Abstract
AIMS: Incretin agonists are used to treat obesity and metabolic dysfunction. Instead of systemically delivering high levels of hormone receptor agonists that can lead to adverse effects, we tested and optimized oral microbead formulations that activate endogenous enteroendocrine signalling systems via distal nutrient-sensing cells. MATERIALS AND METHODS: We report two randomized Phase 1 studies (NCT05713773 and NCT05737927) measuring acute pharmacokinetic/pharmacodynamic responses following consumption of microbeads that deliver glucose to the distal small intestine: these studies compared coating variations and glucose dosing. The primary endpoint was plasma glucagon-like peptide 1 (GLP-1) levels; we also measured GLP-2, PYY, glicentin, oxyntomodulin, glucose-dependent insulinotropic peptide, C-peptide, and insulin as exploratory endpoints. In a subsequent randomized Phase 2a trial (NCT05803772), prediabetic subjects consumed a lead formulation or placebo once daily for 6 weeks each in a two-period, two-sequence crossover design. Oral glucose tolerance was measured at baseline and following treatment in each sequence, with the primary endpoint being the change in the area under the curve. RESULTS: Our microbead formulation successfully targeted the distal small intestine and elicited a robust plurihormonal enteroendocrine response; our Phase 2a data show that the lead formulation improved glucose tolerance in pre-diabetic patients, comparable to results using GLP-1 mimetics. Adverse events were infrequent and modest. CONCLUSIONS: Targeted glucose release activates endogenous enteroendocrine signalling networks, improves a clinically relevant metabolic endpoint, and has minimal adverse effects. The approach to target native enteroendocrine signalling has disruptive potential for the treatment of metabolic disorders, including obesity.