The Pathway to Proof-of-Concept for BNC210, a Negative Allosteric Modulator of the Alpha-7 Nicotinic Acetylcholine Receptor (nAChR), for Treatment of Psychiatric Disease.

BNC210 is an investigational small molecule selective negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7 nAChR). It is an anxiolytic compound with a novel mechanism of action. In a series of Phase 1 clinical trials in healthy volunteers, psychometric test batteries showed that BNC210 did not cause attention, cognition, or memory impairment, negative effects on mood or emotional stability, sedation, or addiction, ruling out undesirable side effects of known anxiolytic compounds. In healthy volunteers, target engagement at the α7 nAChR was demonstrated in a nicotine shift assay using quantitative electroencephalography, and BNC210 demonstrated improvement in panic-like symptoms in a cholecystokinin tetrapeptide panic model. Initial clinical trials used an aqueous suspension formulation of BNC210 to cover a wide dosage range; however, its pharmacokinetic parameters were consistent with solubility-limited absorption and a significant food effect. A dispersible tablet formulation was then developed with improved bioavailability and is being used in Phases 2 and 3 clinical trials. Collectively, the Phase 1 data demonstrated desired properties of BNC210 supporting proof-of-concept clinical trials. BNC210 is currently being developed for acute, as-needed treatment of social anxiety disorder and chronic treatment of post-traumatic stress disorder.