Delnomdedieu Marielle, Duvvuri Sridhar, Li David Jianjun, Atassi Nazem, Lu Ming, Brashear H Robert, Liu Enchi, Ness Seth, Kupiec James W
Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
Mass General Hospital, Boston, MA, USA.
Alzheimers Res Ther. 2016 Mar 1;8(1):12. doi: 10.1186/s13195-016-0177-y.
In the First-In-Human (FIH), 39-week, randomized, adaptive design study, safety, tolerability, pharmacokinetics and biomarkers were measured in patients with mild-to-moderate Alzheimer's disease (AD) after infusion of a humanized monoclonal antibody to amyloid β, AAB-003 (NCT01193608; registered 19 August 2010). AAB-003 was developed by modifying bapineuzumab to reduce Fc-receptor-mediated effector function as a strategy to reduce the removal of amyloid from vessel walls associated with amyloid-related imaging abnormalities with edema/effusions (ARIA-E) without diminishing overall amyloid clearance.
Eighty-eight patients with AD received up to three infusions of AAB-003 (or placebo) 13 weeks apart at doses of 0.5, 1, 2, 4 or 8 mg/kg in the FIH trial. Dose escalation was based on safety data reviews using a Bayesian escalation algorithm. Subjects who completed the FIH study were permitted to enter a 1-year open-label extension trial with four additional intravenous infusions of AAB-003 (NCT01369225; registered 10 May 2011).
Dose-dependent increases in plasma amyloid β and AAB-003 were observed. No significant changes in cerebral spinal fluid biomarkers were observed. Pharmacokinetics elimination half-life (21-28 days) clearance and volume of distribution values were consistent across dose groups indicating linearity. ARIA-E was the most notable safety finding detected by magnetic resonance imaging (MRI) at 8 mg/kg in two patients. Three cases of microhemorrhage were observed. No new safety findings or MRI abnormalities were observed for the 52 subjects who received AAB-003 in the extension trial.
Based on integrated review of laboratory, electrocardiogram, adverse events, and MRI, AAB-003 was safe and well tolerated up to 8 mg/kg for up to 91 weeks (FIH and extension trials) in patients with mild to moderate AD. Asymptomatic and resolvable ARIA-E was observed after the first or second infusion of AAB-003, similar to bapineuzumab. The AAB-003 dose at which ARIA-E was observed was higher compared to bapineuzumab, supporting the hypothesis that reducing Fc-receptor effector function may reduce the ARIA associated with monoclonal antibodies targeting cerebral amyloid.
在一项首次人体（FIH）、为期39周的随机适应性设计研究中，对轻度至中度阿尔茨海默病（AD）患者输注人源化抗淀粉样蛋白β单克隆抗体AAB - 003后（NCT01193608；于2010年8月19日注册），对安全性、耐受性、药代动力学和生物标志物进行了测量。AAB - 003是通过对巴匹兹umab进行修饰以降低Fc受体介导的效应功能而开发的，作为一种策略，旨在减少与伴有水肿/渗出的淀粉样蛋白相关成像异常（ARIA - E）相关的血管壁淀粉样蛋白清除，同时又不降低整体淀粉样蛋白清除率。
在FIH试验中，88例AD患者每隔13周接受高达三次AAB - 003（或安慰剂）输注，剂量分别为0.5、1、2、4或8mg/kg。剂量递增基于使用贝叶斯递增算法的安全性数据审查。完成FIH研究的受试者被允许进入一项为期1年的开放标签扩展试验，再接受四次AAB - 003静脉输注（NCT01369225；于2011年5月10日注册）。
观察到血浆淀粉样蛋白β和AAB - 003呈剂量依赖性增加。脑脊液生物标志物未观察到显著变化。药代动力学消除半衰期（21 - 28天）、清除率和分布容积值在各剂量组间一致，表明呈线性关系。ARIA - E是在8mg/kg剂量下通过磁共振成像（MRI）在两名患者中检测到的最显著的安全性发现。观察到3例微出血。在扩展试验中接受AAB - 003的52名受试者未观察到新的安全性发现或MRI异常。
基于对实验室检查、心电图、不良事件和MRI的综合评估，在轻度至中度AD患者中，AAB - 003在高达8mg/kg剂量下长达91周（FIH和扩展试验）是安全且耐受性良好的。在首次或第二次输注AAB - 003后观察到无症状且可消退的ARIA - E，与巴匹兹umab相似。观察到ARIA - E的AAB - 003剂量高于巴匹兹umab，支持降低Fc受体效应功能可能减少与靶向脑淀粉样蛋白的单克隆抗体相关的ARIA这一假说。
