Study of NSI-189 for Major Depressive Disorder

Inclusion Criteria:

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

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 StatisticalManual of Mental Disorders, 5th edition criteria and confirmed by Structured ClinicalInterview for the Diagnostic and Statistical Manual specific for Clinical Trials.Their major depressive episode must be at least 8 weeks in duration and confirmed viaStructured Clinical Interview for the Diagnostic and Statistical Manual mood moduleinterview administered by a remote, independent raters, prior to the baseline visit.

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

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

6. The following applies to male subjects: Male subjects with a female partner ofchildbearing potential will be required to use double barrier method of birth controlor practice abstinence during this study and for 3 months following discontinuation ofInvestigational Product. Note: These requirements also apply for male subjects whohave 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 byInvestigator discretion (medical history, physical examination, vital signs, ECG, andclinical laboratory assessments).

Exclusion Criteria:

1. Clinically significant history or evidence of cardiovascular, respiratory, hepatic,renal, gastrointestinal, endocrine, neurological, immunological, or other majordisease as determined by the Investigator or designee such that participation in thestudy 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 orsquamous 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 theneurologic examination such that participation in the study would place subjects atincreased risk for serious adverse events.

4. Previous or current diagnosis of bipolar or schizoaffective disorder or psychoticdisorder, 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 StructuredClinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 5thedition, 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 adequatedose (as defined in Massachusetts General Hospital Antidepressant Treatment Response)and duration (at least 8 weeks in duration) during the current major depressiveepisode as determined by the local rater and confirmed by an independent, remote raterprior to the baseline visit.

8. Subjects with clinically significant suicidal ideation and/or behavior currently asdetermined by the Site Investigator, such that participation in the study would placesubjects 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 SiteInvestigator, or any values for Alanine aminotransferase (ALT), Aspartateaminotransferase (AST), total bilirubin or creatinine that are 1.5 times above theupper limit of normal (ULN) and deemed clinically significant by the SiteInvestigator; any clinically significant values as determined by the Site Investigatorfor platelets or hemoglobin that are below the lower limit of normal (LLN); or any outof normal range values for white blood cells (WBC) deemed clinically significant bythe Site Investigator.

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

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

13. Subjects who plan to undergo elective invasive procedures/surgeries at any time duringthe 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 ofMental Disorders, 5th edition criteria and confirmed by Structured Clinical Interviewfor the Diagnostic and Statistical Manual specific for Clinical Trials within 12months prior to Screening.

16. Positive screening test or baseline test for drugs-of-abuse (cocaine, amphetamines,barbiturates, opiates, benzodiazepines, cannabinoids, phencyclidine). Note anypositive test result(s) for benzodiazepine(s), opiates, or psychostimulantsaccompanied by confirmation of a prescription for a valid medical reason will beallowed.

17. Positive serum β-human chorionic gonadotropin (β-HCG) test at Screening or positiveurine 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 mLwithin 56 days prior to dosing. Note: Blood taken for routine medical evaluationstotaling 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 toScreening.

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

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

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

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