NSI-189

Product Pipeline

Therapy Indication Pre-Clinical Phase 1 Phase 2 Phase 3 Objective
Small Molecule: Lead Asset
NSI-189 Major Depressive Disorder (MDD)
Pre-Clinical Phase complete
Phase 1 Phase complete
Phase 2 Phase in progress
Phase 3 Phase not started
Cognition & Depression
Long-term Followup Study (MDD)
Pre-Clinical Phase complete
Phase 1 Phase complete
Phase 2 Phase in progress
Phase 3 Phase not started
Treatment-Refractory Depression (TRD)
Pre-Clinical Phase in progress
Phase 1 Phase not started
Phase 2 Phase not started
Phase 3 Phase not started
Supplementary Preclinical Program for Signal Generation
Angelman Syndrome
Pre-Clinical Phase in progress
Phase 1 Phase not started
Phase 2 Phase not started
Phase 3 Phase not started
Cognition & Motor Recovery
Ischemic Stroke
Pre-Clinical Phase in progress
Phase 1 Phase not started
Phase 2 Phase not started
Phase 3 Phase not started
Enhanced Recovery
Diabetic Neuropathy
Pre-Clinical Phase in progress
Phase 1 Phase not started
Phase 2 Phase not started
Phase 3 Phase not started
Prevention/Reversal of Neuropathy
Irradiation-induced Cognitive Deficit
Pre-Clinical Phase in progress
Phase 1 Phase not started
Phase 2 Phase not started
Phase 3 Phase not started
Neuroprotection from Brain Injury
LTP Enhancement (cognition)
Pre-Clinical Phase in progress
Phase 1 Phase not started
Phase 2 Phase not started
Phase 3 Phase not started
Enhanced Synaptic Plasticity
Alzheimer's Disease
Pre-Clinical Phase in progress
Phase 1 Phase not started
Phase 2 Phase not started
Phase 3 Phase not started
Improved Cognition

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.

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 cognition associaetd with 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.

Large Unmet Medical Needs

16M

U.S. patients3 diagnosed with Major Depressive Disorder

50%

Patients in therapy who fail to receive sufficient benefits

MDD Phase 2a Study – Safety

NSI-189 demonstrated a greater number of MDD-related symptoms in Placebo trials than Active trials, resulting in another sign of positive drug effect.

Side effects

Fewer subjects than the placebo with symptoms and signs associated with MDD

ECG

No clinically significant changes

Suicidal Ideation

No clinical meaningful changes

Vital Signs

No clinically meaningful changes in body weight or BMI

Sexual Functioning Inventory

No clinically meaningful changes

Drop-outs

In Stage 1 = 25 (19%) Placebo: 5 (5%) Active (Suggesting that disease burden is less in active group, a sign of positive drug effect)

Preclinical Insight into NSI-189: Potential for Broad Utility

Potential Treatment for Cognitive Impairment and Angelman Syndrome

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.

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.

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

3 NIMH

4 STAR*D clinical trial. Gen Hosp Psychiatry. 2005 Mar-Apr;27(2):87-96. Rush AJ, Fava M, et al;