背景:ACD856是原肌球蛋白受体激酶(Trk)受体的正变构调节剂,已在各种动物模型中显示具有促认知和抗抑郁样作用。目前正在临床开发中,用于治疗阿尔茨海默氏病和其他认知障碍的疾病,并且还考虑用于适应症,例如抑郁症或其他神经精神疾病。ACD856具有调节Trk受体活性的新作用机制,导致神经营养蛋白信号通路的刺激增加。先前应用单次静脉和口服ACD856剂量的研究表明,健康志愿者受试者对ACD856是安全且耐受性良好的,并且它具有合适的安全性和药代动力学特性,可用于进一步的临床开发。
目的:为了研究健康受试者使用ACD856口服多次递增剂量治疗7天的安全性和耐受性,并表征其药代动力学(PK)特性。此外,使用定量脑电图(qEEG)评估ACD856的药效学效应作为中心靶参与指标.
方法:这是一个前瞻性的,第一阶段,双盲,平行组,安慰剂对照,安全性的随机研究,耐受性,健康受试者中ACD856的多个递增口服剂量的PK和药效学。ACD856或安慰剂在8名受试者的3个递增剂量组中施用。在每个队列中,受试者随机接受ACD856(n=6)或安慰剂(n=2).
方法:该研究是在瑞典的人类第一单位进行的。
方法:24名健康男性和女性受试者。
方法:研究药物以口服溶液的形式给药,与ACD856或相同的内容没有活性成分(安慰剂)。剂量水平范围为10mg至90mg。ACD856每天给药一次,持续7天,瞄准稳态。
方法:安全性和耐受性评估包括不良事件,实验室,生命体征,12导联心电图(ECG),体检,粪便频率评估和问卷调查,以评估焦虑的症状,抑郁症,以及自杀意念和行为。此外,提取心脏动力学心电图以评估心脏安全性.PK参数是根据血浆中ACD856的测量浓度计算的,尿液,和脑脊液(CSF)样本。代谢物剖面,根据和尿液样本进行表征和分析。记录两个最高剂量组(30和90mg/天)中患者的qEEG作为药效学评估,以探索中心目标参与。
结果:ACD856治疗耐受性良好,无严重不良事件。对于任何安全性评估均未观察到治疗紧急或剂量相关趋势。ACD856被快速吸收并在给药后30至45分钟达到最大血浆暴露。在第6天之前达到稳定状态,在稳定状态下的消除半衰期为约20小时。在稳定状态下,ACD856表现出Cmax和AUC的累积比分别为约1.6和1.9。曝光,Cmax和AUC0-24随剂量成比例增加。在尿中没有检测到未改变的ACD856。尿液和血浆中的代谢模式相似,与临床前毒理学研究中观察到的代谢物一致。ACD856在CSF中测定的水平在稳态下随剂量增加而增加,指示中枢神经系统(CNS)暴露在相关水平的药效学效应。ACD856显示qEEG参数的显著剂量依赖性治疗相关变化。具体来说,观察到相对θ功率的增加和快速α和β功率的减少,导致δθ质心的加速和θ/β比的增加。
结论:ACD856在测试剂量水平(10-90mg/天,持续7天)下在健康受试者中具有良好的耐受性。该化合物具有强大的药代动力学特征,具有快速吸收和剂量依赖性暴露。ACD856被证明可以通过血脑屏障,达到中枢神经系统的相关暴露,并诱导qEEG参数的剂量依赖性治疗相关变化,指示中心目标交战。
ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (
Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer\'s disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the
Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development.
To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed.
This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2).
The study was conducted at a First-in-Human unit in Sweden.
Twenty-four healthy male and female subjects.
The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state.
Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement.
Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady state was reached before Day 6, with an elimination half-life at steady state of approximately 20 hours. At steady state, ACD856 exhibited accumulation ratios for Cmax and AUC of approximately 1.6 and 1.9 respectively. The exposure, Cmax and AUC0-24, increased proportionally with the dose. There was no unchanged ACD856 detected in urine. The metabolic pattern in urine and plasma was similar, and in alignment with the metabolites observed in preclinical toxicology studies. The level of ACD856 measured in CSF at steady state increased with dose, indicating Central Nervous System (CNS) exposure at relevant levels for pharmacodynamic effects. ACD856 demonstrated significant dose-dependent treatment-associated changes on qEEG parameters. Specifically, increase of the relative theta power and decrease of the fast alpha and beta power was observed, leading to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio.
ACD856 was well tolerated at the tested dose levels (10-90 mg/daily for 7 days) in healthy subjects. The compound has a robust pharmacokinetic profile, with rapid absorption and dose-dependent exposure. ACD856 was shown to pass the blood-brain-barrier, reach relevant exposure in the CNS and to induce dose-dependent treatment-related changes on qEEG parameters, indicating central target engagement.