Study ObjectiveCurrent treatments for schizophrenia are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides =150mg/dL, high density lipoprotein cholesterol (HDL) <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) =130mmHg or diastolic BP =85mmHg, fasting glucose =100mg/dL. Patients with MetSy have an elevated risk of developing type II diabetes and increased mortality due to cardiovascular disease. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA approved for the treatment of schizophrenia. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials. This post hoc analysis of 2 randomized, double-blind, placebo-controlled studies of patients with an acute exacerbation of schizophrenia compared rates of MetSy with lumateperone and risperidone. Data from an open-label long-term trial of lumateperone were also evaluated.MethodThe incidence and shift in MetSy were analyzed in data pooled from 2 short-term (4 or 6 week) placebo- and active-controlled (risperidone 4mg) studies of lumateperone 42mg (Studies 005 and 302). The pooled lumateperone data were compared with data for risperidone. Data from an open-label 1-year trial (Study 303) evaluated MetSy in patients with stable schizophrenia switched from prior antipsychotic (PA) treatment to lumateperone 42mg.ResultsIn the acute studies (n=256 lumateperone 42mg, n=255 risperidone 4mg), rates of MetSy were similar between groups at baseline (16% lumateperone, 19% risperidone). At the end of treatment (EOT), MetSy was less common with lumateperone than with risperidone (13% vs 25%). More lumateperone patients (46%) compared with risperidone (25%) patients improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. Conversely, more patients on risperidone than on lumateperone developed MetSy during treatment (13% vs 5%). Differences in MetSy conversion rates were driven by changes in triglycerides and glucose. In the long-term study (n=602 lumateperone 42mg), 33% of patients had MetSy at PA baseline. Thirty-six percent of patients (36%) with MetSy at PA baseline improved to no longer meeting criteria at EOT. Fewer than half that percentage shifted from not meeting MetSy criteria to having MetSy (15%).ConclusionsIn this post hoc analysis, lumateperone 42mg patients had reduced rates of MetSy compared with risperidone patients. In the long-term study, patients with MetSy on PA switched to lumateperone 42mg had a reduction in the risk of MetSy. These results suggest that lumateperone 42mg is a promising new treatment for schizophrenia with a favorable metabolic profile.FundingIntra-Cellular Therapies, Inc.

中文翻译：

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Lumateperone (ITI-007) 的心脏代谢安全性：短期随机试验的事后分析和精神分裂症的开放标签长期研究

研究目标目前对精神分裂症的治疗通常与代谢综合征 (MetSy) 的发病率增加有关。MetSy定义为满足以下5个标准中的3个：腰围>40in（男性）或>35in（女性），甘油三酯=150mg/dL，高密度脂蛋白胆固醇（HDL）<40mg/dL（男性）或<50mg/ dL（女性），收缩压（BP）=130mmHg或舒张压=85mmHg，空腹血糖=100mg/dL。MetSy 患者发生 II 型糖尿病的风险增加，心血管疾病导致的死亡率增加。Lumateperone (lumateperone tosylate, ITI-007) 是一种机制新颖的抗精神病药，可同时调节血清素、多巴胺和谷氨酸神经传递，被 FDA 批准用于治疗精神分裂症。这种独特的药理学特征与临床试验中良好的耐受性和不良代谢作用的低风险有关。这项对 2 项针对精神分裂症急性加重患者的随机、双盲、安慰剂对照研究的事后分析比较了 MetSy 与鲁马特哌隆和利培酮的发生率。还评估了 lumateperone 的一项开放标签长期试验的数据。 lumateperone 42mg（研究 005 和 302）。将汇总的 lumateperone 数据与利培酮的数据进行比较。来自一项开放标签的 1 年试验（研究 303）的数据评估了从先前的抗精神病药物 (PA) 治疗转为 lumateperone 42mg 的稳定型精神分裂症患者的 MetSy。结果在急性研究中（n=256 lumateperone 42mg，n=255 利培酮 4mg） ，基线时各组之间的 MetSy 发生率相似（16% lumateperone，19% 利培酮）。在治疗结束 (EOT) 时，Lumateperone 的 MetSy 比利培酮少见（13% 对 25%）。与利培酮 (25%) 相比，更多 lumateperone 患者 (46%) 患者从基线时有 MetSy 改善到在 EOT 时不再符合 MetSy 标准。相反，利培酮治疗期间发生 MetSy 的患者多于卢马泰酮治疗患者（13% 对 5%）。MetSy 转化率的差异是由甘油三酯和葡萄糖的变化驱动的。在长期研究中（n=602 lumateperone 42mg），33% 的患者在 PA 基线时有 MetSy。36% (36%) 在 PA 基线时有 MetSy 的患者在 EOT 时改善到不再符合标准。不到一半的百分比从不符合 MetSy 标准转变为有 MetSy (15%)。结论在这项事后分析中，与利培酮患者相比，lumateperone 42mg 患者的 MetSy 发生率降低。在长期研究中，使用 PA 的 MetSy 患者改用 lumateperone 42mg 降低了 MetSy 的风险。这些结果表明，lumateperone 42mg 是一种很有前途的精神分裂症新疗法，具有良好的代谢特征。FundingIntra-Cellular Therapies, Inc. 不到一半的百分比从不符合 MetSy 标准转变为有 MetSy (15%)。结论在这项事后分析中，与利培酮患者相比，lumateperone 42mg 患者的 MetSy 发生率降低。在长期研究中，使用 PA 的 MetSy 患者改用 lumateperone 42mg 降低了 MetSy 的风险。这些结果表明，lumateperone 42mg 是一种很有前途的精神分裂症新疗法，具有良好的代谢特征。FundingIntra-Cellular Therapies, Inc. 不到一半的百分比从不符合 MetSy 标准转变为有 MetSy (15%)。结论在这项事后分析中，与利培酮患者相比，lumateperone 42mg 患者的 MetSy 发生率降低。在长期研究中，使用 PA 的 MetSy 患者改用 lumateperone 42mg 降低了 MetSy 的风险。这些结果表明，lumateperone 42mg 是一种很有前途的精神分裂症新疗法，具有良好的代谢特征。FundingIntra-Cellular Therapies, Inc.