Regulatory feedback on drug discrimination studies for a small molecule with a novel mechanism of action

• Published in: Journal of pharmacological and toxicological methods Vol. 133; p. 107623
• Main Authors: Greiter-Wilke, Andrea, Roberts, Sonia, Mohr, Susanne, Paehler, Axel, Gerlach, Irene, Hoener, Marius, Tessari, Michela
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2025
• ISSN: 1056-8719
• DOI: 10.1016/j.vascn.2025.107623

A small molecule (compound_x) in phase II development for schizophrenia with a novel mechanism of action was assessed for potential drug abuse liability. In silico and in vitro assays did not show any structural similarity to known drugs of abuse or secondary pharmacology hits in an extended CNS panel. Transient CNS related clinical signs in rat toxicology studies up to 26 weeks at high exposure multiples included salivation, head burrowing, head shaking, and decreased activity, however no effects on general behavior in a GLP Irwin test in rats or in repeat dose toxicity studies in cynomolgus monkeys were observed. With the exception of one subject experiencing euphoria, the adverse event profile in clinical studies in healthy volunteers and patients was not suggestive of abuse potential. We sought feedback from the FDA Controlled Substance Staff (CSS) prior to study initiation, suggesting a withdrawal study (with chlordiazepoxide as positive control), a self-administration (SA) study and a drug discrimination (DD) study (both with amphetamine as positive control) in male Lister hooded rats. Whereas the agency generally agreed to all study outlines, they advised to “more appropriately design the DD study using compound_x as a training drug and cross testing several known drugs of abuse with various mechanisms of action”. Based on the benign non-clinical profile we considered it unlikely that compound_x would provide sufficient discriminative cues from vehicle at 3-fold human therapeutic Cmax exposure. Our response to CSS therefore suggested limiting the training to 50 sessions (25 on compound_x, 25 on vehicle). This was accepted and all studies were initiated. The withdrawal, the SA and the DD study with amphetamine were completed without any signs for abuse potential of compound_x. The training phase of the DD study with compound_x was stopped after 50 sessions due to a lack of success, with PK sampling demonstrating adequate exposure. Therefore, the requested DD study with several drugs of abuse could not be performed as previously planned and the non-clinical abuse liability package for compound_x was considered completed. Regulatory feedback is pending.