Potential schizophrenia treatment, discovered at Vanderbilt and being developed by Neumora Therapeutics, entering Phase 1 clinical trial 

A potential schizophrenia treatment discovered through the Warren Center for Neuroscience Drug Discovery has been cleared by the U.S. Food and Drug Administration for use in phase 1 clinical trials—the third WCNDD therapeutic to reach that benchmark.  

The drug is an allosteric modulator that works through a mechanism that has been clinically validated in the treatment of disorders like schizophrenia. Developed in the labs of WCNDD Director  Craig Lindsley  and Director Emeritus  P. Jeffrey Conn, NMRA-266 has received Investigational New Drug clearance from the FDA. 

“Vanderbilt is proud that a discovery by our researchers at the Warren Center is now a significant step closer to helping improve the lives of people with schizophrenia,” Chancellor Daniel Diermeier said. “Our work with Neumora is the very definition of translational research and the work we aim to do every day, which is applying innovation and discovery to help address the world’s most complex challenges.”  

The clinical trial has been initiated by Neumora Therapeutics Inc., a clinical-stage biopharmaceutical company founded to confront the global brain disease crisis by taking a fundamentally different approach to the way treatments are developed. Vanderbilt and Neumora signed an exclusive, worldwide license and a research collaboration agreement for two novel series of M4 receptor modulator compounds, including NMRA-266, in February 2022. 

Vanderbilt’s agreement with Neumora was centered around the M4 muscarinic receptor, which NMRA-266 targets through positive allosteric modulation. In preclinical studies conducted by Conn and Lindsley, NMRA-266 was found to be highly selective to the M4 receptor, the area of the brain that regulates neurotransmission of dopamine. Overactive transmission of dopamine is connected to the positive, negative and cognitive symptoms of schizophrenia.  

“The M4 PAM story has been a Homer-style Odyssey to get to this point and represents almost 20 years of research funded by National Institutes of Health, the William K. Warren Foundation and pharmaceutical companies,” said Lindsley, also a University Professor of pharmacology, biochemistry and chemistry who holds the William K. Warren, Jr. Chair in Medicine. “This mechanism and NMRA-266 represent a potential game-changer for schizophrenic patients and their families. Moreover, this success is a testament to the virtue of academic drug discovery and Vanderbilt’s commitment to supporting the WCNDD, a clinical-stage biotech enterprise within the university.” 

For the WCNDD to have such regular production of clinical assets when up against diverse neuroscience pipeline is unprecedented among academic drug discovery centers, according to Lindsley. 

“NMRA-266 entering phase 1 trials highlights the complementary relationship between university researchers and industry partners,” said Vice Provost for Research and Innovation Padma Raghavan. “By pairing our faculty’s ingenuity with the private sector’s commercialization know-how, we are able to bring life-changing discoveries to patients in need faster.” 

Schizophrenia spectrum disorders affect 3.7 million U.S. adults, a figure up to three times higher than previously understood, according to a recent study. This fundamentally different mechanism that NMRA-266 acts through is very selective for brain circuits involved in schizophrenia, which means in is unlikely to have the adverse effects of current dopamine antagonists—resulting in an improved standard of care for people with schizophrenia. 

“The initiation of this phase 1 study is an important step in the development of NMRA-266. In pre-clinical studies NMRA-266 demonstrated a favorable pharmacologic profile that includes high potency and selectivity for the M4 receptor subtype, meriting its advancement into the clinic,” Dr. Robert Lenz, executive vice president and head of research and development at Neumora, said in a release. “With its pre-clinical profile and clinical validation of the M4 muscarinic receptor class in treating schizophrenia, we believe that NMRA-266 has strong potential as a treatment for neuropsychiatric disorders.” 

Human clinical trials are a significant advancement in a five-step drug development process. Drug discovery research begins in the lab and is followed by preclinical research to answer basic questions about safety. Then there is clinical research to ensure that the treatment is safe and effective. The FDA then reviews all submitted data. If approved, the therapeutic will be made available for use by the public and be monitored for safety by the FDA for as long as it is available. 

The Vanderbilt-Neumora collaboration was facilitated by the  Center for Technology Transfer and Commercialization. Vanderbilt researchers who contributed to research around NMRA-266 and the power of academic drug discovery include Darren W. Engers, Aaron Bender, Olivier Boutaud, Thomas Bridges, Julie Engers, Alison Gregro, Carrie Jones, Colleen Niswender, Jerri Rook and Kayla Temple.