A bitter taste receptor-activating compound called ARD-101 (taken orally) reduced hunger and produced modest weight loss in people with obesity in a 28-day trial, while also altering gut hormone levels. In obese mice, combining it with a diabetes drug (sitagliptin) prevented weight regain after stopping tirzepatide. These findings point to gut-targeted bitter taste signaling as a potential new approach to managing obesity, possibly alongside existing medications.
Abstract
OBJECTIVES: Obesity management has limited oral pharmacotherapies. Bitter taste receptor (TAS2R) agonists may modulate hunger, satiety, and metabolism via gut-brain signaling. We evaluated denatonium acetate (DA), a gut-restricted TAS2R agonist, across preclinical and clinical settings, and explored its combination with sitagliptin (a dipeptidyl peptidase-4 [DPP-4] inhibitor).
METHODS: In mice transitioned to high-fat diet (HFD) or established with diet-induced obesity (DIO), we tested oral DA (20-80 mg/kg twice daily or 75 mg/kg once daily), a sitagliptin-formulated HFD, the combination, and subcutaneous tirzepatide, including a post-tirzepatide discontinuation phase, to assess weight trajectories and metabolic benefits. In randomized, placebo-controlled clinical studies, ARD-101 (oral DA) was evaluated in adults with obesity (200 mg twice daily for 28 days) and in healthy participants (single 800 mg).
RESULTS: In mice transitioned to HFD, DA reduced weight gain (up to 43.1%), decreased food intake, and improved glucose and lipid measures. In DIO mice, once-daily DA or sitagliptin-HFD prevented weight gain; the combination reduced body weight (-18.8%) with metabolic benefits. In a separate DIO mouse study, tirzepatide reduced weight by 23.7%. Following tirzepatide discontinuation, switching to DA plus sitagliptin-HFD limited weight regain comparable to continued tirzepatide. In adults with obesity, ARD-101 reduced weight versus placebo by 0.8 kg at Day 28 and 1.3 kg at end-of-study and decreased hunger and food cravings. It also altered gut hormone levels in healthy participants.
CONCLUSIONS: Gut-restricted TAS2R agonism warrants further study for hyperphagia in Prader-Willi syndrome, and in combination with DPP-4 inhibition for obesity.
GOV NUMBER: NCT05121441.
INTEGRATED RESEARCH APPLICATION SYSTEM (IRAS) NUMBER: 1011885