0 g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux‐en‐Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine. This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY‐200 for the treatment of obesity and/or T2D.