Downing AnnCatherine M, Kinon Bruce J, Millen Brian A, Zhang Lu, Liu Lin, Morozova Margarita A, Brenner Ronald, Rayle Tami Jo, Nisenbaum Laura, Zhao Fangyi, Gomez Juan Carlos
Eli Lilly and Company, Indianapolis 46285, Indiana, USA.
BMC Psychiatry. 2014 Dec 10;14:351. doi: 10.1186/s12888-014-0351-3.
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.
聚谷氨酸甲硫氨酸（LY2140023一水合物）是一种强效且高度选择性的代谢型谷氨酸mGluR2和mGluR3受体激动剂。我们展示了一项关键临床研究H8Y-MC-HBBM的结果，该研究评估了LY2140023作为单一疗法改善精神分裂症急性加重患者症状的疗效。
纳入在研究入组前2周内经历症状加重的成年精神分裂症患者（年龄18 - 65岁）。患者（N = 1013）在为期1周的盲法安慰剂导入期后，按2:2:2:1随机分为接受安慰剂、每日两次40mg LY（LY40mg BID）、每日两次80mg LY（LY80mg BID）或每日两次2mg利培酮（RIS）治疗6周。主要结局评估了总体精神分裂症患者群体以及一个预定义亚组中，阳性和阴性症状量表（PANSS）总分相对于基线的变化，该亚组排除了在HTR2A SNP rs7330461处具有A/A基因型的非西班牙裔白人患者。
在两个群体中，与安慰剂相比，LY2140023的任何剂量在PANSS总分上均未显示出显著改善（单侧p值[显著性水平]，总体：LY40，p = 0.154[0.01]；LY80，p = 0.698[0.01]，亚组：LY40，p = 0.033[0.0025]；LY80，p = 0.659[0.0025]，混合效应重复测量分析）。在两个群体中，利培酮在统计学上与安慰剂分离（p < 0.001[0.05]）。严重不良事件的发生率无统计学显著差异，且LY2140023未出现癫痫发作。
LY2140023治疗在研究人群中未显示出疗效。总体而言，与先前试验相比，LY2140023治疗一般耐受性良好，未发现新的不良安全性结果。需要进一步了解谷氨酸作为精神分裂症治疗靶点的作用。
一项关于2种剂量LY214（原文有误，应为LY2140023）0023与安慰剂对比治疗DSM-IV-TR精神分裂症患者的2期、多中心、双盲、安慰剂对照比较研究。ClinicalTrials.gov标识符：NCT01086748。
