Takeda Pharmaceuticals USA, Ltd, Cambridge, MA, USA.
Br J Clin Pharmacol. 2021 Dec;87(12):4756-4768. doi: 10.1111/bcp.14912. Epub 2021 Jun 10.
Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069).
Two randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD]).
TAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide.
The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.
组蛋白甲基化表观遗传标记的失调可能导致智力和发育障碍，如在歌舞伎综合征中所见。动物数据表明，通过抑制赖氨酸特异性去甲基酶 1A（LSD1）增加组蛋白甲基化可能改善歌舞伎综合征模型中的认知结果。TAK-418 是一种新型 LSD1 抑制剂，作为中枢神经系统疾病（如歌舞伎综合征）的潜在治疗药物而开发。在这里，我们报告了 TAK-418（ClinicalTrials.gov：NCT03228433，NCT03501069）单剂量和多剂量的安全性、耐受性、药代动力学和药效学特征。
进行了两项口服 TAK-418 的随机、双盲、安慰剂对照、I 期研究，一项是健康成年男性和女性志愿者的首次人体单剂量递增（SRD）研究（5-60mg；安慰剂，n=10；TAK-418，n=30），另一项是健康女性志愿者的 SRD（120-160mg 每日一次 10 天）和多剂量递增（MRD）研究（20-160mg 每日一次 10 天）（安慰剂，n=2 [SRD]和 n=6 [MRD]；TAK-418，n=6 [SRD]和 n=18 [MRD]）。
TAK-418 具有良好的耐受性。未观察到实验室检查结果或生命体征的临床显著变化，也未报告严重不良事件。TAK-418 的药代动力学呈近乎线性，在评估的剂量范围内具有快速吸收和短的终末半衰期。每日给药 10 天后未观察到明显蓄积。与食物一起给药会延迟达峰血浆浓度，但总体暴露不受影响。TAK-418 可快速穿透血脑屏障，通常在外周药效学生物标志物甲酰黄素腺嘌呤二核苷酸中表现出剂量依赖性反应。
具有脑穿透能力的 LSD1 抑制剂 TAK-418 具有良好的耐受性，其药代动力学和药效学作用支持进一步研究。
