Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA.
Parexel, Glendale, CA, USA.
Br J Clin Pharmacol. 2022 Aug;88(8):3872-3882. doi: 10.1111/bcp.15305. Epub 2022 Apr 17.
TAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694).
The study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia.
No serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia.
TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported.
TAK-041（NBI-1065846）是一种口服、研究性小分子 GPR139 激动剂，GPR139 是一种孤儿 G 蛋白偶联受体，在治疗精神分裂症相关症状的临床前研究中显示出良好的前景。在这里，我们报告了一项 I 期研究的结果，该研究旨在评估 TAK-041 在健康成年人中的安全性、耐受性和药代动力学，以及 TAK-041 作为辅助治疗精神分裂症稳定患者的抗精神病药物的探索性疗效评估（ClinicalTrials.gov：NCT02748694）。
该研究包括 4 个部分：第 1-3 部分在健康成年人中进行，第 4 部分在稳定的精神分裂症患者中进行。第 1 部分是单剂量递增研究，第 2 部分是评估血浆暴露和蓄积的多剂量递增研究，第 3 部分评估了片剂制剂与口服混悬剂的生物利用度，第 4 部分是稳定的精神分裂症患者重复多次给药的研究。
没有报告严重的不良事件。TAK-041 的药代动力学呈近线性特征，在所有测试剂量下，吸收迅速，半衰期为 170-302 小时。片剂制剂与口服混悬剂的生物利用度相似，未检测到有意义的食物效应。与健康志愿者相比，精神分裂症患者的全身暴露量降低了 22-30%。在精神分裂症患者中，阳性和阴性症状量表的焦虑-抑郁量表（P = .0002，未校正多重性）和时间体验愉悦量表出现了改善的潜在信号。
TAK-041 在健康志愿者和精神分裂症成年患者中总体耐受性良好。支持进一步研究 TAK-041 在精神分裂症患者中的应用。
