A Phase 2 Study of Zelquistinel or Placebo for the Reduction of Symptoms of Major Depressive Disorder

Inclusion Criteria:

• Male or female subject.

• Aged 18 to 64 years, inclusive.

• Subject has a first episode or recurrent episode diagnosis of MDD, defined by theDiagnosis and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), ≥3weeks and ≤18 months. The diagnosis of MDD will be made by a central rater using theStructured Clinical Interview for DSM-5 Clinical Trials version (SCID-5-CT).

• Subject has a HDRS-17 total score of ≥18 at the Screening Visit (V1) and BaselineVisit (V2) as assessed by a central rater, with no more than a 25% change from theScreening Visit (V1) to the Baseline Visit (V2)

• Subject has HARS total score ≥15 at the Screening Visit (V1) and predose at theBaseline Visit (V2), AND

• Subject has ISI total score ≥10 at the Screening Visit (V1) and predose at theBaseline Visit (V2).

• Female subjects must meet 1 of the following:

• 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,

• If a woman of childbearing 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.

• Male subjects, including those who are surgically sterile, must use a medicallyacceptable form of contraception from the time of randomization until the End ofWeek 6 Visit. Male subjects are strongly advised to inform female partners of theneed for them to use highly effective birth control during this time period.

• 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.

• Provides written informed consent to participate in the study.

• 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.

• Have an appropriate severity of illness of at least moderately ill corresponding toa CGI-S score of ≥4 at the Screening and Baseline Visits (V1 and V2, respectively),as assessed by a central rater.

Exclusion Criteria:

• A subject who meets any of the following criteria will be excluded from studyparticipation:

• 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 (MGH ATRQ) assessed by a site rater.

• Current DSM-5 diagnosis of bipolar (or related disorders), antisocial personalitydisorder, obsessive compulsive disorder, borderline personalitydisorder,attention-deficit/ hyperactivity disorder, post-traumatic stress disorder,or panic attacks. Subjects not meeting full DSM-5 criteria for borderlinepersonality disorder but exhibiting recurrent suicidal gestures, threats, orself-mutilating behaviors should also be excluded.

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

• Subject has a score of >4 on the CADSS at the Screening Visit (V1).

• Active seizure disorder.

• Traumatic brain injury with current signs or symptoms.

• Treatment with esketamine or ketamine, any psychedelic agent, or any experimentalagent being evaluated to treat depression, whether as an antidepressant or for otheruse, within the past 12 months. o Treatment with any other experimental agents not used to treat depression withinthe past 3 months.

• Concomitant treatment with other Food and Drug Administration (FDA)-approvedantidepressants or adjuvant agents or enhancers such as dextromethorphan,antipsychotics, mood stabilizers, sedatives, stimulants, or benzodiazepines. Subjectmust discontinue concomitant treatment at least 14 days prior to the Baseline Visit. o Subjects may continue anxiolytic agents, except for drugs that are also used totreat depression. Subjects may continue sleep aids, so long as they have been on astable dose for at least 3 months and do not intend to change dose during theDouble-Blind Treatment Period (Week 1 [Day 1] through End of Week 6). However,trazodone must be discontinued for at least 14 days prior to the Baseline Visit.

• Use of cannabis or cannabis-derived molecules, including tetrahydrocannabinol (THC),whether natural or chemically-synthesized, including hemp seed oil and cannabidiol (CBD) products (eg, gummies). Subject must discontinue the use of such products atleast 14 days prior to the Baseline Visit, and THC must be below the limit ofdetection at the Baseline Visit.

• Positive test for any drug of abuse.

• Treated with any medical device or digital therapeutics for MDD, anxiety, insomnia,or other CNS indications within 90 days of screening in this study.

• 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.

• Subject has clinically significant renal dysfunction as assessed by the estimatedglomerular filtration rate (eGFR) <70 mL/min/1.73 m2 using the Chronic KidneyDisease Epidemiology Collaboration-creatinine (CKD-EPI creatinine) methodology.

• Subject has liver protein and enzyme (alkaline phosphatase, alanineaminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, totalbilirubin, lactate dehydrogenase) test result >1.5 × upper limit of normal (subjectswith a diagnosis of Gilbert's Syndrome may be eligible if no liver function orenzyme test results other than total bilirubin are >1.5 × upper limit of normal).

• Subject has resting radial pulse rate (supine) <60 or >100 bpm at the ScreeningVisit or predose Baseline, based on a single assessment.

• Subject has resting diastolic blood pressure <50 mmHg at the Screening Visit orpredose Baseline.

• Subject has PR interval >250 msec at the Screening Visit or predose Baseline, or QTcorrected for heart rate by Fridericia's formula (QTcF) or QT corrected for heartrate by Bazett's formula (QTcB) interval >450 msec in males or >470 msec in females,or QRS interval >120 msec, based on a single reading.

• 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 and predose at the Baseline Visit. Alcohol consumption should beavoided for at least 24 hours prior to Baseline Visit.

• Abuse of illicit substances by DSM-5 definition of substance use disorder within the 12 months prior to the Screening Visit.

• Use of nicotine containing products (eg, cigarettes, cigars, vaping, and pipes).Nicotine containing products must be discontinued for at least 14 days prior torandomization, and nicotine or cotinine (metabolite) must be negative at Baseline.

• Use of barbiturates. Prescribed barbiturates may be continued so long as the subjecthas been on a stable dose for at least 3 months and the dose may not change duringthe Double-Blind Treatment Period.

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

• Has laboratory evidence of hypothyroidism at Screening Visit (V1) as measured bythyroid stimulating hormone (TSH) and reflex free thyroxine (T4). If TSH is abnormaland reflex T4 is normal, the subject may be included.

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

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

• Currently working a night shift or may be required to work night shift during thecourse of this study, from Screening through the End of Week 6 Visit or completionof the final polysomnography for subjects who elect to participate in thepolysomnography sessions.

• 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.

• Subject has received new onset psychotherapy or had a change in the intensity ofpsychotherapy within 4-weeks prior to the Screening Visit (V1).

• Currently taking prohibited prescription or over-the-counter medications includingherbal therapies (eg, echinacea, ginseng, ginkgo, elderberry, turmeric, ginger,valerian, chamomile, or St John's wort) and THC- or cannabis-containing products (see Exclusion Criterion 9), which may interfere with the required study psychiatricassessments.

• History of allergy, sensitivity, or intolerance to GATE-251 or NMDAR ligandsincluding ketamine, dextromethorphan, memantine, methadone, dextropropoxyphene, orketobemidone.

• Previously participated in this study or Study GATE-251-C-202 or currently enrolledin any other clinical study.

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

• Subject is an employee of Worldwide or the Investigator or study site with directinvolvement in the study or other studies under the direction of that Investigatoror study site; a family member of an employee of the Investigator; or an employee ofGate Neurosciences, Inc. or a family member of an employee.

• In the opinion of the Investigator, the subject has a significant risk for suicidalbehavior during the course of participation in the study, OR

• At the Screening Visit (V1), the subject scores "Yes" on Items 4 or 5 in theSuicidal Ideation section of the C-SSRS with reference to a 6-month periodprior to Screening Visit (V1), or

• At the Screening Visit (V1), the subject has had 1 or more suicidal attemptswith reference to a 2-year period prior to Screening Visit (V1), or

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

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

• The subject is judged by the Investigator or the Worldwide and Sponsor medicalmonitors to be appropriate for the study for any reason