A Novel Small Molecule-Based Therapy for Schizophrenia.

Schizophrenia is one of the most costly mental disorders in terms of human suffering and societal expenditure. A significant body of preclinical and clinical literature indicates that activation of muscarinic acetylcholine receptors holds tremendous promise for the treatment of the disease. Numerous pharmaceutical companies have made efforts at developing muscarinic agonists but none of these programs has advanced to market. The problem companies encountered was that the compounds that activate d the M1 and M4 receptor subtypes in the central nervous system (CNS), which mediate agonists therapeutic effect, also activate the M2 and M3 receptor subtypes in the periphery, which produce unacceptable side effects. Karuna is pioneering a novel approach that combines the most promising known muscarnic agonist (xanomeline), which has human proof-of-concept data in schizophrenia and Alzheimer's psychosis, with a generic, peripherally restricted muscarnic antagonist (trospium chloride) to decrea se xanomeline's side effects. Like other muscarinic programs, xanomeline was discontinued by the originator despite promising efficacy due to unacceptable side effects. Karuna has licensed xanomeline and has designated the combination of the agonist and antagonist KP7634. In this study, Karuna aims to determine whether KP7634 combination therapy has a superior safety profile to xanomeline alone.