Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. Issue 9 (11th July 2012)

• Record Type: Journal Article
• Authors: Maccecchini, Maria L; Chang, Mee Young; Pan, Catherine; John, Varghese; Zetterberg, Henrik; Greig, Nigel H
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 83:Issue 9(2012)
• Page Start: 894
• Page End: 902
• Publication Date: 2012-07-11
• Subjects: Posiphen -- amyloid precursor protein -- amyloid-β peptide -- inflammatory markers -- mild cognitive impairment -- genetics -- B12 deficiency -- neurochemistry -- Alzheimer's disease -- amyloid -- head injury -- Parkinson's disease; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2012-302589
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Aim: A first in human study to evaluate tolerability and pharmacokinetics followed by an early proof of mechanism (POM) study to determine whether the small orally, available molecule, Posiphen tartrate (Posiphen), lowers secreted (s) amyloid-β precursor protein (APP) α and -β, amyloid-β peptide (Aβ), tau (τ) and inflammatory markers in CSF of patients with mild cognitive impairment (MCI). Study design: Posiphen single and multiple ascending dose phase 1 randomised, double blind, placebo-controlled safety, tolerance, pharmacokinetic studies were undertaken in a total of 120 healthy volunteers to define a dose that was then used in a small non-randomised study of five MCI subjects, used as their own controls, to define target engagement. Main outcome measures: Pharmacodynamic: sAPPα, sAPPβ, Aβ42, τ (total (t) and phosphorylated (p)) and inflammatory marker levels were time-dependently measured over 12 h and compared prior to and following 10 days of oral Posiphen treatment in four MCI subjects who completed the study. Pharmacokinetic: plasma and CSF drug and primary metabolite concentrations with estimated brain levels extrapolated from steady-state drug administration in rats. Results: Posiphen proved well tolerated and significantly lowered CSF levels of sAPPα, sAPPβ, t-τ, p-τ and specific inflammatory markers, and demonstrated a trend to lower CSF Aβ42 . Conclusions: These results confirm preclinical POM studies, demonstrate that pharmacologically relevant drug/metabolite levels reach brain and support the continued clinical optimisation and evaluation of Posiphen for MCI and Alzheimer's disease.