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Viral infections are recognized as contributing factors in the pathogenesis of metabolic diseases. Viruses causing chronic infection are particularly important due to their capacity to induce sustained inflammation. Especially individuals with obesity - who exhibit preexisting metabolic abnormalities, low-grade inflammation, and altered antiviral responses - are at increased risk of viral infection-induced metabolic complications. Despite these associations, the specific metabolic consequences of chronic viral infections in obesity remain insufficiently characterized.

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

Zhenhuan Zheng, Jeremy H. Pettus, Alexa Warner, Bryan Jones, ... Timothy J. Kieffer

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

 

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.

Clinicaltrials.gov number

NCT05121441.

Integrated research application system (IRAS) number

1011885.

 

Articles in Press

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

Zhenhuan Zheng, Jeremy H. Pettus, Alexa Warner, Bryan Jones, ... Timothy J. Kieffer

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

 

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.

Clinicaltrials.gov number

NCT05121441.

Integrated research application system (IRAS) number

1011885.

 

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