title: 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: OBJECTIVE
  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.
authors: Global Research and Development, Pfizer Inc, Groton, CT 06340, USA. jaren.w.landen@pfizer.com
authors: Jaren W
authors: JW
authors: Landen
authors: Qinying
authors: Q
authors: Zhao
authors: Sharon
authors: S
authors: Cohen
authors: Michael
authors: M
authors: Borrie
authors: Michael
authors: M
authors: Woodward
authors: Clare B
authors: CB
authors: Billing
authors: Kelly
authors: K
authors: Bales
authors: Christine
authors: C
authors: Alvey
authors: Fred
authors: F
authors: McCush
authors: Jerry
authors: J
authors: Yang
authors: James W
authors: JW
authors: Kupiec
authors: Martin M
authors: MM
authors: Bednar
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged
chemical_list: D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; C572721:ponezumab