Vanderbilt neuroscience drug advances to clinic

In a first for an academic drug discovery group, the Vanderbilt Center for Neuroscience Drug Discovery has received FDA approval to put a treatment for brain disorders into the clinic without any help from the pharmaceutical industry. A study assessing the safety of the compound, a positive allosteric modulator of muscarinic acetylcholine receptor 1 (M1) for Alzheimer’s disease and schizophrenia, will begin early next year.

Academic drug discovery centers such as VCNDD typically focus on generating early-stage compounds that are spun off into companies or licensed to partners with the cash and experience to push them into clinical studies. Since it was established in 2008, VCNDD has secured several drug discovery partnerships with big pharma firms for preclinical compounds developed in its labs.

But with many drug firms exiting neuroscience research, some of those programs have stalled. For example, Bristol-Myers Squibb decided to exit neuroscience R&D a year into a collaboration with VCNDD to develop positive allosteric modulators of mGlur4 for Parkinson’s disease. Another partner, AstraZeneca, shut down its neuroscience unit, and the Vanderbilt team subsequently regained rights to positive allosteric modulators of M4.

Big pharma’s waning commitment to neuroscience prompted a shift in strategy at VCNDD. For the past two years, the academic team has focused on putting molecules through early clinical studies in the hope that they will have a better chance of getting to patients.

“We rarely see companies license a clinical-stage asset and then back out of it for non-science-based reasons,” notes VCNDD Director P. Jeffrey Conn. “We felt that if we partnered at a later stage, it gives programs a better chance of going the distance.”

That shift has meant building up capabilities beyond drug discovery. Although the VCNDD scientists have tapped some consultants, “we did the bulk of the work” necessary to get the drug candidate to the point where it could enter Phase I studies, notes Craig Lindsley, VCNDD’s director of medicinal chemistry. 

As an academic lab, putting compounds into the clinic without the help of big pharma has also meant “a unique cobbling of money,” Lindsley says. NIH funded much of the basic science on the M1 receptor, and in 2014 the William K. Warren Foundation kicked in $5 million to support the preclinical studies. Those data allowed VCNDD to get grants from the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation to support the Phase I trials.

The M1 modulator addresses cognitive functions—thinking and problem-solving capabilities, for example—as well as negative symptoms such as social withdrawal and irritability, associated with brain disorders.