# ARD-101, a gut-restricted TAS2R agonist, reduces hunger in adults and promotes weight loss in DIO mice with DPP-4 inhibition

## TL;DR

ARD-101, a gut-restricted bitter taste receptor agonist, reduces hunger and promotes weight loss in mice and humans, especially when combined with DPP-4 inhibition.

## Contribution

ARD-101 demonstrates weight loss and metabolic benefits in preclinical and clinical settings, with potential synergy when combined with DPP-4 inhibitors.

## Key findings

- ARD-101 reduced weight gain, food intake, and improved metabolic markers in mice on high-fat diets.
- Combining ARD-101 with sitagliptin enhanced weight loss and glucose control in diet-induced obese mice.
- ARD-101 lowered hunger and supported metabolic health in adults with obesity.

## Abstract

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).

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).

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.

Gut-restricted TAS2R agonism warrants further study for hyperphagia in Prader–Willi syndrome, and in combination with DPP-4 inhibition for obesity.

NCT05121441.

1011885.

•DA reduces weight gain, food intake, and improves metabolic markers in mice on HFD.•DA and sitagliptin synergize to enhance weight loss and glucose control in DIO mice.•Combination therapy sustains weight and metabolic benefits post-GLP-1RA cessation.•Oral ARD-101 lowers hunger and supports metabolic health in adults with obesity.•Oral ARD-101 alters gut hormone levels in healthy participants.

DA reduces weight gain, food intake, and improves metabolic markers in mice on HFD.

DA and sitagliptin synergize to enhance weight loss and glucose control in DIO mice.

Combination therapy sustains weight and metabolic benefits post-GLP-1RA cessation.

Oral ARD-101 lowers hunger and supports metabolic health in adults with obesity.

Oral ARD-101 alters gut hormone levels in healthy participants.