GATE-251 or Placebo for the Reduction of Symptoms of Major Depressive Disorder

Inclusion Criteria:

Each subject must meet all of the following inclusion criteria to be eligible to participate in the study:

1. Male or female subjects.

2. Aged 18 to 64 years, inclusive.

3. Subject has a diagnosis of major depressive disorder (MDD), single or recurrentepisode, defined by the Diagnosis and Statistical Manual of Mental Disorders, FifthEdition (DSM-5); if single episode, the duration must be ≥3 weeks and ≤18 months.The diagnosis of MDD will be made by a site psychiatrist and supported by theStructured Clinical Interview for DSM-5 - Clinical Trials version (SCID-5-CT) andconfirmed by remote, independent raters from the Massachusetts General HospitalClinical Trials Network and Institute with a State versus trait, Assessability, Facevalidity, Ecological validity, and Rule of three Ps (pervasive, persistent, andpathological) (SAFER) interview:

4. The current depressive episode is ≥3 weeks and ≤18 months in duration prior tothe Screening Visit (V1);

5. Have an appropriate severity of illness of at least moderately illcorresponding to a CGI-S score of ≥4 at the Screening and Baseline Visits (V1and V2, respectively); and

6. Importantly, have a sufficient history and/or independent report verifying thatthe current depressive episode is causing clinically significant distress orimpairment in functioning.

7. Subject has a Hamilton Depression Rating Scale-17 (HDRS-17) using the StructuredInterview Guide for the Hamilton Rating Scale for Depression (SIGH-D) total score of ≥22 at the Screening Visit (V1) and Baseline Visit (V2) with no more than a 25%change from the Screening Visit (V1) to the Baseline Visit (V2).

8. Subject has Hamilton Anxiety Rating Scale (HARS) total score ≥15 at the ScreeningVisit (V1) and predose at the Baseline Visit (V2).

9. Subject has Insomnia Severity Index (ISI) total score ≥15 at the Screening Visit (V1) and predose at the Baseline Visit (V2)

10. Female subjects must meet 1 of the following:

11. Surgically sterile or at least 2 years menopausal (ie, postmenopausal isdefined as a woman with the absence of menses for at least 12 consecutivemonths). Menopausal status is to be confirmed by assessing the folliclestimulating hormone level at Screening Visit (V1), or,

12. If a woman of child bearing potential, subject must use an acceptable method ofbirth control from date of Screening to the last evaluation at Day 71. Musthave a documented negative point of care urine pregnancy test within 24 hoursprior to first dosing.

13. Male subjects, including those who are surgically sterile, must use a medicallyacceptable form of contraception from the time of randomization until the lastevaluation at Day 71. Male subjects are strongly advised to inform female partnersof the need for them to use highly effective birth control during this time period.

14. Subject must be medically stable by physical examination, medical history, vitalsigns, laboratory evaluations, and 12-lead electrocardiogram performed at theScreening Visit (V1) and Baseline (V2). If abnormalities are found, the subject maybe included if the Investigator, contract research organization (CRO) and sponsormedical monitors judge the abnormalities to be not clinically significant.

15. Ability to understand the nature and requirements of the study and is willing tocomply with the study restrictions and agree to return for the required assessments.

16. Provides written informed consent to participate in the trial.

17. Is able to communicate with investigational site personnel, able to completepatient-reported outcome measures and in the opinion of the Investigator, can bereliably rated on assessment scales

Exclusion Criteria:

Any subject who meets any of the following criteria will be excluded from study participation:

1. Evidence of treatment-resistant MDD, defined by having an inadequate response (≤25%)to 2 or more different medications approved for the treatment of MDD at an adequatedose (per locally approved label) for an adequate duration during the currentepisode using the Massachusetts General Hospital Antidepressant Treatment RatingQuestionnaire (ATRQ).

2. Current DSM-5 diagnosis of bipolar (or related disorders), antisocial personalitydisorder, obsessive compulsive disorder, borderline personality disorder, orattention-deficit/hyperactivity disorder. Subjects not meeting full DSM-5 criteriafor borderline personality disorder but exhibiting recurrent suicidal gestures,threats, or self-mutilating behaviors should also be excluded.

3. Subject has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD withpsychotic features.

4. Current concomitant treatment with Food and Drug Administration (FDA)-approvedantidepressants, antipsychotics, mood stabilizers, sedatives, or stimulants. Currentor past treatment with esketamine, ketamine, or psychedelics is prohibited. Subjectmust have current concomitant treatment discontinued at least 14 days prior to theBaseline Visit (V2). Subjects may continue anxiolytic agents, except for drugs thatare also used to treat depression, or benzodiazepines, or sleep aids [see Section 5.5.1 for a nonexhaustive list] (except trazodone) so long as they have been on astable dose for at least 3 months and do not intend to change dose duringdouble-blind treatment period (Day 1, Week 1 through end of Week 6 [Day 43]).Subjects who use cannabis or cannabis-derived molecules, includingtetrahydrocannabinol (THC), whether natural or chemically-synthesized, hemp seedoil, or cannabidiol (CBD) products (eg, gummies), must be discontinued for at least 14 days prior to the Baseline Visit (V2).

5. Treatment with any experimental antidepressant agent or treatment with a psychedelicagent in an FDA-approved clinical study within the past 12 months.

6. History of electroconvulsive therapy, vagus nerve stimulation, deep brainstimulation, or repetitive transcranial magnetic stimulation within the past 5 yearsor has had a failure of response to electroconvulsive therapy at any time.

7. Subject has clinically significant renal dysfunction as assessed by the estimatedglomerular filtration rate <70 mL/min using the Chronic Kidney Disease EpidemiologyCollaboration - creatinine (CKD-EPI creatinine) methodology.

8. Subject has liver protein and enzyme (alkaline phosphatase, alanineaminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, totalbilirubin, lactate dehydrogenase test result >1.5 times the upper limit of normal (subjects with a diagnosis of Gilbert's Syndrome may be eligible if no liverfunction or enzyme test results other than total bilirubin are >1.5 times upperlimit of normal).

9. Subject has resting heart rate (supine) <60 or >100 bpm at the Screening Visit (V1)or predose Baseline (V2).

10. Subject has resting diastolic blood pressure <50 mmHg at the Screening Visit (V1) orpredose Baseline (V2).

11. Subject has cardiac PR interval >250 msec at the Screening Visit (V1) or predoseBaseline (V2), or QTcF or QTcB interval >450 msec in males or >470 msec in females,or QRS interval >120 msec.

12. Evidence of alcohol abuse (>4 units of alcohol on most days; 1 unit=½ pint of beer, 1 glass of wine, or 1 ounce of hard liquor/spirits) or a positive saliva alcoholscreen at Screening (V1) and predose at the Baseline Visit (V2). Alcohol consumptionshould be avoided for at least 24 hours prior to Baseline Visit (V2). Note: Subject may not be rescreened.

13. Abuse of illicit substances, including psychedelic mushrooms by DSM-5 definition ofsubstance use disorder within the 12 months prior to the Screening Visit (V1).Nicotine- containing products eg cigarettes, cigars, vaping, and pipes must bediscontinued for at least 14 days prior to randomization. Positive urine test forany drug of abuse is exclusionary.

14. Positive urine test for any drug of abuse (except cannabis or cannabis-derivedmolecules such as THC whether natural or chemically-synthesized [see exclusioncriterion 4]) with the exception of appropriate use of prescribed barbiturates.Subjects may not be rescreened after failing a drug screen.

15. HIV infection, COVID-19 infection, or active hepatitis B or C, syphilis, or otherongoing infectious disease at the Screening Visit (V1).

16. Has laboratory evidence of hypothyroidism at Screening (V1) as measured by thyroidstimulating hormone (TSH) and reflex free thyroxine (T4). If TSH is abnormal andreflex T4 is normal, the subject may be included.

17. Has current unstable diabetes or glycosylated hemoglobin (HbA1c) >7% at Screening (V1).

18. Currently pregnant, planning to become pregnant during the course of the study, ornursing.

19. Currently working a night shift or may be required to work night shift during thecourse of this study, from Screening through completion of final polysomnography.

20. Malignancy in the last 5 years, with the exception of nonmetastatic basal cell orsquamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.

21. Subject has received new onset psychotherapy or had a change in the intensity ofpsychotherapy within 8-weeks prior to the Screening Visit (V1).

22. Currently taking prohibited prescription or over-the-counter medications includingherbal therapies (eg, echinacea, ginseng, ginko, elderberry, turmeric, ginger,valerian, chamomile, or St John's wort) and THC or cannabis-containing products [seeexclusion criteria 4], which may interfere with the required study psychiatricassessments.

23. History of allergy or sensitivity, or intolerance to zelquistinel, NMDAR ligandsincluding ketamine, dextromethorphan, memantine, methadone, dextropropoxyphene, orketobemidone.

24. Received another investigational drug or device within 90 days of screening in thisstudy.

25. Previously participated in this study or currently enrolled in any other clinicalstudy.

26. Body mass index of >40 kg/m2 at the Screening Visit (V1).

27. Subject is an employee of Worldwide Clinical Trials (hereafter referred to asWorldwide), the Investigator or study site with direct involvement in the study orother studies under the direction of that Investigator or study site, as well as afamily member of an employee or of the Investigator, or an employee of GateNeurosciences, Inc., or a family member of an employee.

28. In the opinion of the Investigator,

29. The subject has a significant risk for suicidal behavior during the course ofparticipation in the study, or

30. At the Screening Visit (V1) (the subject scores "Yes" on Items 4 or 5 in theSuicidal Ideation section of the Columbia Suicide Severity Rating Scale (C-SSRS) with reference to a 6-month period prior to Screening Visit (V1), or

31. At Screening (V1) the subject has had 1 or more suicidal attempts withreference to a 2-year period prior to Screening Visit (V1), or

32. The subject is considered to be an imminent danger to themself or others, or

33. At the Baseline Visit (V2) (the subject scores "Yes" on Items 4 or 5 in theSuicidal Ideation section of the C-SSRS

34. The subject is judged by the Investigator or CRO and Sponsor medical monitors to beinappropriate for the study for any reason.