First‐in‐Human Evaluation of Oral Denatonium Acetate (ARD‐101), a Potential Bitter Taste Receptor Agonist: A Randomized, Double‐Blind, Placebo‐Controlled Phase 1 Trial in Healthy Adults

Abstract Preclinical studies in animal models of obesity and inflammation have shown that oral administration of ARD‐101, a potential TAS2R agonist, reduced food intake and body weight and downregulated inflammatory cytokines. We present results from a first‐in‐human phase 1 randomized, placebo‐controlled trial that evaluated safety, pharmacokinetics, and pharmacodynamics of single or multiple ascending doses of oral ARD‐101 (40, 100, and 240 mg) in healthy adults. A total of 43 subjects were randomly assigned and dosed to ARD‐101 or placebo with 42 subjects completing the study treatment. ARD‐101 was found to be >99% restricted to the gut with minimal systemic exposure, demonstrated a favorable safety profile, and was well tolerated at all dose levels. Blood samples taken 1 hour after administration showed that subjects dosed with 240 mg of ARD‐101 had elevated circulating levels of several gut peptide hormones. It is postulated that ARD‐101 activates enteroendocrine cells to achieve its effects regulating metabolism and inflammation. The phase 1 clinical results demonstrated safety of ARD‐101 and indicated activation of gut peptide hormone release in healthy adults. Further clinical trials will evaluate ARD‐101 in patients with metabolic and inflammatory disorders.