Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Hopewell, PO Box 5400, Princeton, NJ 08543, USA.
Clin Drug Investig. 2012 Nov;32(11):761-9. doi: 10.1007/s40261-012-0006-4.
The concentration of amyloid β (Aβ) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Aβ concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability.
This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses.
34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Aβ(1-38), Aβ(1-40) and Aβ(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups.
Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Aβ concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.
脑脊液（CSF）中淀粉样β（Aβ）肽的浓度是阿尔茨海默病（AD）病理的生物标志物，已用于评估 γ-分泌酶抑制的效果。Avagacestat 是一种用于治疗 AD 的选择性 γ-分泌酶抑制剂。本研究的主要目的是评估单次口服 avagacestat 对健康男性受试者 CSF 中 Aβ浓度的影响。次要目标包括 CSF 和血浆中的单次剂量药代动力学、安全性和耐受性。
这是一项双盲、安慰剂对照、随机、单次剂量研究。健康男性受试者被分配至三个连续的 avagacestat 剂量组（50、200 和 400mg）或安慰剂中的一组，作为单次口服剂量。
共纳入 34 名受试者。与安慰剂相比，单次给予 200 或 400mg 的 avagacestat 可显著降低 CSF Aβ（1-38）、Aβ（1-40）和 Aβ（1-42）浓度；50mg 剂量组观察到的降低幅度较小。Avagacestat 迅速被吸收到体循环中，达到最大血浆浓度（t(max)）的平均时间约为 1-2 小时，CSF 的 t(max)约为 3 小时。不良反应不常见，且安慰剂和 avagacestat 组的发生频率相似。
Avagacestat 安全、耐受良好，可显著降低 CSF Aβ 浓度，提示 γ-分泌酶抑制。结果支持在 AD 患者中进一步开展临床研究。
