Posiphen'S Pharmacokinetics and Mechanism-of-action in Mildly Cognitive Impaired Patients

Abstract

Posiphen® is in clinical development as an oral treatment for Alzheimer's disease (AD). In cell cultures, normal, transgenic and trisomic mice Posiphen reduces the rate of synthesis of amyloid-β precursor protein (APP) and, thereby, lowers levels of Aβ and potentially other toxic peptides generated from APP processing. We decided to conduct a trial in mild cognitive impaired (MCI) patients to confirm this mechanism of action (reduced rate of APP synthesis) in humans and correlate it with the pharmacokinetics of the drug and its metabolites in CSF and plasma. In order to avoid potential inter-subject variability we decided to use subjects as their own controls and measure CSF and plasma levels for 12 hours both prior to and following Posiphen dosing of 10 days. 5 MCI patients received Posiphen at 240 mg/ day for 10 days (4x60 mg was found in a multiple dose safety study to be well tolerated in elderly healthy volunteers). Serial CSF samples were collected via indwelling lumbar catheter for 12 hours one day before the start of dosing and immediately after the last dose. Plasma samples were taken at the same sampling times. CSF and plasma/serum samples were analyzed for pK: Posiphen and the primary metabolites: N1-norPositphen, N8-norPosiphen, N1, N8-norPosiphen pD 1: soluble α and βAPP, Aβ 40/42, AChEI/BChEI pD 2: Tau/phospho-Tau, C-terminal fragment/C31 and other potential AD associated markers. pD 3: α-synuclein The patients tolerated the procedure well and we have preliminary data indicating that Posiphen reduces circulating APP levels, consistent with the inhibition of APP synthesis as a key mechanism of action of Posiphen in humans. We also have data showing that the activity of Posiphen is prolonged by some of its metabolites. We are in the process of measuring a number of other markers and will report all the data at ICAD. Posiphen in MCI patients reduced APP levels making it a promising drug to modify the course of AD.