Safety, tolerability, pharmacokinetic and pharmacodynamic effects of the muscarinic M1 positive allosteric modulator VU0467319 for Alzheimer’s disease: a single ascending-dose study in healthy participants
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...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-025-01798-4 |
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| Summary: | 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 M1 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 h post-dose. Tolerability was good with no observed dose limiting side effects throughout the full dose range tested. In the single ascending dose study, there were 47 TEAEs reported across the 5 cohorts, 14 in the placebo group and 33 across the 5 active dose cohorts. In the food effect study, there were 20 TEAEs reported, 6 in the placebo group and 14 in the fed and fasted conditions. Drug exposure increased with dose in a less than dose-proportional manner with a half-life ranging from 30 to 55 h. Peak concentration was observed between 5 and 9.5 h across the dosage groups. 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 M1 receptors for potential cognitive or behavioral benefits. |
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| ISSN: | 1758-9193 |