title: PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses.
abstract: PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD.
authors.affiliation: Mental Health Research Institute, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Noel G
authors.initials: NG
authors.lastname: Faux
authors.forename: Craig W
authors.initials: CW
authors.lastname: Ritchie
authors.forename: Adam
authors.initials: A
authors.lastname: Gunn
authors.forename: Alan
authors.initials: A
authors.lastname: Rembach
authors.forename: Andrew
authors.initials: A
authors.lastname: Tsatsanis
authors.forename: Justin
authors.initials: J
authors.lastname: Bedo
authors.forename: John
authors.initials: J
authors.lastname: Harrison
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Cummings
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Herd
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D019540:Area Under Curve; D001315:Australia; D007464:Clioquinol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000209:etiology*; D003300:Copper / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D056344:Executive Function / Q000187:drug effects; D006801:Humans; D007391:International Cooperation; D007476:Ionophores / Q000494:pharmacology / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D012372:ROC Curve; D013482:Superoxide Dismutase / Q000097:blood; D000072105:Superoxide Dismutase-1; D013548:Sweden; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D007476:Ionophores; C531955:PBT2 compound; D010446:Peptide Fragments; C000606290:SOD1 protein, human; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D003300:Copper; D007464:Clioquinol; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1