Researchers at the Warren Center for Neuroscience Drug Discovery, a clinical-stage biotech within the Vanderbilt University School of Medicine Basic Sciences, have detailed the successful drug discovery of a phase I single ascending dose clinical trial of VU319, a drug for memory loss in people with Alzheimer's disease and schizophrenia.

"This milestone highlights Vanderbilt's ability to drive discovery from research to clinical impact," said Provost and Vice Chancellor for Academic Affairs Cybele Raver. "The success of VU319 exemplifies how collaboration and innovation can bring real hope to patients and families facing Alzheimer's and other neurodegenerative diseases."

The article, "Discovery of VU0467319: an M1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials," is published in ACS Chemical Neuroscience.

John Kuriyan, dean of basic sciences and University Distinguished Professor of Biochemistry and Chemistry, agreed, adding, "The successful phase I trial of VU319 marks a potentially transformative step in drug development for Alzheimer's, showcasing Vanderbilt's capacity to translate fundamental research into therapeutic discovery that brings the hope of real clinical impact."

VU319 is the first Vanderbilt end-to-end drug discovery effort, starting from the earliest basic science research through human clinical trials. The effort spanned a high-throughput screening hit-to-candidate selection to completion of a clinical trial.

"After more than a decade of basic and translational research, the WCNDD was finally able to disclose how VU319, a unique M₁ PAM, was discovered and profiled," said Craig Lindsley, executive director of the WCNDD and University Professor of Pharmacology, Biochemistry and Chemistry who holds the William K. Warren, Jr. Chair in Medicine.

In addition to treating Alzheimer's disease, which affects roughly 6.9 million people over age 65 and has no known cure, VU319 has shown the potential to treat memory loss in schizophrenia, prion diseases, Rett syndrome, vascular dementia, and Lewey body dementia.

The neurotransmitter acetylcholine is responsible for learning and memory, but in Alzheimer's and other neurodegenerative diseases, such as schizophrenia, it is one of the first that stops working and disables neurons from functioning properly. VU319, an M₁ positive allosteric modulator, increases the efficacy of the endogenous neurotransmitter acetylcholine at the M₁ receptor, acting as a dimmer switch to "turn-up"the gain on the receptor selectively, providing the best possible therapeutic index.

In the human trial performed at Vanderbilt by Dr. Paul Newhouse, professor of psychiatry and pharmacology, director of the Vanderbilt Center for Cognitive Medicine, and clinical core director of the Vanderbilt Memory and Alzheimer's Center, the researchers saw signs of target engagement at the highest dose of the treatment that was tested and saw no side effects typical of other drugs working on the same area of the brain.

Following this successful phase I SAD clinical trial, the WCNDD is continuing to develop additional back-up M₁ PAMs to enter into human clinical testing.