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P4‐205: STEADY STATE PKPD RESULTS DEMONSTRATE BIOEQUIVALENCE BETWEEN ONCE‐WEEKLY CORPLEX TM DONEPEZIL TRANSDERMAL DELIVERY SYSTEM AND DAILY ORAL ARICEPT
Author(s) -
Singh Parminder,
Miller Vaeling
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.07.026
Subject(s) - donepezil , tolerability , pharmacology , medicine , transdermal , bioequivalence , pharmacokinetics , pharmacodynamics , oral administration , adverse effect , dementia , disease
injections of granulocyte-macrophage colony-stimulating factor (GM-CSF) in transgenic AD mice reduced cerebral amyloid by greater than 50% and completely reversed their cognitive impairment. We subsequently found that Leukine (recombinant human GM-CSF) treatment of leukopenia in bone marrow transplant patients was associated with a significant improvement in cognitive functioning. Methods:We are conducting a randomized placebocontrolled double-blind Phase II safety and efficacy trial of Leukine in mild-to-moderate AD subjects at 250 mg/m/day SC for 5 days/week for three consecutive weeks with 45and 90-day follow-up visits. Neurological and neuropsychological assessments, MRI and amyloid-PET neuroimaging, and blood biomarker electrochemiluminescence (ECL) analyses are performed to assess treatment effects. Results: Interim analyses of 15 Leukine -treated and 15 placebo-treated subjects showed no drug-related serious adverse events, including no amyloid-related imaging abnormalities (ARIAs). When comparing measures at the end of treatment to baseline, the mean changes of theMMSE score showed improvement in the Leukine group relative to baseline (p1⁄40.0029) and to the placebo group (p1⁄40.0175) by repeated measures mixed model analysis. Differences were not significant by the follow-up visits. Interim ECL analyses of blood biomarkers for 64 analytes suggest that the levels of several cytokines and chemokines change significantly from baseline to end of treatment, correlating with Leukine treatment and neuropsychological score changes. Conclusions:The safety and neuropsychological results, although preliminary and based on a small number of subjects, indicate that completing this three-week trial and continuing our Alzheimer’s Association “Part the Cloud”-funded 24-week trial of GM-CSF/ Leukine in subjects with mild-to-moderate AD are warranted. Furthermore, the observed blood biomarker changes support further analyses with additional subjects from this trial and from the 24-week trial, as well as investigation into whether the Leukine -associated changes in biomarker levels also correlate with changes in AD pathophysiology.