Neuro, OT - Any thoughts on Prana's approach to AD, involving "subtle defects in the metabolism of biological metals that lie at the core of common neurodegenerative conditions"? I see their 12 week Alzheimer's Phase 2a showed statistical significance in several executive function components of the NTB (paper below), and they're planning a 500+ patient Phase 2b. Any thoughts on their chances of getting a high profile partner for the program? They received a $15 mil grant last Fall from the Australian govt, and recently raised an additional $6 mil, but I assume they'll need a pharma partner to start the Phase 2b. Thanks for any insights.
>>> The Lancet Neurology, Volume 7, Issue 9, Pages 779 - 786, September 2008 doi:10.1016/S1474-4422(08)70167-4Cite or Link Using DOIPublished Online: 29 July 2008
Safety, efficacy, and biomarker findings of PBT2 in targeting Aß as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trialOriginal Text
Lars Lannfelt MD a, Kaj Blennow MD b, Henrik Zetterberg MD b, Stellan Batsman MD c, David Ames MD d, John Harrison PhD e i, Colin L Masters MD f, Steve Targum MD g, Ashley I Bush MBBS f, Ross Murdoch PhD h, Janet Wilson RN h, Craig W Ritchie MBChB i , on behalf of the PBT2-201-EURO study group‡
Summary
Background
PBT2 is a metal-protein attenuating compound (MPAC) that affects the Cu2+-mediated and Zn2+-mediated toxic oligomerisation of Aß 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 Aß42 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 Zn2+ and Cu2+ 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 Aß 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. <<<
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