Aardvark Therapeutics has reported positive clinical data from three Phase II trials for its lead product ARD-101, an oral small molecule bitter taste receptor agonist. According to the company, these early results suggest a promising future for a new class of pharmaceuticals that could benefit people afflicted with obesity or other metabolic conditions, particularly those associated with hunger, which is a prominent feature of the rare genetic condition Prader-Willi Syndrome (PWS).
ARD-101 is a first-in-class oral composition of chemical compounds with an extremely bitter taste, which target specific receptors in the mouth and also in the gut, where they trigger appetite-suppressing hormones like GLP-1, GIP, PYY and cholecystokinin. Aardvark’s taste receptor type 2 (TAS2R) agonist acts and stays, almost exclusively in the gut. ARD-101 is a salt of denatonium, a bitter chemical used in antifreeze and other products to prevent ingestion. The compound also reduces the inflammation associated with obesity, which GLP-1 agonists do not address.
ARD-101 is shown to be safe and substantially gut-restricted; yet it conveys systemic effects via activation of gut peptide hormone secretion, including GLP-1, GLP-2, and cholecystokinin (CCK).
CCK has long been recognized as an interesting pharmaceutical target because its release is triggered with food and helps suppress feelings of hunger. ARD-101 stimulates the release of the body's natural CCK, but primarily targets vagal nerve afferents located near the gut; this in turn induces positive effects on hunger, metabolism, and inflammation through gut-brain signalling. The selective local secretion avoids the off-target side effects seen with approaches using systemic exposure of artificial CCK analogue molecules.
In summary, the three studies from unpublished data demonstrate that in:
A placebo-controlled study in 20 patients with general obesity, using the Control of Eating Questionnaire (COEQ), patients treated with ARD-101 experienced a 2.51-fold greater reduction in hunger rating compared to those receiving placebo (p=0.015).
In an open label study with Prader-Willi Syndrome patients, 11 of 12 patients showed a reduction in hyperphagia in only 28 days using the HQ-CT (Hyperphagia Questionnaire for Clinical Trials) assessment with an average reduction of 7 points and demonstrating often beneficial changes to behaviour. Four of the twelve subjects had a near complete resolution of hunger symptoms.
In an open label post-bariatric surgery study in 11 subjects who continued to gain weight after surgery, there was a consistent reduction in hunger scores, as well as cravings for sweets and savoury foods.
Overall, ARD-101 did not demonstrate appreciable nausea or diarrhoea that is common among the GLP-1 drugs currently being marketed.
While the neural pathways regulating these sensations overlap, according to the company ARD-101 is thought to be the only drug in development with a significant impact on the hunger axis. This is particularly relevant to individuals with Prader-Willi Syndrome (PWS) who have a lifelong insatiable hunger and have inhibited ability to release their endogenous CCK. Thus far, no drug has been approved by the FDA to address the hyperphagia in PWS.