The best-known bitter taste receptors are in the mouth, where they deter children from eating broccoli and, more usefully, warn all of us against the ingestion of truly toxic substances. Less well known are the bitter taste receptors that occur elsewhere. These are the extraoral bitter taste receptors. They appear throughout the body—in the gut, on the skin, in the lung, and in the bladder—and they are evolutionally well conserved.

Because they are well conserved across species, the receptors are amenable to preclinical investigation with animal models. For example, preclinical models of metabolic and inflammatory disease have been used to demonstrate the potential of drugs that act via bitter taste receptors to activate innate homeostatic pathways. This approach is being explored by Aardvark Therapeutics, which is targeting bitter taste receptors that are expressed on the enteroendocrine I and L cells in the digestive tract.

There are approximately 25 subtypes of bitter taste receptors in humans. Eight of these subtypes are hit by Aardvark’s lead drug candidate, ARD-101. According to Aardvark, ARD-101 demonstrates the potential of bitter taste receptor agonists to treat obesity, diabetes, and (eventually) inflammatory diseases.

Bitter taste activation triggers “antitoxin” responses in the body, including responses that shut down the appetite and decrease inflammation, explains Tien Lee, MD, Aardvark’s founder and CEO. “We’re at the cusp of several Phase II studies in obesity and Prader-Willi syndrome,” he continues. “And we anticipate a public financing to facilitate expansion of programs into other therapeutic indications.”

Blockbuster potential

When Aardvark conducted research with ARD-101, the company noticed that the drug engaged receptors in the gut to help suppress appetite. But that was not all. “We saw that in addition to suppressing the appetite, ARD-101 also reduced low-density lipoprotein cholesterol, triglycerides, glucose, and hemoglobin A1C,” Lee recalls. These results indicated that ARD-101 could be useful in treating diabetes, hyperlipidemia, and obesity—the pillars of metabolic syndrome.

Further analysis and preclinical work also showed that ARD-101 profoundly lowers levels of pro-inflammatory cytokines. “This discovery really excited our team, and it was part of our motivation in raising Series B funding,” Lee points out. “Our next foray is to expand the potential therapeutic scope of our lead compound and advance additional pipeline programs.”

Another surprising finding emerged from Aardvark’s early research. “[We showed that] our drug is about 99% gut restricted—it stays in the gut, yet it conveys systemic effects,” Lee reports. “This is antithetical for most small-molecule drugs.” Lee adds that his team thinks ARD-101 triggers a series of events. The drug stimulates enteroendocrine cells in the gut, and then these cells activate signals that affect inflammatory and metabolic pathways throughout the body.

Because ARD-101 is retained in the gut, the potential for systemic toxicity is largely constrained, thus enhancing its safety profile. ARD-101 is delivered orally and, notably, is not shown to be as effective when delivered in other ways, such as by injection.

Bryan Jones, PhD, Aardvark’s chief business officer, speculates that because ARD-101 has the potential to address both diabetes and inflammatory diseases, it could be the first product to truly address metabolic syndrome: “We’ve known for a long time that both of these conditions overlap, but most of the therapeutics on the market affect only one or the other. It is unique to have a drug that affects both.”

Lee predicts that ARD-101 “could be a blockbuster drug, given its anticipated safety and efficacy as well as its potential to be combined with standard-of-care drugs.”

Multiple Phase II trials

Near the end of 2021, Aardvark launched three Phase II trials. They include a double-blind, placebo-controlled trial involving obese patients and another which addresses weight regain in post-bariatric surgery patients. The primary endpoint is weight loss, but secondary endpoints include such things as changes in hemoglobin A1C and blood lipid concentrations—specifically total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.

The third trial is for Prader-Willi syndrome, a rare pediatric disease in which patients have an unabating appetite. This trial was designed with meaningful support and guidance from the Foundation for Prader-Willi Research.

In 2022, Aardvark plans to launch two more Phase II trials. One will involve diabetes. The other will involve an as-yet-to-be determined inflammatory condition.

Aardvark is one of only a few companies exploring bitter taste receptors and, in some ways, benefits from the novelty of this approach. There’s little to benchmark its therapeutics against.

“Our mechanism of action is so distinct and the expected level of safety so high that we see no reason our therapeutic can’t be added atop standard-of-care treatments,” Lee declares. “We don’t expect additive toxicities with standard-of-care drugs.” Instead, Aardvark anticipate additive or synergistic efficacy. Lee suggests that if patients are prescribed ARD-101 in the future, there “may be few reasons to take them off it.”

Exploring neglected pathways

Aardvark was founded in 2017 as the result of Lee’s quest to find interesting science. “I was the chief strategy officer at my previous company, Nantkwest,” Lee says. “As a serial entrepreneur, I was agnostic as to what my next company would be. I became fascinated by the literature around bitter taste receptors and the core related pathways in the body, and I realized there was no visible commercial effort to develop a drug targeting these pathways.”

After testing the initial hypothesis that extraoral bitter taste receptors could be used for appetite suppression, the company focused its efforts there, with the help, Lee notes, of “former colleagues with whom I had worked at my previous company.”

While Lee says company development has been driven by a series of fortuitous events, he acknowledges that leveraging luck also requires working with the right people. “My general rule is to work with folks who are smarter than me,” Lee relates, smiling.

As Aardvark moves forward, the challenge is to identify a path to market, Lee says. That means continuing to get evidence that ARD-101 works for obesity and diabetes and, eventually, to demonstrate that the company’s approach is an appropriate way to address metabolic syndrome.

In addition to its programs in the gut, Aardvark is exploring other classes of bitter taste receptors in preclinical programs. “One is orally absorbed,” Jones says, “and it works on a different tissue—the bladder—so, it may be used to treat urinary incontinence.”

In that example, preclinical evidence shows that the active compound in the drug is absorbed systemically but accumulates in the bladder, where it induces relaxation. The hope is that it will do so without the side effects associated with other urinary drugs that cause many patients to stop taking them, often within the first year. “We’re doing medicinal chemistry and lead selection now,” Lee remarks. “It’s very exciting.”

The company is also looking at reformulating other drugs. One, for example, may become a topical treatment for psoriasis. “The interesting question,” Jones says, “is how many of these bitter taste receptors are primarily working as protection from toxins versus regulating other essential physiological pathways.”  

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