CCK

Depression is one of the most common mental illnesses in the world, but current anti-depressants have yet to meet the needs of many patients. Neuroscientists recently discovered a small molecule that can effectively alleviate stress-induced depressive symptoms in mice by preventing aversive memory formation with a lower dosage, offering a new direction for developing anti-depressants in the future. Depression is one of the most common mental illnesses in the world, but current anti-depressants have yet to meet the needs of many patients. Neuroscientists from City University of Hong Kong (CityU) recently discovered a small molecule that can effectively alleviate stress-induced depressive symptoms in mice by preventing aversive memory formation with a lower dosage, offering a new direction for developing anti-depressants in the future. "Depression affects millions of individuals worldwide, necessitating more effective treatments. Conventional methods, such as drug therapy with delayed onset of action and psychotherapy, have limitations in yielding satisfactory results for many patients. A pioneering advancement in treatment is urgently needed," said Professor He Jufang, Wong Chun Hong Chair Professor in Translational Neuroscience at CityU. Previous research found that stress leads to neural plasticity changes in brain's valence-coding systems ("valence" refers to the degree to which something is pleasurable or aversive), which are strongly associated with depression, post-traumatic stress disorders and anxiety disorders. Also, some studies revealed that depression is correlated with the hyperactivated amygdala. "However, the neural mechanism that mediates depression in amygdala is still poorly understood," said Professor He. Over the years, Professor He's research group has focused on memory formation and encoding studies. Previously, they discovered that cholecystokinin (CCK), a key neuromodulator, is crucial for inducing long-term potentiation (LTP) -- a lasting increase in communication strength between neurons -- to enable memory formation. They also found that the CCK and CCK-B receptors (CCKBR is one of three known types of CCK receptors in the central nervous system) mediate neuroplasticity, as well as visual and sound associative memory formation, in the auditory cortex, and trace fear memory formation in the amygdala. Other studies have found that CCKBR antagonist (which blocks the binding of the CCK and CCK-B receptors, thus inhibiting the effect of the binding) exhibited an anti-depressant effect in mice. So Professor He's group hypothesized that CCK might facilitate aversive memory formation by enabling LTP in the basolateral amygdala (BLA) -- a brain region involved in processing emotional memories and thought to be dysregulated in depression, thus enhancing the development of depression. In their latest study, they tested this hypothesis using various experimental methods, including in vitro electrophysiological recording, optogenetic manipulation, drug manipulation and behavioural analysis of mice, to examine the critical role of CCK and CCKBR in depression. They found that a CCKBR antagonist called YM022 had an anti-depressant-like effect by blocking neuroplasticity-caused aversive memory formation in mice. The results of the in-vitro recording in the BLA showed that the YM022 significantly suppressed neuroplasticity. The neuroplasticity induction rate reached 72.3% in the control group; but it was only 10.2% in the drug-treated group. Moreover, the team underwent a series of behavioural tests to determine the antagonist's efficacy. The results showed that depressive behaviours in mice treated with a CCKBR antagonist was reduced. "Remarkably, the YM022 shows anxiolytic effects with a dose of 3.0 ug/kg, which is 3,000 times lower than the required dosage of current antidepressants," said Professor He. "These results indicate that CCKBR is a potential target for depression treatment, and that the selected antagonist, YM022, may be a good anti-depressant candidate due to its extremely small effective dose. This paves the way for targeted drug development that specifically addresses the abnormalities observed in the basolateral amygdala." Next, the research team will focus on the precise mechanisms and potential side effects of CCKBR antagonists to set the stage for future clinical trials involving human subjects. The research was supported by Hong Kong Research Grants Council, the Innovation and Technology Fund, the Health and Medical Research Fund, and the following charitable foundations: the Wong Chun Hong Endowed Chair Professorship, the Charlie Lee Charitable Foundation, and the Fong Shu Fook Tong Foundation.

The FDA granted Aardvark Therapeutics a Rare Pediatric Designation for the use of ARD-101 in Prader-Willi Syndrome (PWS), a rare genetic disease characterized by extreme and unabating hunger. Aardvark's Phase 2 trial of oral ARD-101 in young adults with PWS is now open for enrollment of additional subjects. SAN DIEGO, Aug. 3, 2023 /PRNewswire/ -- Aardvark Therapeutics, Inc., a clinical stage biopharmaceutical company, today reported receipt of a Rare Pediatric Disease Designation in Prader-Willi Syndrome (PWS) from the FDA for its lead program ARD-101. This designation means Aardvark is eligible for a Rare Pediatric Disease Priority Review Voucher when ARD-101 receives approval in PWS. The early clinical study results suggest a promising future for a new class of pharmaceuticals that could benefit people with insatiable hunger (hyperphagia) and aggressive food-seeking behaviors, as well as for obesity and metabolic conditions, which are prominent features of the rare genetic condition PWS. Thus far, no drug has been approved by the FDA to treat the hyperphagia associated with PWS. Prader-Willi Syndrome (PWS) PWS is a severe neurodevelopmental disorder with a prevalence of about 1 in 15,000-20,000 births. The disorder is caused by the loss of function of several genes located on chromosome 15. PWS impacts multiple organ systems and is characterized by metabolic, endocrine, and neurological dysfunction. One of the hallmark characteristics of PWS is morbid obesity in early childhood, accompanied by developmental delays and musculoskeletal malformations. Obesity in PWS is driven by hyperphagia and mitigated by strict control of food intake. Strict food control, if anything, exacerbates hyperphagia, anxiety and aggressive food-seeking behavior, which is most stressful for those afflicted as well as their caregivers. About PWS Clinical Study Previously, Aardvark had enrolled 12 subjects in a Phase 2 study of oral ARD-101 in PWS (ClinicalTrials.gov ID NCT05153434) led by Dr. Diane Stafford at Stanford Children's Health and Dr. Shawn McCandless at Colorado Children's Hospital. Based on promising results, Aardvark is enrolling additional subjects and exploring higher drug doses. About ARD-101 Aardvark's lead product, ARD-101, is a first-in-class oral composition that has shown promising activity in reducing hunger cravings in clinical studies and promoting weight loss in pre-clinical studies. ARD-101 is substantially gut-restricted and has minimal systemic exposure. It is postulated that ARD-101 conveys its systemic effects by activating secretion of several gut peptide hormones, including glucagon-like peptides-1 and -2(GLP-1, GLP-2), and cholecystokinin (CCK). Gut CCK is considered a "satiety signal" that acts via the gut-brain axis to control hunger. PWS patients have a normal CCK receptor but their CCK release from gut enteroendocrine I-cells in response to food is impaired, leaving PWS patients with a continuous sense of extreme hunger. Phase I studies demonstrated safety and tolerability in healthy human volunteers. Three Phase II studies have demonstrated an impact on hunger suppression. About Aardvark Therapeutics, Inc. Aardvark Therapeutics is a clinical stage biopharmaceutical company focused on developing novel small molecule therapeutics to activate innate homeostatic pathways for the treatment of metabolic diseases, inflammation, and other indications. Founded in 2017, the company has now advanced ARD-101 to Phase II clinical trials. Aardvark has multiple other programs in its pipeline. For more information visit .

SAN DIEGO, Aug. 3, 2023. Aardvark Therapeutics, Inc., a clinical stage biopharmaceutical company, today reported receipt of a Rare Pediatric Disease Designation in Prader-Willi Syndrome (PWS) from the FDA for its lead program ARD-101. This designation means Aardvark is eligible for a Rare Pediatric Disease Priority Review Voucher when ARD-101 receives approval in PWS. The early clinical study results suggest a promising future for a new class of pharmaceuticals that could benefit people with insatiable hunger (hyperphagia) and aggressive food-seeking behaviors, as well as for obesity and metabolic conditions, which are prominent features of the rare genetic condition PWS. Thus far, no drug has been approved by the FDA to treat the hyperphagia associated with PWS. Prader-Willi Syndrome (PWS) PWS is a severe neurodevelopmental disorder with a prevalence of about 1 in 15,000-20,000 births. The disorder is caused by the loss of function of several genes located on chromosome 15. PWS impacts multiple organ systems and is characterized by metabolic, endocrine, and neurological dysfunction. One of the hallmark characteristics of PWS is morbid obesity in early childhood, accompanied by developmental delays and musculoskeletal malformations. Obesity in PWS is driven by hyperphagia and mitigated by strict control of food intake. Strict food control, if anything, exacerbates hyperphagia, anxiety and aggressive food-seeking behavior, which is most stressful for those afflicted as well as their caregivers. About PWS Clinical Study Previously, Aardvark had enrolled 12 subjects in a Phase 2 study of oral ARD-101 in PWS (ClinicalTrials.gov ID NCT05153434) led by Dr. Diane Stafford at Stanford Children's Health and Dr. Shawn McCandless at Colorado Children's Hospital. Based on promising results, Aardvark is enrolling additional subjects and exploring higher drug doses. About ARD-101 Aardvark's lead product, ARD-101, is a first-in-class oral composition that has shown promising activity in reducing hunger cravings in clinical studies and promoting weight loss in pre-clinical studies. ARD-101 is substantially gut-restricted and has minimal systemic exposure. It is postulated that ARD-101 conveys its systemic effects by activating secretion of several gut peptide hormones, including glucagon-like peptides-1 and -2(GLP-1, GLP-2), and cholecystokinin (CCK). Gut CCK is considered a "satiety signal" that acts via the gut-brain axis to control hunger. PWS patients have a normal CCK receptor but their CCK release from gut enteroendocrine I-cells in response to food is impaired, leaving PWS patients with a continuous sense of extreme hunger. Phase I studies demonstrated safety and tolerability in healthy human volunteers. Three Phase II studies have demonstrated an impact on hunger suppression. About Aardvark Therapeutics, Inc. Aardvark Therapeutics is a clinical stage biopharmaceutical company focused on developing novel small molecule therapeutics to activate innate homeostatic pathways for the treatment of metabolic diseases, inflammation, and other indications. Founded in 2017, the company has now advanced ARD-101 to Phase II clinical trials. Aardvark has multiple other programs in its pipeline. SOURCE Aardvark Therapeutics, Inc. Posted: August 2023