A potential new drug for Alzheimer’s disease and schizophrenia developed by Vanderbilt University scientists was administered July 29 to the first volunteer enrolled in a first-in-human phase 1 clinical trial at the Vanderbilt Institute for Clinical and Translational Research.
Animal studies suggest that the compound, a small molecule called VU319, may have potential for reducing memory impairments in brain disorders such as Alzheimer’s disease and schizophrenia.
The randomized, double-blind and placebo-controlled study will be conducted in about 50 healthy adult volunteers over the next 12 months to determine the compound’s safety, tolerability and bioavailability when taken orally with or without food.
VU319 was developed by a team of scientists at the Vanderbilt Center for Neuroscience Drug Discovery led by center director P. Jeffrey Conn and Craig W. Lindsley, VCNDD co-director and director of Medicinal Chemistry.
“This new small-molecule approach to potentially treating Alzheimer’s disease represents an exciting advance from currently available therapies,” said Paul Newhouse, director of the Center for Cognitive Medicine at Vanderbilt University Medical Center, who designed and is leading the study.
“We are very pleased to collaborate with Drs. Conn and Lindsley and their team to develop new treatments for this devastating illness,” said Newhouse, who is the Jim Turner Professor in Cognitive Disorders at Vanderbilt University School of Medicine.
Research on the potential drug began more than a decade ago. Last November Conn, the Lee E. Limbird Professor of Pharmacology, and Lindsley, the William K. Warren, Jr. Professor of Medicine, and their colleagues received approval from the U.S. Food and Drug Administration to begin human testing.
Conn said this was the first instance he knew of where an academic drug discovery group has moved a molecule designed to treat a chronic brain disorder from laboratory bench to early clinical trials without a pharmaceutical company partner.
If VU319 passes its human safety trial, the next step would be to test its efficacy in improving cognitive function in patients with Alzheimer’s disease and possibly schizophrenia and other brain disorders, he said.
VU319 is called a positive allosteric modulator, or PAM, because it tunes up the activity of a receptor in the brain like the dimmer switch in an electrical circuit. In this case, the target is the M1 muscarinic acetylcholine receptors, which are located on neurons activated by the neurotransmitter acetylcholine.
Previous efforts to ramp up M1 activity have failed due to adverse effects, including an abnormally slow heart rate and gastrointestinal distress caused by collateral activation of other muscarinic receptors. Because VU319 selectively tunes up the activity of the M1 receptor, it should avoid these effects, the researchers said.
Conn and Lindsley credited The William K. Warren Foundation of Tulsa, Oklahoma, which has provided more than $8 million since 2014 to VCNDD to support its development of fundamental new treatments for schizophrenia and other brain disorders, including Alzheimer’s disease.
Newhouse has received funding from the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation to support the Phase 1 human trials for VU319.
A NIH National Cooperative Drug Discovery/Development grant funded the early basic science and discovery of VU319. The Alzheimer’s Drug Discovery Foundation and Harrington Discovery Institute also supported some of the key toxicity studies that the FDA required.
Carrie K. Jones, assistant professor of pharmacology, coordinated the drafting and submission of the investigational new drug application to the FDA and is playing a major role in coordinating the collaboration between VCNDD and VUMC to conduct the trial.
Vanderbilt officials including Vanderbilt University Provost Susan Wente, Vice Provost for Research Padma Raghavan, and Lawrence Marnett, dean of Basic Sciences in the School of Medicine, also were instrumental in laying the groundwork for the clinical trial.
Other contributors included Colleen Niswender, research associate professor of pharmacology, and research assistant professors of pharmacology Jerri Rook, Thomas Bridges and Anna Blobaum.