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Bruce J. Kinon - One of the best experts on this subject based on the ideXlab platform.
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Group II metabotropic glutamate receptor agonist prodrugs LY2979165 and LY2140023 attenuate the functional imaging response to ketamine in healthy subjects
Psychopharmacology, 2018Co-Authors: Mitul A. Mehta, Bruce J. Kinon, Anne Schmechtig, Vasileia Kotoula, Juliet Mccolm, Kimberley Jackson, Claire Brittain, Sitra Tauscher-wisniewski, Paul D. Morrison, Thomas PollakAbstract:Background Aberrant glutamate neurotransmission, and in particular dysfunction of the N -methyl- d -aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system. Objective To test the attenuation of the ketamine-induced BOLD signal by pretreatment with either a metabotropic glutamate receptor (mGluR) 2/3 or a mGluR2 agonist in healthy volunteers Methods We used a ketamine challenge pharmacological magnetic resonance imaging (phMRI) paradigm to assess the modulatory effects of single acute doses of LY2140023 (Pomaglumetad Methionil), the methionine prodrug of the mGluR2/3 agonist LY404039 (10, 40, and 160 mg; N = 16 subjects) and of LY2979165, and the alanine prodrug of the selective orthosteric mGluR2 agonist 2812223 (20 and 60 mg; N = 16 subjects). Results A reduction in the ketamine-evoked BOLD phMRI signal relative to placebo was observed at the highest doses tested of both LY2140023 and LY2979165. A relationship was observed between reduction of the BOLD signal and increasing plasma levels of 2812223 in the LY2979165 cohort. Conclusions These results identify pharmacologically active doses of the group II mGluR agonist prodrugs LY2140023 and LY2979165 in humans. They also extend the classes of compounds that have been experimentally shown to reverse the ketamine-evoked phMRI signal in humans, further supporting the use of this method as a neuroimaging biomarker for assessing functional effects.
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Group II metabotropic glutamate receptor agonist prodrugs LY2979165 and LY2140023 attenuate the functional imaging response to ketamine in healthy subjects
Psychopharmacology, 2018Co-Authors: Mitul A. Mehta, Bruce J. Kinon, Anne Schmechtig, Vasileia Kotoula, Juliet Mccolm, Kimberley Jackson, Claire Brittain, Sitra Tauscher-wisniewski, Paul D. Morrison, Thomas A PollakAbstract:Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-d-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system. To test the attenuation of the ketamine-induced BOLD signal by pretreatment with either a metabotropic glutamate receptor (mGluR) 2/3 or a mGluR2 agonist in healthy volunteers We used a ketamine challenge pharmacological magnetic resonance imaging (phMRI) paradigm to assess the modulatory effects of single acute doses of LY2140023 (Pomaglumetad Methionil), the methionine prodrug of the mGluR2/3 agonist LY404039 (10, 40, and 160 mg; N = 16 subjects) and of LY2979165, and the alanine prodrug of the selective orthosteric mGluR2 agonist 2812223 (20 and 60 mg; N = 16 subjects). A reduction in the ketamine-evoked BOLD phMRI signal relative to placebo was observed at the highest doses tested of both LY2140023 and LY2979165. A relationship was observed between reduction of the BOLD signal and increasing plasma levels of 2812223 in the LY2979165 cohort. These results identify pharmacologically active doses of the group II mGluR agonist prodrugs LY2140023 and LY2979165 in humans. They also extend the classes of compounds that have been experimentally shown to reverse the ketamine-evoked phMRI signal in humans, further supporting the use of this method as a neuroimaging biomarker for assessing functional effects.
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Clinical Study Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison
2016Co-Authors: David H. Adams, L. Zhang, Brian A. Millen, Bruce J. Kinon, J.c. GómezAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We tested the hypothesis that long-term treatment with Pomaglumetad Methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either Pomaglumetad Methionil
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Serotonin 2A Receptor SNP rs7330461 Association with Treatment Response to Pomaglumetad Methionil in Patients with Schizophrenia
Journal of personalized medicine, 2016Co-Authors: Laura Nisenbaum, David H. Adams, Brian A. Millen, Bruce J. Kinon, J.c. Gómez, Anncatherine M. Downing, Fangyi Zhao, Leanne M. Munsie, Michelle Ann PennyAbstract:This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with Pomaglumetad Methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to Pomaglumetad Methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ≤ 0.05) greater improvement in Positive and Negative Syndrome Scale (PANSS) total scores during treatment with Pomaglumetad Methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving Pomaglumetad Methionil had significantly (p ≤ 0.05) greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC) treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to Pomaglumetad Methionil compared to the A/A genotype.
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exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2 3 receptor agonist Pomaglumetad Methionil in schizophrenia
Biological Psychiatry, 2015Co-Authors: L. Zhang, Brian A. Millen, Bruce J. Kinon, David L MckinzieAbstract:Abstract Background Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of the existing clinical trial database of Pomaglumetad Methionil (Pomaglumetad) to demonstrate treatment response in targeted patient populations. Methods Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized. Patients with schizophrenia were randomly assigned to receive either Pomaglumetad, 40 or 80 mg twice daily (BID), placebo, or risperidone, 2 mg BID, for up to 6 weeks. Patient subgroups were analyzed to determine the efficacy of Pomaglumetad treatment in patients early-in-disease (≤3 years) and late-in-disease (≥10 years) (HBBM, 40 mg, n = 206, 80 mg, n = 198; integrated analysis, 40 mg, n = 382, 80 mg, n = 381) and in patients previously treated with central nervous system drugs with prominent serotonin 2A receptor antagonist activity (S2 group) or with predominant dopamine D2 receptor antagonist activity (D2 group; HBBM, 40 mg, n = 275, 80 mg, n = 269; integrated analysis, 40 mg, n = 590, 80 mg, n = 506). Results In the HBBM study and integrated analysis, only patients early-in-disease or previously treated with D2 drugs exhibited significantly greater improvement relative to those receiving placebo, when treated with Pomaglumetad, 40 mg (but not 80 mg) BID. Treatment response to risperidone did not appear to depend upon these patient subgroups. Conclusions Demonstration of antipsychotic efficacy of a potential glutamate-based pharmacotherapy for schizophrenia may require the identification of appropriate patient subgroups whose treatment responsiveness may be fundamentally related to dysregulation of central nervous system glutamatergic tone.
Brian A. Millen - One of the best experts on this subject based on the ideXlab platform.
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Clinical Study Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison
2016Co-Authors: David H. Adams, L. Zhang, Brian A. Millen, Bruce J. Kinon, J.c. GómezAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We tested the hypothesis that long-term treatment with Pomaglumetad Methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either Pomaglumetad Methionil
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Serotonin 2A Receptor SNP rs7330461 Association with Treatment Response to Pomaglumetad Methionil in Patients with Schizophrenia
Journal of personalized medicine, 2016Co-Authors: Laura Nisenbaum, David H. Adams, Brian A. Millen, Bruce J. Kinon, J.c. Gómez, Anncatherine M. Downing, Fangyi Zhao, Leanne M. Munsie, Michelle Ann PennyAbstract:This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with Pomaglumetad Methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to Pomaglumetad Methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ≤ 0.05) greater improvement in Positive and Negative Syndrome Scale (PANSS) total scores during treatment with Pomaglumetad Methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving Pomaglumetad Methionil had significantly (p ≤ 0.05) greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC) treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to Pomaglumetad Methionil compared to the A/A genotype.
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exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2 3 receptor agonist Pomaglumetad Methionil in schizophrenia
Biological Psychiatry, 2015Co-Authors: L. Zhang, Brian A. Millen, Bruce J. Kinon, David L MckinzieAbstract:Abstract Background Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of the existing clinical trial database of Pomaglumetad Methionil (Pomaglumetad) to demonstrate treatment response in targeted patient populations. Methods Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized. Patients with schizophrenia were randomly assigned to receive either Pomaglumetad, 40 or 80 mg twice daily (BID), placebo, or risperidone, 2 mg BID, for up to 6 weeks. Patient subgroups were analyzed to determine the efficacy of Pomaglumetad treatment in patients early-in-disease (≤3 years) and late-in-disease (≥10 years) (HBBM, 40 mg, n = 206, 80 mg, n = 198; integrated analysis, 40 mg, n = 382, 80 mg, n = 381) and in patients previously treated with central nervous system drugs with prominent serotonin 2A receptor antagonist activity (S2 group) or with predominant dopamine D2 receptor antagonist activity (D2 group; HBBM, 40 mg, n = 275, 80 mg, n = 269; integrated analysis, 40 mg, n = 590, 80 mg, n = 506). Results In the HBBM study and integrated analysis, only patients early-in-disease or previously treated with D2 drugs exhibited significantly greater improvement relative to those receiving placebo, when treated with Pomaglumetad, 40 mg (but not 80 mg) BID. Treatment response to risperidone did not appear to depend upon these patient subgroups. Conclusions Demonstration of antipsychotic efficacy of a potential glutamate-based pharmacotherapy for schizophrenia may require the identification of appropriate patient subgroups whose treatment responsiveness may be fundamentally related to dysregulation of central nervous system glutamatergic tone.
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A double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia
BMC Psychiatry, 2014Co-Authors: Anncatherine M. Downing, L. Zhang, Brian A. Millen, Bruce J. Kinon, Laura Nisenbaum, Ronald Brenner, Tami Jo Rayle, Lin Liu, Margarita A Morozova, Fangyi ZhaoAbstract:Background 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. Methods 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. Results 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
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A Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia
BMC psychiatry, 2014Co-Authors: Anncatherine M. Downing, L. Zhang, Brian A. Millen, Bruce J. Kinon, Laura Nisenbaum, Ronald Brenner, Tami Jo Rayle, Lin Liu, Margarita A Morozova, Fangyi ZhaoAbstract: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
David P. Walling - One of the best experts on this subject based on the ideXlab platform.
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Effect of Pomaglumetad Methionil on the QT interval in subjects with schizophrenia.
International journal of clinical pharmacology and therapeutics, 2015Co-Authors: Wei Zhang, William F. Annes, Jennifer Witcher, Mary Pat Knadler, Malcolm I. Mitchell, Amanda Long, David P. Walling, Mosun Ayan-oshodiAbstract:OBJECTIVE: 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. METHODS: 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. RESULTS: 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 450 msec or increase in QTcF from predose > 30 msec.
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A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of Pomaglumetad Methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia
BMC Psychiatry, 2013Co-Authors: David H. Adams, Brian A. Millen, Bruce J. Kinon, Simin Baygani, Isabella Velona, Sara Kollack-walker, David P. WallingAbstract:Background 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). Methods 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). Results 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). Conclusion 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. Trials registration 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 ClinicalTrials.gov identifier: NCT00845026 .
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A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of Pomaglumetad Methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia
BMC psychiatry, 2013Co-Authors: David H. Adams, Brian A. Millen, Bruce J. Kinon, Simin Baygani, Isabella Velona, Sara Kollack-walker, David P. WallingAbstract: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 ClinicalTrials.gov identifier: NCT00845026 .
David H. Adams - One of the best experts on this subject based on the ideXlab platform.
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Clinical Study Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison
2016Co-Authors: David H. Adams, L. Zhang, Brian A. Millen, Bruce J. Kinon, J.c. GómezAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We tested the hypothesis that long-term treatment with Pomaglumetad Methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either Pomaglumetad Methionil
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Serotonin 2A Receptor SNP rs7330461 Association with Treatment Response to Pomaglumetad Methionil in Patients with Schizophrenia
Journal of personalized medicine, 2016Co-Authors: Laura Nisenbaum, David H. Adams, Brian A. Millen, Bruce J. Kinon, J.c. Gómez, Anncatherine M. Downing, Fangyi Zhao, Leanne M. Munsie, Michelle Ann PennyAbstract:This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with Pomaglumetad Methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to Pomaglumetad Methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ≤ 0.05) greater improvement in Positive and Negative Syndrome Scale (PANSS) total scores during treatment with Pomaglumetad Methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving Pomaglumetad Methionil had significantly (p ≤ 0.05) greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC) treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to Pomaglumetad Methionil compared to the A/A genotype.
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Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison
Schizophrenia research and treatment, 2014Co-Authors: David H. Adams, L. Zhang, Brian A. Millen, Bruce J. Kinon, J.c. GómezAbstract:We tested the hypothesis that long-term treatment with Pomaglumetad Methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either Pomaglumetad Methionil () or aripiprazole (). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The Pomaglumetad Methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group (−2.8 ± 0.4 versus 0.4 ± 0.6; ). However, change in Positive and Negative Syndrome Scale (PANSS) total scores for aripiprazole was significantly greater than for Pomaglumetad Methionil (−15.58 ± 1.58 versus −12.03 ± 0.99; ). The incidences of SAEs (8.2% versus 3.1%; ) and discontinuation due to AEs (16.2% versus 8.7%; ) were significantly higher for Pomaglumetad Methionil compared with aripiprazole. No statistically significant differences in the incidence of TEAEs, EPS, or suicidal ideation or behavior were noted between treatment groups. In conclusion, long-term treatment with Pomaglumetad Methionil resulted in significantly less weight gain than aripiprazole. This trial is registered with ClinicalTrials.gov NCT01328093.
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Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison
Hindawi Limited, 2014Co-Authors: David H. Adams, L. Zhang, Brian A. Millen, Bruce J. Kinon, J.c. GómezAbstract:We tested the hypothesis that long-term treatment with Pomaglumetad Methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either Pomaglumetad Methionil (n=516) or aripiprazole (n=162). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The Pomaglumetad Methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group (−2.8 ± 0.4 versus 0.4 ± 0.6; P
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A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of Pomaglumetad Methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia
BMC Psychiatry, 2013Co-Authors: David H. Adams, Brian A. Millen, Bruce J. Kinon, Simin Baygani, Isabella Velona, Sara Kollack-walker, David P. WallingAbstract:Background 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). Methods 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). Results 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). Conclusion 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. Trials registration 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 ClinicalTrials.gov identifier: NCT00845026 .
Simin Baygani - One of the best experts on this subject based on the ideXlab platform.
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A short-term, multicenter, placebo-controlled, randomized withdrawal study of a metabotropic glutamate 2/3 receptor agonist using an electronic patient-reported outcome device in patients with schizophrenia.
Journal of clinical psychopharmacology, 2014Co-Authors: Virginia L Stauffer, Bruce J. Kinon, Simin Baygani, Judith O. Krikke-workelAbstract: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.
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A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of Pomaglumetad Methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia
BMC Psychiatry, 2013Co-Authors: David H. Adams, Brian A. Millen, Bruce J. Kinon, Simin Baygani, Isabella Velona, Sara Kollack-walker, David P. WallingAbstract:Background 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). Methods 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). Results 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). Conclusion 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. Trials registration 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 ClinicalTrials.gov identifier: NCT00845026 .
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A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of Pomaglumetad Methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia
BMC psychiatry, 2013Co-Authors: David H. Adams, Brian A. Millen, Bruce J. Kinon, Simin Baygani, Isabella Velona, Sara Kollack-walker, David P. WallingAbstract: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 ClinicalTrials.gov identifier: NCT00845026 .