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.