NSI 189

NSI-189 is an experimental, potential antidepressant that is under investigation by Neuralstem, Inc. for the treatment for major depressive disorder (MDD), as well as for cognitive impairment and neurodegeneration. Research into NSI-189 has been funded by the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH). The mechanism of action of NSI-189 appears to be activation of neurogenesis in the hippocampus and possible enlargement of this structure, but how the drug mediates these effects is unknown and binding studies have so far failed to identify any certain molecular targets for the drug. As stated by Neuralstem, NSI-189 is a "new chemical entity with [a] novel mechanism of action, molecular target yet unknown, but not mediated by SSRI or SNRI or by BDNF release or via any known GPCRs, kinases, or channels." The drug was discovered via high-throughput screening of a library of 10,269 compounds for neurogenic effects in vitro.

NSI-189 successfully completed a phase I clinical trial for MDD in 2011, where it was administered to 41 healthy volunteers. A phase Ib clinical trial for treating MDD in 24 patients started in 2012 and completed in July 2014, with results published in December 2015. Neuralstem is now preparing to initiate phase II clinical studies for MDD in the first quarter of 2016, with results expected in the second half of 2017. In the two clinical studies conducted thus far, NSI-189 has shown statistically significant effectiveness in reducing depressive symptoms, has been found to be safe and well-tolerated (with no major adverse effects observed), and has been found to improve cognitive deficits in depressed patients. In addition to MDD, Neuralstem intends to pursue clinical development of NSI-189 for a variety of other neurological conditions, including traumatic brain injury, Alzheimer's disease, post-traumatic stress disorder, stroke, and natural cognitive and memory decline in aging.

NSI-189's neuronal targets remain elusive. NSI-189 lacks significant binding affinity for the 52 different enzymes, ion channels, and receptors tested by Neuralstem.