BackgroundSEP-363856 is a novel psychotropic agent without dopamine D2 receptor occupancy. Although its mechanism of action has not been fully elucidated, preclinical data suggest that agonism at trace amine receptor 1 (TAAR1) and the serotonin 5-H1A receptor contributes to its efficacy. In a double-blind (DB), placebo-controlled study, SEP−363856 demonstrated significant efficacy in the treatment of an exacerbation of schizophrenia (Koblan et al, NEJM 2020; 82:1497–1506). We present results of a 6-month extension study whose aim was to evaluate the safety and effectiveness of longer-term treatment with SEP−363856.MethodPatients with an acute exacerbation of schizophrenia who completed a 4-week, DB, placebo-controlled, flexible-dose (50 or 75 mg) study of SEP−363856 were given the option to enroll in an extension study in which they were treated, open-label (OL), with flexible doses (25/50/75 mg/d) of SEP−363856 for 26-weeks. The primary outcomes were safety measures; effectiveness outcomes were secondary and included the PANSS total score and the Brief Negative Symptom Scale (BNSS) total score.ResultsA total of 193 patients completed the 4-week DB study, and 156 (80.8%) were dosed in the OL extension study and received at least one dose of SEP−363856 (safety population). Study completer rate was 66.9%; reasons for discontinuation consisted of adverse event (11.5%), withdrawal of consent (10.2%), lack of efficacy (5.1%), and other (6.4%). 15 patients experienced an SAE: schizophrenia (n=11); acute psychosis (N=1); uterine hemorrhage and suicidal ideation (N=1 each); there were no deaths in the study. Individual AEs with an incidence =2% were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decreased (3.2%), and prolactin increased (2.6%). On movement scales, minimal mean change from OL-baseline to Week 26 occurred on the Barnes total score (−0.1), AIMS total score (0.0) and SAS score (−0.1). Mean month 6 change from DB baseline in weight was −0.3 kg. No clinically meaningful median changes were observed at week 26 in metabolic laboratory parameters (total and LDL cholesterol, triglycerides, hemoglobin A1c) or in prolactin levels. During 6 months of OL treatment, one patient had an increase in QTcF =60 msec; no patients had a QTcF interval =480 msec. Treatment with SEP−363856 was associated with significant improvement from OL baseline to week 26 in PANSS total score (−22.6) and BNSS total score (−11.3).ConclusionTreatment with SEP−363856 was associated with continued improvement from open-label baseline in the PANSS total (−22.6) and BNSS total (−11.3) scores. The most frequently reported adverse events (= 5%) were schizophrenia, headache, insomnia and anxiety. SEP−363856 had minimal effects on weight, lipids, glycemic indices, prolactin, and was associated with minimal risk of extrapyramidal symptom.FundingSunovion Pharmaceuticals Inc.

中文翻译：

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SEP-363856 在精神分裂症中的安全性和有效性：为期 6 个月的开放标签扩展研究的结果

背景SEP-363856 是一种没有多巴胺D2 受体占据的新型精神药物。尽管其作用机制尚未完全阐明，但临床前数据表明微量胺受体 1 (TAAR1) 和血清素 5-H1A 受体的激动作用有助于其疗效。在一项双盲 (DB) 安慰剂对照研究中，SEP-363856 在治疗精神分裂症恶化方面表现出显着疗效（Koblan 等人，NEJM 2020；82:1497-1506）。我们展示了一项为期 6 个月的扩展研究的结果，其目的是评估 SEP-363856 长期治疗的安全性和有效性。 - SEP-363856 的剂量（50 或 75 毫克）研究可以选择参加一项对其进行治疗的扩展研究，开放标签 (OL)，具有灵活剂量 (25/50/75 mg/d) 的 SEP-363856，持续 26 周。主要结果是安全措施；有效性结果是次要的，包括 PANSS 总分和简要阴性症状量表（BNSS）总分。 结果共有 193 名患者完成了为期 4 周的 DB 研究，156 名（80.8%）在 OL 扩展研究中给药并接受至少一剂 SEP-363856（安全人群）。学习完成率为66.9%；停药原因包括不良事件 (11.5%)、撤回同意 (10.2%)、缺乏疗效 (5.1%) 和其他 (6.4%)。15 名患者出现 SAE：精神分裂症（n=11）；急性精神病（N=1）；子宫出血和自杀意念（N = 1）；研究中没有死亡。发生率 = 2% 的个别 AE 是精神分裂症 (12.2%)、头痛 (11.5%)、失眠 (8.3%)、焦虑 (5.1%)、嗜睡 (4.5%)、鼻咽炎 (4.5%)、恶心 (3.8%)、易怒 (3.2%)、流感 (3.2%)、体重下降 (3.2%) 和催乳素增加（2.6%）。在运动量表上，从 OL 基线到第 26 周的最小平均变化发生在 Barnes 总分 (-0.1)、AIMS 总分 (0.0) 和 SAS 分数 (-0.1) 上。体重从 DB 基线的平均第 6 个月变化为 -0.3 kg。在第 26 周，代谢实验室参数（总胆固醇和 LDL 胆固醇、甘油三酯、血红蛋白 A1c）或催乳素水平未观察到有临床意义的中位变化。在 6 个月的 OL 治疗期间，一名患者的 QTcF 增加 =60 毫秒；没有患者有 QTcF 间期 =480 毫秒。SEP-363856 治疗与从 OL 基线到第 26 周的 PANSS 总分（-22. 6) 和 BNSS 总分 (-11.3)。结论 SEP-363856 治疗与 PANSS 总分 (-22.6) 和 BNSS 总分 (-11.3) 的开放标签基线持续改善有关。最常报告的不良事件（= 5%）是精神分裂症、头痛、失眠和焦虑。SEP-363856 对体重、血脂、血糖指数、催乳素的影响最小，并且与锥体外系症状的风险最小相关。资助 Sunovion Pharmaceuticals Inc.