ly-2140023 and Schizophrenia

Topics: Amino Acids; Antipsychotic Agents; Clinical Trials as Topic; Drug Discovery; Humans; Molecular Targeted Therapy; Receptors, Metabotropic Glutamate; Schizophrenia; Synaptic Transmission

Based on the glutamate hypothesis of schizophrenia, extensive studies to develop drugs acting on glutamate receptors have been conducted. Among glutamate receptors, metabotropic glutamate (mGlu) receptors, all of which are GPCRs, have 8 subtypes, and are involved in regulation of glutamate transmissions. Of these, much attention has been paid to mGlu2/3 receptors and mGlu5 receptor. mGlu2/3 receptor agonists improve behavioral abnormalities such as locomotor hyperactivity and cognitive deficits induced by NMDA receptor antagonists. In addition, mGlu2/3 receptor agonists attenuate glutamate overflow in the prefrontal cortex, and regulate dopamine release and 5-HT2A receptor activity, all of which have been presumed to be involved in antipsychotic actions of mGlu2/3 receptor agonists. Recently, LY2140023, an mGlu2/3 receptor agonists developed by Eli Lilly, has been demonstrated to be effective for the treatment of positive and negative symptoms of schizophrenic patients in a phase II study, while it did not cause unwanted side effects often observed with current antipsychotic medications. Moreover, a series of experiments has demonstrated that mGlu5 receptor potentiators exert antipsychotic effects in animal models of schizophrenia. Therefore, mGlu2/3 receptor and mGlu5 receptor may provide exciting targets for the development of novel medications for schizophrenia.

Topics: Amino Acids; Animals; Antipsychotic Agents; Clinical Trials, Phase II as Topic; Disease Models, Animal; Dopamine; Drug Design; Glutamic Acid; Humans; Molecular Targeted Therapy; Receptor, Metabotropic Glutamate 5; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate; Schizophrenia

This thorough QT/QTc (TQT) study assessed the effects of a supratherapeutic dose of pomaglumetad methionil, a potential treatment for schizophrenia, compared to placebo on the QT interval in subjects with schizophrenia.. This double-blind, 3-period crossover study enrolled 86 subjects aged 22 - 63 years, who met Diagnostic and Statistical Manual, Fourth Edition, Test Revision (DSM-IV-TR) criteria for schizophrenia; 78 subjects completed the study. Subjects were randomly assigned to sequences of 3 treatment periods of single oral doses of pomaglumetad methionil 400 mg, moxifloxacin 400 mg, and placebo. Quadruplicate electrocardiograms (ECGs) were extracted from 2 hours predose to 12 hours postdose and were overread by a blinded central reader. Time-matched pharmacokinetic (PK) parameters were assessed.. At all-time points, the upper bound of the 90% 2-sided confidence interval (CI) for the least squares (LS) mean difference in changes from baseline in Fridericia's corrected QT interval (ΔQTcF) between pomaglumetad methionil and placebo was < 10 milliseconds (msec). Sufficient assay sensitivity was not achieved, likely due to food effect; although the maximum observed drug concentration (Cmax) with moxifloxacin (1,410 ng/mL) was lower than expected, the slope of the regression line of moxifloxacin plasma concentrations versus placebo-subtracted ΔQTcF was similar to that reported in the literature.. A single supratherapeutic dose of 400 mg pomaglumetad methionil did not prolong QTcF to a clinically significant degree and, importantly, did not result in any absolute QTcF > 450 msec or increase in QTcF from predose > 30 msec.

Topics: Administration, Oral; Adult; Amino Acids; Cross-Over Studies; Double-Blind Method; Drug Monitoring; Electrocardiography; Excitatory Amino Acid Agonists; Female; Heart Rate; Humans; Least-Squares Analysis; Male; Middle Aged; Prodrugs; Risk Assessment; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States; Young Adult

This 6-week, multicenter, randomized withdrawal, placebo-controlled trial sought to determine whether symptoms of physical dependence occur after abrupt cessation of pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate 2/3 receptor agonist, in patients with schizophrenia. Eligible outpatients, 18 to 65 years old who required a modification or initiation of antipsychotic medication received 4 weeks of pomaglumetad methionil during open-label treatment and then were randomized, double-blind, to continue pomaglumetad methionil or receive placebo for 2 weeks. The primary outcome compared results of the 3-day moving mean of the total score on the Discontinuation Symptom Checklist-Modified Rickels for pomaglumetad methionil-treated patients with those on placebo during the randomized withdrawal phase. An electronic patient-reported outcome (ePRO) device was used daily to record these results. During the withdrawal phase, 103 patients were randomized, and 98 patients completed the trial. There was no statistically significant evidence of withdrawal symptoms associated with placebo compared with pomaglumetad methionil continuation as measured by Discontinuation Symptom Checklist-Modified Rickels (P = 0.170). The results are supported by secondary analyses with the clinician-rated, Clinical Institute Withdrawal Assessment of Alcohol Scale Revised, which showed no statistically significant differences between treatment groups. Using the ePRO device, 82.5% of the patients achieved 75% to 100% of compliance. No discontinuations due to worsening of schizophrenia, serious adverse events, deaths, or seizures were reported during either phase of the study. These findings suggest that there is no evidence of withdrawal symptoms associated with the abrupt discontinuation of pomaglumetad methionil and that an ePRO device can be successfully used in a multicenter schizophrenia trial.

Topics: Adolescent; Adult; Aged; Amino Acids; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Outcome Assessment; Psychiatric Status Rating Scales; Receptors, Metabotropic Glutamate; Schizophrenia; Self Report; Substance Withdrawal Syndrome; Young Adult

Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia.. Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N = 1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461.. Neither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p = .154 [0.01]; LY80, p = .698 [0.01], subpopulation: LY40, p = .033 [0.0025]; LY80, p = .659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p < .001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023.. LY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed.. A Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT01086748.

Topics: Adult; Aged; Amino Acids; Antipsychotic Agents; Dopamine Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Receptors, Metabotropic Glutamate; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

We compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole).. Study HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n = 130) or SOC (n = 131).. There was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P = .184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P = .044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P = .505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P = .011) and akathisia (P = .029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P = .004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P = .444).. These data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics.. A Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR Schizophrenia.

Topics: Adolescent; Adult; Aged; Amino Acids; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Male; Middle Aged; Olanzapine; Piperazines; Quinolones; Risperidone; Schizophrenia; Standard of Care; Treatment Outcome; Young Adult

This study tested whether treatment with pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate receptor 2/3 agonist compared with placebo (PBO), when added to a fixed-dose second-generation antipsychotic (SGA) demonstrated significantly greater reduction of negative symptoms, as assessed by the 16-item Negative Symptom Assessment scale (NSA-16), in patients with schizophrenia. This parallel-group, 16-week study enrolled adults with schizophrenia who were receiving standard of care (SOC) therapy, which included ≥3months treatment with one of four SGAs: aripiprazole, olanzapine, risperidone, or quetiapine. Patients received either 20mg of twice daily LY2140023 monohydrate (LY2140023) or concurrent PBO SGA. The primary efficacy measure was change from baseline to final visit in NSA-16 total score. Secondary measures included additional measures of efficacy, cognition, and assessments of safety. Of 352 patients screened, 167 were randomly assigned to treatment, and 110 patients completed the study. Patients treated with LY2140023 and SOC failed to demonstrate a statistically significant improvement over patients treated with PBO and SOC on NSA-16 total score at endpoint or at any point during the study (all p>0.131). Changes in secondary efficacy measures were not significantly different between groups at endpoint. With the exception of vomiting which was greater in the LY2140023 group, there were no statistically significant differences in safety and tolerability measures. This study found no benefit of adjunctive LY2140023 versus PBO for negative symptoms in patients with schizophrenia receiving treatment with SOC. LY2140023 was generally well-tolerated in these patients.

Topics: Adolescent; Adult; Aged; Amino Acids; Analysis of Variance; Antipsychotic Agents; Cognition Disorders; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Visual Analog Scale; Young Adult

The goal of this study was to identify genetic markers associated with LY2140023 monohydrate response in patients with schizophrenia. Variants in eight candidate genes related to the mechanism of action of LY2140023 or olanzapine were investigated in a genetic cohort collected from two clinical trials. Results from this genetic analysis indicate that 23 single nucleotide polymorphisms (SNPs) were associated with a change in Positive and Negative Syndrome Scale total score in response to LY2140023 at 28 days (P<0.01; false discovery rate <0.2). Sixteen of these SNPs were located in the serotonin 2A receptor (HTR2A). Bioinformatic analyses identified a putative antisense nested gene in intron 2 of HTR2A in the region of the genetic markers associated with LY2140023 response. These data suggest a genetic association exists between SNPs in several genes, such as HTR2A, and response to LY2140023 treatment. Additional clinical trials are needed to establish replication of these results.

Topics: Adult; Amino Acids; Antipsychotic Agents; Benzodiazepines; Excitatory Amino Acid Agonists; Female; Haplotypes; Humans; Introns; Male; Neuregulin-1; Olanzapine; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate; Russia; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States

The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.

Topics: Adolescent; Adult; Aged; Amino Acids; Antipsychotic Agents; Benzodiazepines; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Inpatients; Male; Medication Adherence; Middle Aged; Olanzapine; Prodrugs; Psychiatric Status Rating Scales; Receptors, Metabotropic Glutamate; Schizophrenia

Glutamate neurotransmission has been considered as one of pathogenetic factors of schizophrenia though all antipsychotics widely used in modern psychiatric practice are dopamine antagonists. LY2140023 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors with antipsychotic effect. In the present study, we have assessed clinical efficacy of LY2140023 in patients with schizophrenia compared to the control group receiving olanzapine in a randomized double-blind placebo-controlled trial. The statistically significant reduction of positive and negative symptoms measured with the PANSS (p<0.001) was observed for both antipsychotics at week 4 of treatment compared to placebo. The treatment with LY2140023 was safe and well-tolerated; treated patients did not differ from the placebo group by hyperprolactinemia and extrapyramidal symptoms, and weight gain. The results suggest that the agonist for 2/3 (mGlu2/3) receptors has antipsychotic properties and provides a new, alternative to dopamine agonists, method for pharmacotherapy of schizophrenia.

Topics: Adolescent; Adult; Aged; Amino Acids; Antipsychotic Agents; Female; Humans; Male; Middle Aged; Receptors, Metabotropic Glutamate; Schizophrenia; Treatment Outcome; Young Adult

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.

Topics: Amino Acids; Animals; Antipsychotic Agents; Humans; Psychotic Disorders; Receptors, Metabotropic Glutamate; Schizophrenia; Treatment Outcome

Two recent Phase II results show opposing outcomes for the potential of activators of mGlu2 in the treatment of schizophrenia. The first outcome revealed that Eli Lilly's mGlu2/3 agonist, pomaglumetad methionil (LY2140023), failed to meet the primary efficacy end point. The second report showed the mGlu2 positive allosteric modulator (PAM) from Addex (ADX71149) in conjunction with Janssen Research & Development met the primary objectives of safety, tolerability and demonstrated an effect on negative symptoms in patients.

Topics: Allosteric Regulation; Amino Acids; Antipsychotic Agents; Humans; Receptors, Metabotropic Glutamate; Schizophrenia

Pomaglumetad methionil (LY2140023 monohydrate, hereafter referred to as LY2140023) is currently in clinical development as a potential new treatment for schizophrenia. If found to be effective, LY2140023 would represent a novel non-dopaminergic based therapy for this disorder that may restore balance to the glutamate dysregulation hypothesized to underlie schizophrenia. This article presents available clinical trial data that describe the safety, tolerability, and efficacy of LY2140023 in patients with schizophrenia. Data indicate that this compound appears to have an efficacy profile consistent with currently available antipsychotic drugs, although confirmation of its efficacy awaits further clinical testing. LY2140023 is generally well tolerated and appears to have a low association with adverse events related to dopamine D2 receptor antagonism and with weight gain, which are commonly seen with current antipsychotics. A potential association of LY2140023 treatment and seizure events has been identified, although an accurate and reliable understanding of the incidence of these events requires further clinical testing, which is underway. Evaluation of the safety, tolerability, and efficacy of LY2140023 is continuing. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Topics: Amino Acids; Antipsychotic Agents; Clinical Trials, Phase II as Topic; Excitatory Amino Acid Agonists; Humans; Schizophrenia

In recent years, evidence has been accumulating indicating a major role of glutamate in the pathogenesis and pathophysiology of schizophrenia. Of particular importance in this regard are the metabotropic glutamate receptors (GRM). Thus, a recently published trial of the amino acid analogue LY2140023, which exerts its effects through the activation of the glutamate receptors GRM3/GRM2, showed an improvement of positive and negative symptoms comparable to treatment with olanzapine. A functional variant of GRM3 has been described which modulates synaptic glutamate levels. We assessed whether this functional variant rs6465084 is related to schizophrenia in a large sample of patients and controls. We found an increased frequency of the A allele (p=0.027) and the AA genotype (p=0.024) in schizophrenia patients. Moreover, in an assessment of schizophrenia endophenotypes, patients of the AA genotype performed poorly in the digit symbol test, a measure of attention (p=0.008). Our results provide further evidence for the potential importance of the glutamate receptor GRM3 in schizophrenia, and indicate that the novel antipsychotic LY2140023 may actually be targeting a pathogenic pathway of schizophrenia.

Topics: Adult; Amino Acids; Antipsychotic Agents; Benzodiazepines; Chi-Square Distribution; Excitatory Amino Acid Antagonists; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Male; Neuropsychological Tests; Olanzapine; Pharmacogenetics; Receptors, Metabotropic Glutamate; Schizophrenia