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Research paper
Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans


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.

  • 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

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  • Funding This work was supported in part by QR Pharma, Inc. Henrik Zetterberg was supported by the Swedish Research Council (grant numbers K2010-63P-21562-01-4 and K2011-61X-20401-05-6) and the Swedish State Support for Clinical Research. Nigel H Greig was supported by the Intramural Research Program, National Institute on Aging, NIH.

  • Competing interests MLM and MYC are employees of QR Pharma, Inc. NHG is an inventor on the original Posiphen patent. Having assigned all rights to the US government, he declares that he has no ownership, financial interest or any other competing interests. All other authors declare no competing interests.

  • Ethics approval The human studies were conducted at and approved by the IRB and Ethics Committees of CEDRA/World Wide Clinical Trials (King of Prussia, PA) and the PRACS Institute (East Grand Forks, MN).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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