Study of NSI-189 for Major Depressive Disorder

The screening period will range from a minimum of 14 days to a maximum of 28 days. The
Investigators will determine that the subjects meet eligibility criteria and will collect
the demographic and medical data permitting full characterization of the subject.

The duration of the randomization period will be 12 weeks. Subjects who meet
inclusion/exclusion criteria at the Baseline Visit will be randomized to NSI-189 80
milligrams/day, given as 40 milligrams twice per day, NSI-189 40 milligrams/day, given once
a day, or placebo. The treatment will be double-blinded.

Inclusion Criteria:

1. Subject has the ability to understand the purpose, potential benefits and risks of
the study and to provide signed and dated informed consent, authorizing the use of
protected health information in accordance with national and local Subject privacy
regulations.

2. Males and females 18 to 60 years of age, inclusive, at the time of informed consent.

3. Diagnosis of major depressive disorder, recurrent, as per Diagnostic and Statistical
Manual of Mental Disorders, 5th edition criteria and confirmed by Structured Clinical
Interview for the Diagnostic and Statistical Manual specific for Clinical Trials.
Their major depressive episode must be at least 8 weeks in duration and confirmed via
Structured Clinical Interview for the Diagnostic and Statistical Manual mood module
interview administered by a remote, independent raters, prior to the baseline visit.

4. Montgomery-Asberg Depression Scale (MADRS) score of 20 or greater, at Screening and
Baseline (MADRS score confirmed to be 20 or greater via remote SAFER interview by an
independent rater prior to the baseline visit).

5. The following applies to female Subjects: Non-pregnant, non-lactating females of
childbearing potential are eligible as long as they agree to use a double barrier
method of birth control from Screening until 3 months following discontinuation of
IP. Women who are not of childbearing potential (bilateral oophorectomy, bilateral
tubal ligation, hysterectomy, or post-menopausal for at least 1 year) will not
require such parameters in order to be eligible.

6. The following applies to male subjects: Male subjects with a female partner of
childbearing potential will be required to use double barrier method of birth control
or practice abstinence during this study and for 3 months following discontinuation
of Investigational Product. Note: These requirements also apply for male subjects who
have had a vasectomy.

7. Body mass index (BMI) ≥19.5 and ≤38.0 kg/m2, at Screening. Bodyweight must be >50 kg.

8. Of stable medical health, in the opinion of the Site Investigator, as determined by
Investigator discretion (medical history, physical examination, vital signs, ECG, and
clinical laboratory assessments).

Exclusion Criteria:

1. Clinically significant history or evidence of cardiovascular, respiratory, hepatic,
renal, gastrointestinal, endocrine, neurological, immunological, or other major
disease as determined by the Investigator or designee such that participation in the
study would place subjects at increased risk for serious adverse events.

2. History of cancer or malignancy within the last 5 years. Note: Subjects with basal or
squamous cell carcinoma may be permitted into the study on a case by case basis.

3. History of seizures; head trauma; or any clinically significant finding on the
neurologic examination such that participation in the study would place subjects at
increased risk for serious adverse events.

4. Previous or current diagnosis of bipolar or schizoaffective disorder or psychotic
disorder, or any psychotic symptoms during the current major depressive episode
(according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition).

5. Subjects who have a concurrent primary psychiatric diagnosis, diagnosed by Structured
Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 5th
edition, other than depression.

6. Subjects with delirium, dementia, Parkinson's disease, or Huntington's disease.

7. Subjects who have failed to respond to more than two antidepressant trials of
adequate dose (as defined in Massachusetts General Hospital Antidepressant Treatment
Response) and duration (at least 8 weeks in duration) during the current major
depressive episode as determined by the local rater and confirmed by an independent,
remote rater prior to the baseline visit.

8. Subjects with clinically significant suicidal ideation and/or behavior currently as
determined by the Site Investigator, such that participation in the study would place
subjects at increased risk for serious adverse events.

9. Subjects with any current homicidal ideation.

10. Clinically significant abnormal clinical chemistry values, as determined by the Site
Investigator, or any values for Alanine aminotransferase (ALT), Aspartate
aminotransferase (AST), total bilirubin or creatinine that are 1.5 times above the
upper limit of normal (ULN) and deemed clinically significant by the Site
Investigator; any clinically significant values as determined by the Site
Investigator for platelets or hemoglobin that are below the lower limit of normal
(LLN); or any out of normal range values for white blood cells (WBC) deemed
clinically significant by the Site Investigator.

11. Clinically significant (as determined by the Investigator) 12-lead Electrocardiogram
(ECG) abnormalities, including corrected QT interval using Bazett's correction method
of >450 msec for males and >470 msec for females.

12. Subjects with (current) severe Post-Traumatic Stress Disorder (PTSD), severe
Obsessive Compulsive Disorder (OCD), severe binge eating disorder, or subjects with
anorexia or bulimia nervosa active within the past three years.

13. Subjects who plan to undergo elective invasive procedures/surgeries at any time
during the study through End-of-study.

14. Subjects taking excluded medications (See Appendix 1)..

15. History of alcohol or drug-dependence or abuse by Diagnostic and Statistical Manual
of Mental Disorders, 5th edition criteria and confirmed by Structured Clinical
Interview for the Diagnostic and Statistical Manual specific for Clinical Trials
within 12 months prior to Screening.

16. Positive screening test or baseline test for drugs-of-abuse (cocaine, amphetamines,
barbiturates, opiates, benzodiazepines, cannabinoids, phencyclidine). Note any
positive test result(s) for benzodiazepine(s), opiates, or psychostimulants
accompanied by confirmation of a prescription for a valid medical reason will be
allowed.

17. Positive serum β-human chorionic gonadotropin (β-HCG) test at Screening or positive
urine pregnancy test at baseline that is consistent with pregnancy (females only).

18. Donation or loss of whole blood >200 mL within 30 days prior to dosing or ≥500 mL
within 56 days prior to dosing. Note: Blood taken for routine medical evaluations
totaling less than 50 mL will be permitted.

19. Females who are pregnant, lactating, or planning to become pregnant during the study.

20. Does not tolerate venipuncture.

21. Subjects who have had electroconvulsive therapy within the 6 months prior to
Screening.

22. Current enrollment in any other drug, biologic, device, or clinical study, or
treatment with an Investigational Product or approved therapy for investigational use
within 45 days (or 5 half-lives, whichever is longer) prior to Day 1 of
Investigational Product administration.

23. Any concurrent disease or condition that, in the opinion of the Investigator, would
make the subject unsuitable for participation in the clinical study.

24. Subject who, in the opinion of the Site Investigator, are unable to understand the
protocol requirements, instructions and study-related restrictions, the nature, scope
and possible consequences of the clinical study.

25. Subject who, in the opinion of the Site Investigator, are unlikely to comply with the
protocol requirements, instructions and study-related restrictions; e.g.,
uncooperative attitude, inability to return for follow-up and improbability of
completing the clinical study.