Vanderbilt University Medical Center - Exploratory Phase 1 Study of VU0467319 (VU319) in Healthy Volunteers

Sep 15, 2026

This work investigates VU0467319 (VU319), a positive allosteric modulator of the muscarinic acetylcholine receptor subtype M1, as a cognition-focused therapeutic approach for Alzheimer’s disease and related neuropsychiatric conditions. A Phase 1 first-in-human study evaluated safety and brain activity using cognitive tasks and event-related potentials in single-ascending dose and food-effect designs. Oral dosing in 52 healthy volunteers (18–55) showed good tolerability without dose-limiting side effects across tested doses, with dose-related exposure and increased absorption with food. Exploratory cognitive and electrophysiological results indicated CNS activity and target engagement supporting further M1 PAM development.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages27

Reading Time1 h 8 min

AccessFree to download

Background and Rationale

Cholinergic stimulation and M1 targeting

Limitations of existing therapies

Study Design and Methods

Phase 1 single-ascending dose and food effect

Participants and dosing

Safety and pharmacokinetics

Exploratory Cognitive and Electrophysiological Findings

ERP and task outcomes

Summary and Implications for Future Research

Vanderbilt University Medical Center Emory University School of Medicine University of Nebraska Medical Center Alzheimer’s Therapeutic Research Institute, University of Southern California Vanderbilt University Medical Center Vanderbilt University Medical Center Vanderbilt University Vanderbilt University Vanderbilt University Vanderbilt University Vanderbilt University Vanderbilt University Medical Center muscarinic acetylcholine receptor subtype 1 (M1), positive allosteric modulator (PAM), cognition, metabolism, pharmacokinetics, pharmacodynamics April 4th, 2025 [https://doi.org/10.21203/rs.3.rs-6271510/v1](https://doi.org/10.21203/rs.3.rs-6271510/v1) 􀁱 􀅏 This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License No competing interests reported. A version of this preprint was published at Alzheimer's Research & Therapy on July 1st, 2025. See the published version at [https://doi.org/10.1186/s13195-025-01798-4](https://doi.org/10.1186/s13195-025-01798-4) . The development of cholinergic neurotransmitter based cognitive enhancers for Alzheimer’s disease and other neuropsychiatric disorders have focused recently on allosteric modulation of speci«c 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 «rst-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 «ve 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 «ve ascending cohorts appeared to have a favorable safety pro«le and a PK pro«le 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 bene«ts. Alzheimer’s disease (AD) is a chronic and irreversible neurodegenerative disease characterized by progressive deterioration of memory and other cognitive functions, impairments in normal daily living, and severe neuropsychiatric symptoms and behavioral disturbances ( 1, 2) . Recent approvals of disease-modifying treatments (DMTs) have been revolutionary for the «eld, as antiamyloid monoclonal antibodies have demonstrated the potential for limiting the progression of cognitive decline. Despite these advances, there are caveats with these new therapeutics, as they can have potentially serious adverse effects, related to the occurrence of amyloid-related imaging abnormalities (ARIA), which consist of edemas or microhemorrhages while cleaving amyloid from the blood vessels around the brain (3) . The slowing of disease progression across an 18-month period for the three monoclonal antibodies as measured by Clinical Dementia Rating sum of box score was under 30%, with disease progression continuing (4) . In addition, the use of monoclonal antibodies is logistically complex, requ

FAQs

What is VU0467319 (VU319) and why is it being studied for Alzheimer’s disease?

VU0467319 (VU319) is a positive allosteric modulator of the M1 muscarinic acetylcholine receptor. It targets cholinergic system functioning with an emphasis on avoiding dose-limiting side effects seen with earlier non-selective approaches.

How was the Phase 1 study designed?

The Phase 1 first-in-human program assessed safety and brain activity using cognitive tasks and event-related potentials in single-ascending dose and food-effect studies. VU319 was administered orally to 52 healthy volunteers aged 18–55.

What were the key safety, pharmacokinetic, and exposure findings?

Tolerability was good, with no observed dose-limiting side effects across the tested dose range. Drug exposure increased with dose in a less than dose-proportional manner, and absorption increased with food.

Sep 15, 2026

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