Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans
- Maria L Maccecchini1,
- Mee Young Chang1,
- Catherine Pan2,
- Varghese John3,
- Henrik Zetterberg4,
- Nigel H Greig5
- 1QR Pharma, Inc., Berwyn, Pennsylvania, USA
- 2Inarian Neurodiagnostics, LLC., Mercer Island, Washington, USA
- 3Alzheimer's Drug Discovery Network, Buck Institute for Research on Aging, Novato, California, USA
- 4Clinical Neurochemistry Laboratory, Sahlgrenska University, Hospital/ Mölndal, Mölndal, Sweden
- 5Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
- Correspondence to Dr Nigel H Greig, Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd., Room 05C220, Baltimore, Maryland 21224, USA; Maria Maccecchini;
Contributors MLM contributed to the conception and design of the study, oversaw analyses (both experimental and statistical) and provided input into manuscript writing. MYC undertook experimental studies and analyses associated with CSF sAPPα and sAPPβ quantification. CP undertook experimental studies and analyses associated with CSF Aβ, p-τ, t-τ, C3 and factor H. VJ aided in study design, was responsible for assays related to CSF Aβ, sAPPα and sAPPβ quantification, and provided input into manuscript writing. HZ aided in study design, was responsible for assays related to CSF MCP-1, YKL-40 and sCD14, and provided input into manuscript writing. NHG contributed to the study conception and design, the generation of Posiphen and metabolites, rodent studies, and the manuscript.
- Received 23 February 2012
- Revised 21 May 2012
- Accepted 23 May 2012
- Published Online First 11 July 2012
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.
- amyloid precursor protein
- amyloid-β peptide
- inflammatory markers
- mild cognitive impairment
- B12 deficiency
- Alzheimer's disease
- head injury
- Parkinson's disease
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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