First successful clinical trial of VU319 brings Alzheimer’s treatment one step closer

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.”

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 potential to treat memory loss in schizophrenia, prion diseases, Rett syndrome, vascular dementia, and Lewey body dementia.

“Funding from the National Institute of Mental Health allowed the WCNDD to discover and develop VU319. An important philanthropic gift from the William K. Warren Foundation then enabled us to partner with DavosPharma to conduct critical early-stage studies and earn approval from the FDA as an investigational new drug, paving the way for the Alzheimer’s Association award to Dr. Paul Newhouse for the phase I trial,” Lindsley said. “Overall, it has been incredibly rewarding to drive a program from the most basic discovery stage and translate it into human clinical testing, all at Vanderbilt.”

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.

The article, “Discovery of VU0467319: an M1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials,” was published in ACS Chemical Neuroscience on Dec. 11. 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. 

The WCNDD extends traditional academic pursuits in basic science to take the most exciting advances in our understanding of human disease and drug targets to a point where these breakthroughs can directly impact patient care. Established with a $20-million gift from The William K. Warren Foundation in Tulsa, Oklahoma, the WCNDD houses approximately 100 renowned scientists with a diverse set of interests and skills working to translate research ideas into viable new drugs that prevent or treat serious brain disorders, such as Alzheimer’s disease, schizophrenia, and Parkinson’s disease.

The Warren Foundation has been a longstanding supporter of Vanderbilt and its research efforts. Seven endowed faculty chairs currently are supported by the foundation.

“Supporting novel, research-based methods to combat devastating cognitive impairments and mental illnesses lies at the heart of our foundation’s mission,” said John-Kelly Warren, CEO of the Warren Foundation and grandson of the founders, in 2020. “It is also gratifying to support this research at Vanderbilt University, an institution that has made a significant impact on the lives of so many, including my family.”

Collaborators

WCNDD co-authors on this study include Michael S. Poslunsey, Michael R. Wood, Changho Han, Shaun R. Stauffer, Joseph D. Panarese, Bruce J. Melancon, Julie L. Engers, Jonathan W. Dickerson, Weimin Peng, Meredith J. Noetzel, Hyekyung P. Cho, Alice L. Rodriguez, Corey R. Hopkins, Ryan Morrison, Rachel D. Crouch, Thomas M. Bridges, Anna L. Blobaum, Olivier Boutaud, J. Scott Daniels, Jerri M. Rook, Colleen M. Niswender, Carrie K. Jones, and P. Jeffrey Conn.

DavosPharma collaborators include Michael J. Kates and Arlindo Castelhano, who conducted the investigational new drug–enabling studies, process chemistry, drug product, and regulatory work.