VU319 Shows Safe Profile and Potential as M1 Allosteric Modulator for MCI

Alexander C. Conley, PhD

Results from a phase 1 study evaluating VU319, an investigational positive allosteric modulator of the M₁ muscarinic acetylcholine receptor (mAChR) developed for cognitive enhancement in Alzheimer disease (AD) and other disorders, demonstrated a safe profile and a likely enhancement of the cholinergic system.^1,2

Analysis on both cognitive performance and safety and pharmacokinetics of VU319 were presented virtually by Alexander C. Conley, PhD, research instructor, Vanderbilt University Medical Center, at the Alzheimer’s Association International Conference (AAIC) 2020 annual meeting.

VU319 was originally developed by a team of scientists at the Vanderbilt Center for Neuroscience Drug Discovery, led by center director P. Jeffrey Conn, PhD, and Craig W. Lindsley, PhD.³

Single-dose treatment showed improvements in cognitive and event-related potential (ERP) performance on the higher doses of VU319 compared to placebo. Furthermore, single dose of VU319 appeared to have a favorable safety profile and a pharmacokinetics profile consistent with once daily dosing. There were no documented dose-limiting adverse effects and no observed significant adverse events (AEs) suggesting non-M₁ mAChR stimulation throughout the full dose range of the first 5 cohorts.

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The double-blind, phase 1 Single Ascending Dose (SAD) study featured a total of 40 healthy participants, each separated into 5 cohorts of 8 participants, 6 of which received oral VU319 and 2 who received placebo. Conley and colleagues escalated the dosage in each cohort, from 60 mg to 120 mg, 240 mg, 400 mg, and 600 mg. The Food Effect substudy consisted of 12 patients not included in SAD, 10 of which received VU319 and 2 of which received placebo. Those in the Food Effect substudy were dosed with food compared to a fasted state.

Researchers documented that the drug showed good oral absorption and bioavailability with a half-life consistent with once daily dosing. Additionally, the absorption of VU319 was increased in a fed compared to fasted state. Higher fasting doses of VU319 were linked to greater functional target engagement based off cognitive and electrophysiological results.

Patients who were administered with 600-mg VU319 responded significantly faster to targets on the continuous performance test compared to placebo (P = .03; effect size d = 1.2). Additionally, patients who received 400- and 600-mg VU319 showed larger P300 amplitudes on the incidental memory task compared to placebo, when present with repeated compared to novel images (d > 0.8).

Researchers also examined the relationship between plasma levels of VU319 and cognitive performance which showed that the treatment had an improved response time of psychomotor speed measures with increasing blood concentration of VU319 across all doses (r > 0.38).

Overall, Conley and colleagues noted that the results from both analyses indicate the potential measures that are sensitive to cognitive activity by M₁ allosteric modulators and open the possibility for a multiple ascending dose study and a phase 2a proof of concept trial involving patients with mild cognitive impairment (MCI).

REFERENCES

1. Conley AC, Key AP, Blackford JU, et al. Cognitive performance effects following a single dose of the M1 Muscarinic Positive Allosteric Modulator VU319. Presented virtually at AAIC 2020. Poster 45339.

2. Newhouse PA, Conley AC, Key AP, et al. Safety and pharmacokinetics of the muscarinic positive allosteric modulator VU319: a phase 1 single dose study. Presented virtually at AAIC 2020. Poster 45359.

3. Vanderbilt begins Phase 1 trials of new Alzheimer’s drug [press release]. Nashville, TN. Vanderbilt. Published August 7, 2017. Accessed July 29, 2020. news.vumc.org/2017/08/07/vanderbilt-begins-phase-1-trials-of-new-