Background

Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo.

Objectives

The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials.

Methods

This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated.

Results

No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function.

Conclusions

Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses.

Trial registration

EUDRACT No. 2015-003721-33, filed 30 October 2015.

中文翻译：

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评估 KDM1A 抑制剂 Vafidemstat 的安全性、耐受性、药代动力学和药效学的首次人体随机试验

背景

Vafidemstat 是组蛋白赖氨酸特异性去甲基化酶 KDM1A 的抑制剂，可纠正啮齿动物模型中的认知缺陷和行为改变。在这里，我们报告了 vafidemstat 在健康的年轻和年长成人志愿者中的首次人体试验结果。共有 110 名志愿者参加：87 名接受伐非他汀治疗，23 名接受安慰剂治疗。

目标

该研究旨在确定 vafidemstat 的安全性和耐受性，表征其药代动力学和药效学特征，评估其中枢神经系统 (CNS) 暴露，并获取必要的数据以选择合适的剂量用于长期治疗患有II 期试验中的中枢神经系统疾病。

方法

这项单中心、随机、双盲、安慰剂对照的 I 期试验包括单次和 5 天重复剂量递增和开放标签 CNS 渗透子研究。主要结果是安全性和耐受性；次要结局包括药代动力学和药效学分析，包括基于化学探针的外周血单核细胞 (PBMC) 中 KDM1A 靶标参与 (TE) 和血小板单胺氧化酶 B (MAOB) 抑制的免疫分析。还评估了中枢神经系统和认知功能。

结果

在剂量递增阶段没有报告严重的不良事件（AE）。在所有剂量水平均报告了 AE；没有一个是剂量依赖性的，在积极治疗和安慰剂之间没有观察到显着差异。生物化学、尿液分析、生命体征、心电图和血液学没有随着剂量增加而发生显着变化，除了为此目的加入的额外剂量水平中血小板计数的短暂减少。Vafidemstat 在治疗 5 天后表现出快速口服吸收、近似剂量比例的暴露和适度的全身蓄积。脑脊液与血浆的未结合比率显示 CNS 穿透。Vafidemstat 以剂量依赖性方式结合 PBMC 中的 KDM1A。未检测到 MAOB 抑制。Vafidemstat 不影响 CNS 或认知功能。

结论

Vafidemstat 显示出良好的安全性和耐受性。该 I 期试验证实了 KDM1A TE 和 CNS 渗透，并允许表征血小板动力学和选择 IIa 期剂量。

试用注册

EUDRACT No. 2015-003721-33，2015 年 10 月 30 日提交。