Optimization and Development of Non-Hallucinogenic 5-HT2A/2C Agonists as Opioid Use Disorder Therapeutics

PROJECT SUMMARY: Opioid use disorder (OUD) is a critical global health crisis, impacting approximately 16 million individuals worldwide and costing over $750 billion annually. Tragically, it also leads to over 120,000 opioid-related deaths each year globally. Current treatments have significant limitations, including the risk of misuse. atai Therapeutics, Inc. ("atai") is addressing this urgent issue by developing innovative therapeutics that aim to effectively promote sustained recovery and potentially manage opioid withdrawal symptoms without the risk of misuse associated with current therapies. Psychedelic drugs, such as psilocybin, that activate the 5-HT2A and 5-HT2C receptors have shown promise for OUD. However, they have significant liabilities, including cardi- ovascular toxicity related to activation of the 5-HT2B receptor, long hallucination episodes that result in extensive and costly clinical monitoring, and misuse potential. atai is leveraging the therapeutic potential of psychedelics while mitigating their liabilities to develop highly selective 5-HT2A/2C receptor agonists that lack the hallucino- genic activity, cardiac risks, and misuse potential. This innovative approach could revolutionize treatment by allowing patients to achieve a durable abstinence and manage withdrawal symptoms without extensive clinical monitoring and its associated cost. atai has identified two lead chemical series, including EGX-J and EGX-I lead compounds, that in preliminary studies exhibited non-hallucinogenic potential and engaged their targets in a manner reflective of the polypharmacology of psilocybin. Compounds within both series show 100-fold agonist selectivity for 5-HT2A/2C receptors over the 5-HT2B receptor (mitigate cardiac risk). The clinical and commercial potential of atai's selective 5-HT2A/2C receptor agonists are significant as they could be more effective than current treatments and could simplify and reduce the cost of care by decreasing the need for intense clinical supervision. In this UG3/UH3 project, atai will: 1) optimize two lead chemical series, enhancing their drug-like properties, 5-HT2A/2C over 5-HT2B receptor agonist selectivity, oral bioavailability, safety, and efficacy (UG3). This rigorous process will position atai to confidently select both the development and backup candidates, setting the stage for advancements in their drug development pipeline; 2) scale up and validate manufacturing of the development candidate, complete critical toxicity and safety pharmacology studies required for an Investigational New Drug submission, and perform preclinical efficacy durability/repeat dosing studies to inform clinical trial design (UH3). Successful completion of this project will position atai for the first-in-human Phase I clinical trial. As current drugs for OUD have failed to adequately address the opioid crisis, atai's novel 5-HT2A/2CR agonists could redefine the OUD standard of care, providing a more effective, safer, scalable, and patient-friendly treat- ment.