No synergistic effect of subtherapeutic doses of donepezil and EVP‐6124 in healthy elderly subjects in a scopolamine challenge model

Abstract

Introduction Donepezil is a widely used cholinesterase inhibitor in the management of Alzheimer's disease. Despite large-scaled evidence for its efficacy, elevated peripheral ACh levels often lead to side effects and are dose limiting. The present exploratory study is designed to determine the potentiation of the effects of donepezil by cotreatment with EVP-6124, an alpha-7 nicotinic agonist, to reduce scopolamine-induced cognitive deficits in healthy elderly subjects. Secondary objectives are to explore safety and pharmacokinetic and pharmacodynamics effects of EVP-6124 alone and in combination with donepezil compared to placebo. Methods A phase I randomized, single-center, placebo-controlled, double-blind, five-way, partial crossover study was performed with donepezil 2.5, 5 mg or placebo combined with EVP-6124 0.3, 1, 2, 4 mg or placebo in three cohorts of healthy elderly subjects in a scopolamine (0.3 mg i.v.) challenge test. Safety, pharmacokinetic, and pharmacodynamics outcomes were assessed. Results A total of 36 subjects completed the study. Donepezil pharmacokinetic parameters were similar with and without EVP-6124. Effective dose combinations were donepezil/EVP-6124(5/2 mg) and donepezil/EVP-6124 (5/0.3 mg) and showed improvements of the delayed recall of the Visual Verbal Learning Test (1.2; CI = 0.1–2.3) and reaction time during the two-back condition of the N-back (−42; CI = −77, −8), respectively. Overall, no marked reversal of scopolamine effects was observed. Discussion This study shows no synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in a scopolamine challenge model in healthy elderly subjects. Dosing of scopolamine and the combination of donepezil and EVP-6124 requires further study.

Cholinergic models of memory impairment in animals and man: scopolamine vs. biperiden

“…Lenz et al, 2012;Chen and Yeong, 2020;Cieslik et al, 2021). Various human studies indeed showed that a cholinesterase inhibitor, as expected, reverses the effects of scopolamine in cognitive tasks (Wesnes et al, 1991;Snyder et al, 2005;Cho et al, 2011;AstraZeneca, 2017;Laczó et al, 2017;Baakman et al, 2019). Although the reversal effects are mixed, these findings support the notion that scopolamine is useful to model cognitive deficits in Alzheimer's disease.…”

A randomized single and multiple ascending dose study in healthy volunteers of LTI‐291, a centrally penetrant glucocerebrosidase activator

“…Both in SAD and MAD, the NeuroCart®, a CNS test battery, was used to exclude any adverse effects of LTI‐291 on CNS functioning. The test battery consists of neurophysiological, psychomotor and cognitive tests and has been extensively used previously in clinical drug development 16–20 . In short, measurements consist of saccadic and smooth pursuit eye movements, the adaptive tracking test (a visuo‐motor task sensitive to disturbances in vigilance and attention), the body sway (a test of postural stability), the Bond and Lader test (visual analogue scale [VAS] of alertness, calmness and mood), the Visual Verbal Learning Test (VVLT) (a test of immediate and delayed memory), and pharmaco‐EEG.…”

“…The test battery consists of neurophysiological, psychomotor and cognitive tests and has been extensively used previously in clinical drug development. 16 , 17 , 18 , 19 , 20 In short, measurements consist of saccadic and smooth pursuit eye movements, the adaptive tracking test (a visuo‐motor task sensitive to disturbances in vigilance and attention), the body sway (a test of postural stability), the Bond and Lader test (visual analogue scale [VAS] of alertness, calmness and mood), the Visual Verbal Learning Test (VVLT) (a test of immediate and delayed memory), and pharmaco‐EEG. Tests were performed in a quiet room with ambient illumination with only one subject in the same room (and a research assistant) per session.…”

Multi-factor combined biomarker screening strategy to rapidly diagnose Alzheimer's disease and evaluate drug effect based on a rat model

“…Due to the rigorous biomarker screening criteria of our strategy, the screened biomarkers were the most discriminating metabolites between the control and AD model groups. Donepezil did not actually cure AD in the clinic, although it is a widely used drug in the management of AD [ 29 ]. In this study, donepezil did not restore all potential biomarkers screened out by our strategy to normal levels consistently.…”