默沙东阿尔茨海默氏症BACE抑制剂MK-8931 Ib期临床取得积极数据

2013年7月15日讯 /生物谷BIOON/ --默沙东（Merck & Co）7月14日公布了在轻度至中度阿尔茨海默氏症（Alzheimer's Disease）患者中开展的有关实验性口服β-淀粉样前体蛋白裂解酶（BACE1或β分泌酶）抑制剂MK-8931的Ib期临床试验结果。

该项研究中，以β淀粉样蛋白的水平作为BACE活性的一种衡量方法。数据显示，经MK-8931治疗后，观察到了β淀粉样蛋白水平的降低，表明MK-8931在减少β淀粉样蛋白水平方面具有积极的作用，为进一步了解BACE1抑制作用在阿尔茨海默氏症根本性病理中所发挥的作用提供了一个机会。

该随机、双盲、安慰剂、多剂量研究在32例轻度至中度阿尔茨海默氏症患者中开展，评估了MK-8931的安全性、耐受性、药代动力学、药效学属性。研究中，患者随机接受每天一次连续7天口服3种剂量之一（12mg、40mg、60mg）的MK-8931或安慰剂，并通过腰椎导管收集脑脊液样本（CFS），分析β淀粉样蛋白40（Aβ40）、β淀粉样蛋白42（Ab42）及可溶性淀粉样前体蛋白β（sAPPb）的水平，作为BACE1活性的生物标志物。

研究中，MK-8931剂量组（12mg、40mg、60mg），脑脊液中Ab40水平显示出剂量依赖的、持续性的降低，分别从基线水平降低了57%、79%、84%。研究中未发生严重不良事件或因不良事件停药的记录。与MK-8931相关的生命体征及实验室评估（包括肝功能试验）分析结果无统计学显着差异。

此前，默沙东在2012年美国神经病学学会（AAN）年度会议上提交的I期临床试验数据表明，健康志愿者口服MK-8931后，使脑脊液Ab40水平从基线降低了超过90%。

BACE抑制理论很简单，研究者认为该途径是抑制β淀粉样蛋白产生的一种方法。其中心思想是，如果能够降低脑脊液中β淀粉样蛋白的水平，那么就有可能能够影响疾病的进程。

该项研究的数据，确保了默沙东在BACE抑制剂开发中的领先地位，该领域还包括阿斯利康（AZN）和礼来（Eli Lilly）。

目前，默沙东正在开展一项更大更长期的II/III期研究（EPOCH），在轻度至中度阿尔茨海默氏症患者中对MK-8931进行更进一步的评估。（生物谷Bioon.com）

英文原文：Merck reports positive results for lead Alzheimer's drug

Sunday, July 14, 2013 8:30 am EDT Merck, known as MSD outside the United States and Canada, today announced the presentation of results from a Phase Ib study showing a dose-dependent decrease in β amyloid levels in cerebral spinal fluid (CSF) following administration of MK-8931, Merck’s investigational oral β-site amyloid precursor protein cleaving enzyme (BACE1 or β secretase) inhibitor, in patients with mild to moderate Alzheimer’s disease (AD). In the study, β amyloid levels were analyzed as a measure of BACE activity. The data were presented during an oral session at the Alzheimer’s Association International Conference (AAIC) in Boston, July 13-18 (Abstract O1-06-05).

“The amyloid β reduction observed with MK-8931 may offer an opportunity to further understand the role BACE1 inhibition plays in the underlying pathology of Alzheimer’s disease,” said Darryle Schoepp, Ph.D., vice president of Neuroscience Early Development and Discovery Sciences, Merck. “Further evaluation of MK-8931 continues in our EPOCH study, a Phase II/III trial in patients with mild to moderate Alzheimer’s.”

Results of MK-8931 Phase Ib Study

The randomized, double-blind, placebo-controlled multiple dose study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamic profile of MK-8931 in patients with mild to moderate AD (n=32). Patients were randomized to receive one of three doses (12 mg, 40 mg and 60 mg) orally of MK-8931 or placebo once-daily for seven days. Samples of CSF were collected via a lumbar catheter and analyzed for levels of amyloid β 40 (Aβ40), amyloid β 42 (Ab42) and soluble amyloid precursor protein β (sAPPb) as biomarkers of BACE1 activity.

In this study, administration of MK-8931 at doses of 12, 40 and 60 mg resulted in a dose-dependent and sustained reduction in the levels of Ab40, a measure of BACE1 activity, in CSF from baseline of 57, 79 and 84 percent, respectively. The mean percentage of baseline in biomarkers Aβ40, Aβ42 and sAPPβ for each dose of MK-8931 as measured following a seven day dosing period is shown in the table.

No serious adverse events or study discontinuations due to adverse events were recorded. Analysis of vital signs and laboratory assessments, including liver function tests, showed no statistically significant changes related to the administration of MK-8931. Adverse events reported in two or more subjects in at least one dose group included: headache, dizziness, nausea, vomiting, insomnia and back pain. All adverse events were generally mild to moderate in intensity and transient in duration. No dose-dependent increase in the incidence of adverse events was observed.

Previously, Merck researchers presented findings of a single dose Phase I study at the 2012 American Academy of Neurology (AAN) Annual Meeting, which demonstrated that administration of MK-8931 to healthy volunteers resulted in a reduction of Ab40 CSF levels of greater than 90 percent from baseline.  

Other MK-8931 Presentations at AAIC 2013

Consistency of BACE1-mediated Brain Amyloid Production Inhibition by MK-8931 in Alzheimer’s Patients and Healthy Young Adults (Oral Session; July 17, 2013; 2:15 PM; Presentation #O4-05-05)
About the EPOCH Study

EPOCH (NCT01739348) is a 78-week, randomized, placebo-controlled, parallel-group, double-blind Phase II/III clinical trial to evaluate the efficacy and safety of three oral doses of MK-8931 (12, 40 or 60 mg) administered daily versus placebo in patients with mild to moderate AD. The study is currently enrolling the 200 patient Phase II portion of the study and is anticipated to enroll up to 1,700 patients in the main Phase III cohort. The primary efficacy outcomes of the study are the change from baseline in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and the change from baseline in the Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) score.

About BACE Inhibition and MK-8931

The amyloid hypothesis asserts that the formation of amyloid peptides that lead to amyloid plaque deposits in the brain is a primary contributor to the underlying cause of Alzheimer's disease. BACE is believed to be a key enzyme in the production of amyloid β peptide. Evidence suggests that inhibiting BACE decreases the production of amyloid β peptide and may therefore reduce amyloid plaque formation and modify disease progression.

Merck is advancing several innovative mechanisms in Alzheimer's disease, including candidates designed to modify disease progression and improve symptom control. Merck's major effort in disease modification is our lead BACE inhibitor, MK-8931, and Merck is continuing to develop other BACE inhibitor candidates.

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