57982
document
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 . 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 .
57983
Intervention_Pharmacological
ponezumab
57984
Intervention_Control
placebo-controlled
57985
Intervention_Pharmacological
Ponezumab
57986
Outcome_Other
tolerated
57987
Outcome_Adverse-effects
upper respiratory tract infection , headache , and back pain
57988
Outcome_Adverse-effects
mild hypersensitivity reaction
57989
Outcome_Adverse-effects
slight enlargement of a preexisting midbrain lesion
57990
Outcome_Physical
Electrocardiography and laboratory values ( including CSF )
57991
Outcome_Physical
microhemorrhage , vasogenic edema , or meningoencephalitis
57992
Outcome_Physical
CSF ponezumab concentrations
57993
Participant_Condition
mild-to-moderate Alzheimer disease