Landen Jaren W, Zhao Qinying, Cohen Sharon, Borrie Michael, Woodward Michael, Billing Clare B, Bales Kelly, Alvey Christine, McCush Fred, Yang Jerry, Kupiec James W, Bednar Martin M
Global Research and Development, Pfizer Inc, Groton, CT 06340, USA.
Clin Neuropharmacol. 2013 Jan-Feb;36(1):14-23. doi: 10.1097/WNF.0b013e31827db49b.
Ponezumab is a humanized antiamyloid beta (Aβ) monoclonal antibody designed to treat Alzheimer disease (AD).
This randomized, double-blind, single-dose-escalation study evaluated the safety, pharmacokinetics, and pharmacodynamics of 0.1, 0.3, 1, 3, and 10 mg/kg ponezumab (n = 4, 4, 4, 6, and 8, respectively) versus placebo (n = 11) after a 2-hour intravenous infusion in subjects with mild-to-moderate AD. Cerebrospinal fluid (CSF) samples were obtained from the 1- and 10-mg/kg groups at baseline and at day 29. The subjects were followed for 1 year.
All subjects completed the trial. Ponezumab was well tolerated with no drug-attributed serious adverse events. The most common adverse events were upper respiratory tract infection, headache, and back pain, all mild to moderate. One subject (10 mg/kg) experienced a mild hypersensitivity reaction. Another subject (0.1 mg/kg) demonstrated slight enlargement of a preexisting midbrain lesion. Electrocardiography and laboratory values (including CSF) were unremarkable. No evidence of new microhemorrhage, vasogenic edema, or meningoencephalitis was noted. Plasma maximum observed concentration increased approximately dose proportionally, and the area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUC(inf)) increased slightly more than dose proportionally. Mean terminal half-life was approximately 6 weeks. Two subjects (10 mg/kg) had measurable CSF ponezumab concentrations (~0.5% of plasma values) at day 29. Plasma Aβ(1-x) and Aβ(1-40) increased dose dependently, and mean CSF Aβ(1-x) increased 38% from baseline with 10 mg/kg (P = 0.002 vs placebo).
A 2-hour infusion of 0.1 to 10 mg/kg ponezumab was well tolerated in subjects with mild-to-moderate AD. Plasma pharmacokinetic profile was approximately linear. Plasma Aβ increased with dose, and CSF Aβ increased at the highest dose, suggesting that intravenous ponezumab alters central Aβ levels.
泊奈珠单抗是一种人源化抗淀粉样β蛋白（Aβ）单克隆抗体，旨在治疗阿尔茨海默病（AD）。
本随机、双盲、单剂量递增研究评估了0.1、0.3、1、3和10mg/kg泊奈珠单抗（分别为n = 4、4、4、6和8例）与安慰剂（n = 11例）在轻度至中度AD患者中静脉输注2小时后的安全性、药代动力学和药效学。在基线和第29天从1mg/kg和10mg/kg组采集脑脊液（CSF）样本。对受试者随访1年。
所有受试者均完成试验。泊奈珠单抗耐受性良好，无药物相关严重不良事件。最常见的不良事件为上呼吸道感染、头痛和背痛，均为轻度至中度。1例受试者（10mg/kg）发生轻度过敏反应。另1例受试者（0.1mg/kg）原有中脑病变略有增大。心电图和实验室检查值（包括脑脊液）均无异常。未发现新的微出血、血管源性水肿或脑膜脑炎证据。血浆最大观察浓度大致呈剂量比例增加，从零时间外推至无限时间的血浆浓度-时间曲线下面积（AUC(inf)）增加略高于剂量比例。平均终末半衰期约为6周。2例受试者（10mg/kg）在第29天脑脊液中可检测到泊奈珠单抗浓度（约为血浆值的0.5%）。血浆Aβ(1-x)和Aβ(1-40)呈剂量依赖性增加，10mg/kg时脑脊液平均Aβ(1-x)较基线增加38%（与安慰剂相比，P = 0.002）。
在轻度至中度AD患者中，静脉输注0.1至10mg/kg泊奈珠单抗2小时耐受性良好。血浆药代动力学特征大致呈线性。血浆Aβ随剂量增加，最高剂量时脑脊液Aβ增加，提示静脉注射泊奈珠单抗可改变中枢Aβ水平。
