BACKGROUND: PBT2 is a metal-protein attenuating compound (MPAC) that affects the 
Cu2(+)-mediated and Zn2(+)-mediated toxic oligomerisation of Abeta seen in 
Alzheimer's disease (AD). Strong preclinical efficacy data and the completion of 
early, clinical safety studies have preceded this phase IIa study, the aim of 
which was to assess the effects of PBT2 on safety, efficacy, and biomarkers of 
AD.
METHODS: Between December 6, 2006, and September 21, 2007, community-dwelling 
patients over age 55 years were recruited to this 12-week, double-blind, 
randomised trial of PBT2. Patients were randomly allocated to receive 50 mg 
PBT2, 250 mg PBT2, or placebo. Inclusion criteria were early AD (mini-mental 
state examination [MMSE] score between 20 and 26 points or Alzheimer's disease 
assessment scale-cognitive subscale (ADAS-cog) score between 10 and 25 points), 
taking a stable dose of acetylcholinesterase inhibitor (donepezil, galantamine, 
or rivastigmine) for at least 4 months, a modified Hachinski score of 4 points 
or less, and CT or MRI results that were consistent with AD. The principal 
outcomes were safety and tolerability. Secondary outcomes were plasma and CSF 
biomarkers and cognition. Analysis was intention to treat. The trial is 
registered with ClinicalTrials.gov, number NCT00471211.
FINDINGS: 78 patients were randomly assigned (29 to placebo, 20 to PBT2 50 mg, 
and 29 to PBT2 250 mg) and 74 (95%) completed the study. 42 (54%) patients had 
at least one treatment emergent adverse event (10 [50%] on PBT2 50 mg, 18 [62%] 
on PBT2 250 mg, and 14 [48%] on placebo). No serious adverse events were 
reported by patients on PBT2. Patients treated with PBT2 250 mg had a 
dose-dependent (p=0.023) and significant reduction in CSF Abeta(42) 
concentration compared with those treated with placebo (difference in least 
squares mean change from baseline was -56.0 pg/mL, 95% CI -101.5 to -11.0; 
p=0.006). PBT2 had no effect on plasma biomarkers of AD or serum Zn(2+) and 
Cu(2+) concentrations. Cognition testing included ADAS-cog, MMSE, and a 
neuropsychological test battery (NTB). Of these tests, two executive function 
component tests of the NTB showed significant improvement over placebo in the 
PBT2 250 mg group: category fluency test (2.8 words, 0.1 to 5.4; p=0.041) and 
trail making part B (-48.0 s, -83.0 to -13.0; p=0.009).
INTERPRETATION: The safety profile is favourable for the ongoing development of 
PBT2. The effect on putative biomarkers for AD in CSF but not in plasma is 
suggestive of a central effect of the drug on Abeta metabolism. Cognitive 
efficacy was restricted to two measures of executive function. Future trials 
that are larger and longer will establish if the effects of PBT2 on biomarkers 
and cognition that are reported here translate into clinical effectiveness.