Data from our novel EGX series shows translational antidepressant-like effects, similar to those seen with psilocybin
atai Life Sciences
Healing mental health disorders so that everyone, everywhere can live a more fulfilled life.
We are committed to bringing the next generation of mental health treatments to patients through industry leading innovation. One way we do this is by using Artificial Intelligence (AI) and Machine Learning (ML) to speed up the drug discovery process, allowing us to efficiently identify high potential new chemical entities (NCEs). Last week at the Society for Neuroscience 2023 Conference in Washington D.C., our Senior Director of Neurobiology, Carrie Bowen, presented preclinical research findings on EGX-A and EGX-B, which are novel molecules we discovered using an AI, ML and medicinal chemistry (medchem) approach. We present a summary of these findings below, and you can find the full poster presentation on our website here .
Research Overview
Treatment-resistant depression represents a huge unmet medical need. It is estimated that almost 300 million people worldwide suffer from depression [1]. Current treatment options lack efficacy for a large portion of these patients and long-term side effects are a barrier to successful treatment for many [2].?Research suggests the potential of serotonergic psychedelic compounds, such as psilocybin, to produce rapid and lasting antidepressant activity after a single dose [3].
Two novel 5-HT2A receptor agonists discovered using our bespoke AI/ML/medchem approach, EGX-A and EGX-B, were investigated for antidepressant drug-like effects. We used translational electroencephalography (EEG)-based measures in an animal model of treatment-resistant depression (Wistar Kyoto rats). This strain of rat exhibits characteristics consistent with depression in humans, in particular increased rapid eye movement (REM) sleep. Traditional antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (SSRIs) demonstrate a limited ability to suppress the increased REM sleep in Wistar Kyoto rats, which makes these rodents a potentially valuable genetic model for studying treatment-resistant depression.?
The Compounds
EGX-A and EGX-B are potent and robust activators of 5-HT2A receptors (a type of serotonin receptor), which are known to underlie the hallucinogenic effects of serotonergic psychedelic drugs. These novel compounds exhibit greater potency and efficacy to activate 5-HT2A compared to 5-HT2B receptors, a highly desirable profile, as persistent activation of 5-HT2B receptors has been linked to cardiovascular safety risks. The EGX compounds also induce a head twitch response in mice, supporting in vivo 5-HT2A receptor activation and hallucinogenic potential of these novel molecules.?
The table below outlines the compound profiles compared to psilocin, the pharmacologically active compound in the body after ingestion of psilocybin.?
The Results
This study in an animal model of treatment-resistant depression demonstrated that acute administration of each of the EGX compounds produced effects on REM sleep and quantitative EEG (qEEG) profiles of brain electrical activity measured during waking, which were consistent with the effects of psilocybin.??
REM sleep:
Our study demonstrated that acute administration of novel 5-HT2A agonists delayed the onset of REM sleep and decreased its overall duration. These effects on REM sleep align closely with what has been observed following acute and chronic antidepressant treatment in healthy and depressed subjects [8-9] and psychedelic drug administration in both healthy individuals and rodents [4-7]. These results provide encouraging support for translational antidepressant-like effects of the novel EGX compounds.
领英推荐
qEEG profile during the waking period:
Our novel 5-HT2A agonists EGX-A and EGX-B acutely increased the power of brain oscillations in the theta (4-7 Hz) and beta (14-30 Hz) frequency bands and decreased power in the high gamma (50-100 Hz) band in WKY rats, a profile of effects similar to those seen with psilocybin. These results provide encouraging support for translational psychedelic-like effects of the novel compounds. The decrease in waking high gamma power is consistent with reports of serotonergic psychedelics (e.g., psilocybin/psilocin, LSD, mescaline) generating EEG power decreases during waking in healthy subjects and rodents [6,7],[10-12]. The overall qEEG profiles observed in the present work may differ from other psychedelic EEG studies due to several factors, including experimental setup and data quantification and analysis techniques.?
Overall, we’re encouraged by these findings. Our EGX compounds showed significant effects on translational EEG-based measures of REM sleep and waking brain activity, resembling the effects of psychedelic and antidepressant drugs. EGX-B also demonstrated a more limited impact on body temperature and movement, compared to EGX-A or psilocybin. In future clinical trials, these EEG-based measures could be valuable in confirming how these novel EGX compounds influence brain activity in human subjects. Furthermore, an even more precise approach may be possible through identifying baseline EEG patterns.??
Beyond the EGX series, we continue to make great progress within drug discovery. Central to our mission is identifying novel compounds that optimize for greater convenience, flexible dosing options and most importantly, patient access. We anticipate sharing further updates on our drug discovery work in the near future.??
Forward-Looking Statements:
Please note that the information provided above contains forward-looking statements.?We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy, short-term and long-term business operations and objectives, and financial needs. These forward-looking statements are subject to a number of important factors that could cause actual results to differ materially from those in the forward-looking statements, including the risks, uncertainties, and assumptions described under "Summary Risk Factors" below, “Risk Factors” in Item 1A of Part I, “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in Item 7 of Part II and elsewhere in our Form 10-K for the year ended December 31, 2022, filed with the Securities and Exchange Commission (SEC), as may be updated by other filings we file with or furnish to the SEC.
Any forward-looking statements made herein speak only as of the date of this communication, and you should not rely on forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee that the future results, performance, or achievements reflected in the forward-looking statements will be achieved or will occur. Except as required by applicable law, we undertake no obligation to update any of these forward-looking statements for any reason after the date hereof or to conform these statements to actual results or revised expectations.
About atai Life Sciences:
atai is a clinical-stage biopharmaceutical company aiming to transform the treatment of mental health disorders. Founded as a response to the significant unmet need and lack of innovation in the mental health treatment landscape, atai is dedicated to acquiring and efficiently developing innovative therapeutics to treat depression, anxiety, addiction, and other mental health disorders. By pooling resources and best practices, atai aims to responsibly accelerate the development of new medicines to achieve clinically meaningful and sustained behavioral change in mental health patients. atai's vision is to heal mental health disorders so that everyone, everywhere can live a more fulfilled life. For more information, please visit?www.atai.life .
References
?
Marketing @ thirdweb
1 年????