Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL 60015, United States of America.
Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL 60015, United States of America.
Schizophr Res. 2019 Feb;204:289-294. doi: 10.1016/j.schres.2018.08.028. Epub 2018 Sep 3.
TAK-063 is a potent, selective inhibitor of phosphodiesterase 10A, an enzyme selectively expressed in medium spiny neurons of the striatum. This randomized, parallel-group study evaluated the efficacy and safety of 20-mg daily TAK-063 versus placebo in subjects with acutely exacerbated symptoms of schizophrenia (NCT02477020).
Adults aged 18 to 65 with diagnosed schizophrenia and psychotic symptoms that exacerbated within 60 days before screening were included. Subjects who discontinued psychotropic medications before screening were randomized 1:1 to 6 weeks of placebo (n = 81) or 20-mg TAK-063 (n = 83). Weekly efficacy visits were conducted during the treatment period, and dose de-escalation was allowed (blinded) to 10-mg TAK-063 for intolerability.
The primary endpoint, change from baseline in the Positive and Negative Syndrome Scale total score at week 6, was not achieved (least-squares mean difference vs placebo [standard error] = -5.46 [3.44]; p = 0.115). Secondary endpoints were generally supportive of antipsychotic efficacy. Consistent with previous phase 1 studies, TAK-063 was safe and well tolerated, and most adverse events were mild or moderate in severity and did not result in discontinuation. No deaths occurred, and the incidence of akathisia and dystonia, categories of extrapyramidal syndromes, was more frequent in the TAK-063 group than placebo.
Although the study did not meet the primary endpoint (effect size = 0.308), the effects of TAK-063 on the primary and secondary endpoints may be suggestive of antipsychotic activity. Interpretation of these results is confounded by a relatively high placebo effect and a lack of dose-ranging or active reference.
TAK-063 是一种有效的、选择性的磷酸二酯酶 10A 抑制剂，该酶在纹状体的中间多棘神经元中选择性表达。这项随机、平行分组研究评估了每日 20mg TAK-063 与安慰剂在急性加重精神分裂症症状的受试者中的疗效和安全性（NCT02477020）。
年龄在 18 至 65 岁之间，经诊断患有精神分裂症且在筛选前 60 天内症状恶化的成年患者被纳入研究。在筛选前停止使用精神药物的患者被随机分为 1:1 组，接受 6 周的安慰剂（n=81）或 20mg TAK-063（n=83）治疗。在治疗期间进行每周一次的疗效访视，并允许（盲法）剂量减至 10mg TAK-063 以减轻不耐受性。
主要终点是第 6 周时阳性和阴性综合征量表总分的基线变化，未达到（最小二乘均数差值与安慰剂[标准误差]为-5.46[3.44]；p=0.115）。次要终点通常支持抗精神病疗效。与之前的 1 期研究一致，TAK-063 安全且耐受性良好，大多数不良事件的严重程度为轻度或中度，且不会导致停药。无死亡发生，TAK-063 组比安慰剂组的锥体外系综合征类别中的静坐不能和肌张力障碍的发生率更高。
尽管该研究未达到主要终点（效应大小=0.308），但 TAK-063 对主要和次要终点的影响可能提示其具有抗精神病活性。这些结果的解释受到安慰剂效应较高以及缺乏剂量范围或活性对照的影响。
