CAMBRIDGE, Mass.--(BUSINESS WIRE)--SAGE Therapeutics, a biopharmaceutical company developing novel medicines to treat central nervous system (CNS) diseases, today announced it has discovered an innate mechanism to allosterically modulate the N-methyl-D-aspartate (NMDA) receptor that could prove key to treating a wide range of neuropsychiatric disorders, including Alzheimer's, schizophrenia, autism, and depression. The research, published in the Journal of Neuroscience, also showed that a proprietary compound developed by SAGE effectively restored behavioral and cognitive function in preclinical studies using this newly discovered approach to target the NMDA receptor.
"These findings point to a tractable allosteric site, which has been quite difficult to characterize and is critically needed to develop therapies focused on restoring the natural balance of brain activity in a number of CNS diseases," said Albert J. Robichaud, Ph.D., chief scientific officer of SAGE. "This adds to an already robust data set that SAGE's approach of allosteric modulation is highly differentiated with the potential to target areas of the brain that existing drugs cannot and yield therapies for many poorly treated CNS disorders."
NMDA receptors play a key role in regulating synaptic function in the CNS and are thought to underlie human learning, memory and social behaviors. They are validated targets, both in pre-clinical and clinical studies, in a range of neurologic and psychiatric diseases, but traditional approaches of inhibiting or activating the NMDA pathway have resulted in significant toxicities. By "fine-tuning" brain activity, SAGE's approach of allosteric modulation of the NMDA receptor has the potential to more effectively treat these diseases, while limiting the potential side effects seen with many CNS drugs. Identifying such allosteric sites and selective molecules to modulate NMDA receptor function, however, has historically proven challenging.
By screening a series of endogenous oxysterols and related compounds, the SAGE team working with its scientific collaborators identified 24(S)-hydroxycholesterol (24(S)-HC), a brain-specific metabolite of cholesterol, as a potent and selective positive allosteric modulator of NMDA receptor function. The company's scientists determined that 24(S)-HC binds to a modulatory site that is unique to the oxysterol class of molecules and serves as a novel approach to correcting NMDA receptor dysregulation seen in many CNS diseases. Subsequent drug discovery efforts identified a number of potent synthetic analogs of (24(S)-HC) with excellent drug-like properties. Treatment with SAGE's proprietary molecule SGE-301 reversed NMDA receptor-related cognitive and social deficits in a variety of preclinical models.
"These findings illustrate the power of SAGE's chemistry platform to efficiently generate drug candidates that have the potential to make a meaningful difference for patients with CNS diseases," said Jeff Jonas, chief executive officer of SAGE. "Alzheimer's disease, schizophrenia, autism, depression and other serious CNS disorders represent a large area of unmet need and pose a significant burden on families and society. SAGE's approach of allosteric modulation of NMDA and GABAA receptors is highly differentiated, and we are planning on advancing rapidly into the clinic with several programs during the next year, some independently and others via partnerships. "
About SAGE Therapeutics
SAGE Therapeutics is a neuroscience company developing therapies to treat CNS specialty and orphan diseases. The company has identified several product opportunities with clear and accelerated paths to regulatory approval. SAGE's initial pipeline includes programs in status epilepticus, anesthesia, Fragile X Syndrome and traumatic brain injury, where CNS drugs poorly address the areas of most urgent patient need and are often accompanied by considerable side effects. The company's Positive and Negative Allosteric Modulator (PANAM) platform has generated multiple new chemical entities supported by promising preclinical data with the potential to lead to products with utility for multiple indications over the next several years. SAGE Therapeutics is a private company launched in 2011 by a proven team of R&D leaders, renowned CNS experts and funded by Third Rock Ventures and Arch Ventures. For more information, please visit www.sagerx.com.
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