title: When is a Proof-of-Concept (POC) not a POC? Pomaglumetad (LY2140023) as a Case Study for Antipsychotic Efficacy.
abstract: Pomaglumetad methionil (LY2140023) is a mGlu2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. While there was some evidence of an antipsychotic effect in these studies on an a priori specified genetically-defined subpopulation based on single nucleotide polymorphisms of the 5-hydroxytryptamine2A receptor gene (HTR2A) , these effects were modest when compared to very limited effects in the overall population of schizophrenic patients responding to SOC second generation antipsychotic drugs. Post-hoc analyses also suggested antipsychotic efficacy for pomaglumetad methionil in subjects with a disease duration equal/less than 3 years or subjects previously treated with antipsychotic drugs predominantly acting at dopamine D2 receptors compared to 5-HT2A receptors. Orthogonal to these results with the mGlu2/3 receptor agonist prodrug, a 5-HT2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson's disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu2/3 receptor agonists and 5-HT2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer's disease psychosis.
authors.affiliation: Astellas Pharma Global Development, Global Medical Science, CNS and Pain, 1 Astellas Way, Northbrook, IL 60062, USA. gerard.marek@astellas.com.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Marek
mesh_terms: D000596:Amino Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D011618:Psychotic Disorders / Q000188:drug therapy / Q000503:physiopathology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; C534551:LY 2140023; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3