Abstract
The development of cholinergic neurotransmitter based cognitive enhancers for Alzheimer’s disease and other neuropsychiatric disorders have focused recently on allosteric modulation of specific muscarinic acetylcholine receptor (mAChR) subtypes to reduce dose-limiting side-effects that have been the hallmark of earlier orthosteric mAChR agonists. VU0467319 (VU319) is an investigational positive allosteric modulator of the M 1 mAChR. A Phase 1 first-in-human study was conducted assessing safety and brain activity utilizing cognitive tasks and event-related potentials (ERPs) in single-ascending dose and food effect studies. VU319 was given orally to 52 healthy volunteers aged 18–55 years. The single ascending dose study tested 40 participants in five dose escalating cohorts (60, 120, 240, 400, 600 mg; 6 VU319/2 placebo per dose). The food effect study involved 12 participants, 10 VU319 (120 mg)/2 placebo. Exploratory cognitive and electrophysiological tasks were examined pre-dosing and at 5 hours post-dose. Tolerability was good with no observed dose limiting side effects throughout the full dose range tested. Drug exposure increased with dose in a less than dose-proportional manner with a half-life ranging from 36 to 43 hours. Absorption was increased with food. Exploratory cognitive/ERP testing showed evidence for drug-induced CNS activity on higher doses of VU319 compared to placebo. Single dose VU319 across five ascending cohorts appeared to have a favorable safety profile and a PK profile consistent with once daily dosing. Target engagement results suggest stimulation of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide a strong foundation for further studies of positive allosteric modulators of muscarinic M 1 receptors for potential cognitive or behavioral benefits.
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