Bitter as sweet?The company has developed bitter taste receptors as a treatment

2022-06-16 0 By

Editor’s note: Humans have about 25 types of bitter taste receptors, not only in the mouth, but also in other areas such as the gut and bladder.Moreover, recent studies have found that bitter taste receptors may not only sense bitterness, but also have other important physiological functions, which have the potential to be used to prevent or treat diseases.Today, we look at Aardvark Therapeutics, a company that specializes in bitter taste receptors.Hope this article can bring some inspiration and help to the relevant industry personage and readers.Bitter receptors The most famous bitter receptors are found in the mouth.These bitter receptors aren’t just responsible for making kids hate eating broccoli. More importantly, they warn us against eating something truly toxic.But bitter taste receptors are actually found in many parts of the body besides the mouth — the gut, skin, lungs, and bladder.Although the bitter-taste receptors in these parts may be relatively unknown, they have been well preserved through evolution.Because bitter taste receptors are well conserved between species, animal models can be used for preclinical studies.For example, preclinical models of metabolic and inflammatory diseases have been used to confirm the potential of certain drugs to activate innate immune homeostasis through bitter taste receptors.A company called Aardvark Therapeutics is currently conducting research that looks at bitter taste receptors expressed by endocrine I and L cells in the gut.Humans have about 25 bitter receptor subtypes.Aardvark’s drug candidate, ARD-101, acts on eight of these subtypes.According to Aardvark, arD-101 has great potential as a bitter receptor agonist in the treatment of obesity, diabetes and inflammatory diseases.”The activation of bitter taste triggers’ antitoxin ‘responses in the body, including appetite suppression and inflammation reduction,” explains Tien Lee, PhD, founder and CEO of Aardvark.We are in a phase II study of ARD-101 in patients with obesity and Prader-Willi syndrome (PWS).We look forward to additional public funding to expand the ARD-101 candidate to other therapeutic areas.”(Editor’s note: Prader-Willi syndrome is the most common obesity syndrome, and its pathogenesis is the loss of paternal gene expression in the discrete region of the long arm of chromosome 15, and its causes include paternal chromosome deletion or maternal paradiploid.)The potential of ARD-101 When Aardvark studied ArD-101, they found that the drug was associated with receptors in the gut that could suppress appetite, but that’s not all.”We found that in addition to suppressing appetite, ARD-101 reduced LDL cholesterol, triglycerides, glucose, and a1c,” Lee recalled.”These results suggest that ARD-101 can be used to treat diabetes, hyperlipidemia and obesity, suggesting that arD-101 has great potential to treat metabolic syndrome.”Further analysis and preclinical work also showed that ARD-101 significantly reduced pro-inflammatory cytokine levels.”This discovery was very exciting for our team, and it was one of the motivations for us to raise series B funding,” Lee noted.Our next steps will be to try to expand the potential therapeutic range of the lead compound and move forward with other related projects.”Another surprise came from Aardvark’s earlier study.”About 99 percent of drugs are limited by the gut,” Lee notes.However, WHILE ARD-101 stays in the gut, it can be transmitted throughout the body, with systemic effects.This is the opposite of most small molecule drugs.”Lee added that his team believes ARD-101 triggered a chain of events.The drug stimulates intestinal endocrine cells in the gut, which in turn activate signals that affect inflammation and metabolic pathways throughout the body.Because ARD-101 is retained in the gut, its systemic toxicity is largely limited, thus improving its safety.It is important to note that ARD-101 is an oral drug and is not as effective when administered in other ways, such as by injection.Dr. Bryan Jones, Chief commercial officer of Aardvark, speculates that arD-101 may be the first product to truly treat metabolic syndrome because of its potential to treat diabetes and inflammatory diseases.”Ard-101 has the potential to treat both diabetes and inflammatory diseases,” he said.But most treatments on the market only work for one of these conditions.”It’s unique that there is a drug that works in both conditions.”Ard-101 is likely to become a blockbuster, Lee predicts, given the expected safety, efficacy, and potential in combination with standard treatments.In late 2021, Aardvark initiated three Phase 2 clinical trials.The first was a double-blind, placebo-controlled trial of obese patients, and the second looked at patients who regained weight after bariatric surgery.The primary end point was weight loss, and secondary measures included changes in hba1c and lipid concentrations — specifically total cholesterol, triglycerides, HIGH-DENSITY lipoprotein cholesterol, and low-density lipoprotein cholesterol.The third trial is for PWS, a rare childhood disease that causes patients to lose their appetite.The trial was strongly supported and directed by the Prader-Willi Research Foundation.Aardvark plans to conduct two more Phase 2 trials in 2022.One was about diabetes and the other was about an inflammation of unknown cause.Aardvark is one of the few companies working on bitter taste receptors.To some extent, the company benefited from this innovative approach because there was no yardstick against which to measure it.”Our mechanism of action is so unique and the expected level of safety is so high that we have no reason to think that our treatment cannot be added to standard care,” Lee said. “We do not believe that arD-101 will be toxic when added to standard care.Instead, Aardvark expects synergies or synergies.””If patients are prescribed ARD-101 in the future, there may be no reason to stop them,” Lee suggested.Aardvark was founded in 2017 as the result of a scientific quest by founder Lee.”I was the chief strategy officer at my previous company, Nantkwest,” Lee says.As a non-stop entrepreneur, I had no idea what my next company would be.It wasn’t until I became fascinated by the literature on bitter receptors and core-related pathways in the body that I realized there was no commercial effort to develop drugs for these pathways.””After testing the initial hypothesis that exooral bitter taste receptors could be used to suppress appetite, Aardvark focused on that with the help of my former colleague [Nantkwest’s former colleague],” Lee says.While Lee says the company’s growth was driven by a series of happenstance, he admits it was a combination of luck and working with the right people.”My rule is to work with people smarter than I am.”Lee said with a laugh.As Aardvark grows, Lee says, it faces a challenge — finding a way to market.That means continuing access to research data to demonstrate arD-101’s effectiveness in obesity and diabetes, and ultimately to demonstrate that the company’s treatment is an appropriate solution for metabolic syndrome.In addition to the gut, Aardvark is also exploring other types of bitter taste receptors in preclinical trials.”The other one is also absorbed orally,” Jones says, “but it acts on another tissue — the bladder.Therefore, it may be used to treat urinary incontinence.”In this case, preclinical evidence suggests that the active compound in the drug is systematically absorbed, but accumulates in the bladder and is released there.It is hoped that the drug will not cause side effects associated with other urinary drugs, which can cause many patients to stop taking them within a year.”We are now studying the chemistry of the drug and screening for lead compounds,” Lee said. “This is very exciting.”The company is also considering reformulating other drugs.For example, a possible topical treatment for psoriasis.”The interesting question is, how many of these bitter receptors are primarily protective, protecting the body from toxins, and how many are regulating other physiological pathways that are necessary,” Jones said.Original link:https://www.genengnews.com/topics/drug-discovery/bitter-taste-receptors-represent-a-therapeutic-sweet-spot/ | author GailDutton | He Xiaolu