NSI-189

About Major Depressive Disorder (MDD)

Major depressive disorder (MDD) is a mental disorder characterized by episodes of all-encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. MDD is the leading cause of disability in the United States (U.S.) for persons age 15 to 44. In 2015, an estimated 16.1 million adults aged 18 or older in the U.S. had at least one major depressive episode in the prior year. This number represented 6.7% of all U.S. adults.¹ Treatment of MDD is characterized by a high level of patient turnover due to low efficacy and high side effects. It is estimated that 67% of patients will fail their first line therapy, 75% will then fail their second line prescription² and 80% will then fail their third line prescription. These factors combine to create a significant opportunity for a differentiated therapeutic agent, particularly one that may act through a novel mechanism of action with few side effects.

^{1 https://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml. Accessed February 13, 2017.
2 Rush AJ, Fava M, et al; STAR#D Investigators Group.Sequenced Treatment Alternatives to Relieve Depression (STAR*D); rationale and design Control Clin Trials. 2004 Feb;25(1):119-42}

NSI-189 as a Potential Treatment

NSI-189 is the lead compound in our neurogenic small molecule drug discovery program.  It is being developed for the treatment of MDD and other psychiatric and/or cognitive impairment indications associated with hippocampal atrophy.

We believe that NSI-189 may treat MDD by promoting synaptogenesis or neurogenesis in the hippocampus. NSI-189 stimulates neurogenesis of human hippocampus derived neural stem cells in vitro and stimulates neurogenesis in young, normal, healthy mouse hippocampus in vivo. The neurogenic effect by NSI-189 is believed to have a highly specific effect in the hippocampus and subventricular zone, the two well-known neurogenic regions in adult CNS, and nowhere else in the CNS.

Preclinical Insight into NSI-189:  Potential for Broad Utility

Potential Treatment for Cognitive Impairment and Angelman Syndrome

Treatment of normal mouse brain slices with NSI-189 produced a concentration and time dependent enhancement of the magnitude of long term potentiation (LTP), a measure of synaptic plasticity, which is an in vitro biomarker of memory. Additionally, NSI-189-induced LTP enhancement requires protein synthesis, suggesting structural synaptic plasticity.

NSI-189 treatment of brain slices from mice with a genetic defect that models Angelman Syndrome (which in humans leads to inherited intellectual disability) restored LTP to normal levels.

NSI-189 treatment ameliorated behavioral and memory function and preserved hippocampal neurogenesis in a rat model of cognitive impairment induced by irradiation.

Potential Treatment for Type 1 and Type 2 Diabetes

NSI-189 was demonstrated to be effective in the prevention and reversal of peripheral neuropathies in a mouse model of Type 1 and preventative in a mouse model of Type 2 diabetes. Data from these studies, which includes reversal of neuropathic pain and decreased nerve conductance associated with the onset of diabetic symptoms, suggest that NSI-189 may have broad applicability in the treatment of central and peripheral neuropathies arising from diverse etiologies.

Potential Treatment for Ischemic Stroke

Oral administration of NSI-189 to mice with ischemic stroke led to a significant increase in neurogenesis in the hippocampus accompanied by a significant recovery from motor deficit. This evidence suggests that NSI-189 can induce recovery from stroke-induced brain damage. The improvements were maintained post the termination of NSI-189 therapy for an additional 12-week, drug-free, observational period. The sustained improvement suggests that NSI-189 initiated a host brain repair mechanism enabling tissue remodeling of the stroke brain. NSI-189 demonstrated the upregulation of growth factors such as stem cell factor (SCF) and brain-derived neurotrophic factor (BDNF), as well as increasing neurite outgrowth.