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Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study.

Abstract：

OBJECTIVES:Ponezumab is a humanized antiamyloid beta (Aβ) monoclonal antibody designed to treat Alzheimer disease (AD). METHODS: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. RESULTS: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). CONCLUSIONS: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.

journal_name

Clin Neuropharmacol

journal_title

Clinical neuropharmacology

authors

Landen JW,Zhao Q,Cohen S,Borrie M,Woodward M,Billing CB Jr,Bales K,Alvey C,McCush F,Yang J,Kupiec JW,Bednar MM

doi

10.1097/WNF.0b013e31827db49b

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

14-23

issue

eissn

0362-5664

issn

1537-162X

pii

00002826-201301000-00004

journal_volume

pub_type

杂志文章,多中心研究,随机对照试验

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Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study.