Multiple Ascending Dose Phase 1 Study of ALA-3000

Inclusion Criteria:

1. Male or female subject aged between 18 and 65 at screening visit and is able toprovide informed consent prior to initiation of any study related procedures.

2. At screening visit, subjects meet Diagnostic and Statistical Manual of MentalDisorders-fifth edition (DSM-5) criteria for single-episode major depressivedisorder (MDD) or recurrent MDD, without psychotic features, based upon clinicalassessment and confirmed by the Mini International Neuropsychiatric Interview (MINI).

3. Subject is medically stable on basis of physical examination, medical history, vitalsigns (blood pressure, pulse rate, respiration rate, blood oxygen saturation, andtemperature), clinical laboratory tests, and 12-lead ECG performed at screeningvisit, and/or prior to SC administration on Day 1. Subjects with abnormalities thatare judged to be not clinically significant (NCS) at the discretion of theinvestigator may be included. This determination must be recorded in the subject'ssource documents and initialed by the investigator.

4. At screening visit, subjects must have insufficient response to at least 2 oral ADtreatments, at least one of which is in the current episode of depression.Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) will be used to assess AD treatment response during the current episode;prior medication history (e.g., medical/pharmacy/prescription records or a letterfrom a treating physician, etc.) will be used to determine AD treatment response inprior episode(s). If the subject's current episode of depression is > 2 years, theupper limit of duration for assessing treatment response is applicable to only thelast 2 years.

5. Subject has a MADRS total score of ≥ 22 at screening.

6. Male and female subjects of childbearing potential must be willing to use a reliablemethod of contraception (e.g., total abstinence, condom and spermicide, intrauterinedevice [IUD], oral contraception which has been stable for 30 days) during theentire trial and at least 4 months after stopping the investigational product.

7. Female subjects of childbearing potential must have a negative serum β-humanchorionic gonadotropin (β-hCG) at screening visit and a negative urine pregnancytest prior to SC administration on Day 1.

8. Male and female subjects must agree not to donate sperm or eggs (ova, oocytes)during the study and for at least 3 months after receiving the investigational drug.

9. Agree to adhere to the prohibitions and restrictions specified in this protocol.

Exclusion Criteria:

1. Subject has a history of, or current signs and symptoms of, liver or renalinsufficiency; significant cardiac, vascular, pulmonary, gastrointestinal,endocrine, neurologic, hematologic, rheumatologic, metabolic disturbances, orfibromyalgia.

2. Subject has uncontrolled hypertension despite diet, exercise or a stable dose of apermitted anti-hypertensive treatment at screening visit, or prior to SCadministration on Day 1 (defined as a supine SBP > 140 mmHg or DBP > 90 mmHg); orany past history of hypertensive crisis.

3. Subject has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2 ×the upper limit of normal (ULN) or total bilirubin > 1.5 × ULN.

4. Subjects with history of or current DSM-5 diagnosis of psychotic disorder, or MDDwith psychotic features, post-traumatic stress disorder (PTSD), bipolar or relateddisorders (confirmed by MINI), obsessive compulsive disorder (current only),intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 319), autism spectrum disorder, borderline personality disorder, antisocialpersonality disorder, histrionic personality disorder, or narcissistic personalitydisorder.

5. Subject has suicidal ideation with intent to act within 6 months prior to screeningvisit or Study Day 1 (predose) based on investigator's discretion or C-SSRS, or hasa history of suicidal behavior within the past year as assessed on the C-SSRS; orsubject has homicidal ideation/intent at screening visit or on Day 1.

6. Subject had previously no treatment response to ketamine, S-ketamine, R-ketamine,all of the available AD treatment options in the double-blind phase (based onMGH-ATRQ), or an adequate course of electroconvulsive therapy (defined as at least 7treatments with unilateral/bilateral electroconvulsive therapy [ECT]), in thecurrent major depressive episode according to clinical judgment.

7. Subject has a score of ≥ 5 on the STOP-Bang questionnaire, in which case obstructivesleep apnea must be ruled out (e.g., apnea-hypopnea index [AHI] must be < 30). Asubject with obstructive sleep apnea can be included if he or she is using apositive airway pressure device or other treatment/therapy that is effectivelytreating (i.e., AHI < 30) his or her sleep apnea.

8. Subjects who meet DSM-5 criteria for moderate or severe substance or alcohol usedisorder, except for nicotine or caffeine, within 6 months prior to screening visit.

9. Subjects with lifetime history of ketamine, phencyclidine (PCP), lysergic aciddiethylamide (LSD), or 3,4-methylenedioxymethamphetamine (MDMA) hallucinogen-relateddisorder are exclusionary.

10. Subjects with positive urine drug test result(s) at screening visit or predose onDay 1 for barbiturates, methadone, opiates, cocaine, phencyclidine (PCP), andamphetamine/methamphetamines will be excluded. A positive test result forcannabinoids predose on Day 1 is exclusionary.

11. Subjects with positive alcohol breath test result at screening visit or predose onDay 1, or predose on Day 8.

12. Subject has a history of malignancy within the 5 years prior to screening.

13. Subject has known allergies, hypersensitivity, intolerance, or contraindication toketamine, S-ketamine, R-ketamine, or excipients in the investigational drug.

14. Subject has taken any prohibited therapies.

15. Subjects have received an investigational drug, treatment of ketamine, S-ketamine,R-ketamine, vaccine, or used an invasive investigational medical device within 60days before planned Study Day 1 or currently enrolled in an investigational study.

16. Subjects are pregnant or lactating at screening visit or prior to the SCadministration on Day 1 or planning to become pregnant during the study.

17. Subject has any condition or situation/circumstance for which, in the opinion of theinvestigator, participation would not be in the best interest of the subject (e.g.,compromise the well-being) or that could prevent, limit, or confound theprotocol-specified assessments.

18. Subject has had major surgery, (e.g., requiring general anesthesia) within 2 weeksbefore screening visit, or will not have fully recovered from surgery, or hassurgery planned during the time the subject is expected to participate in the study.

19. Subjects is an employee of the investigator or the trial site, with directinvolvement in the proposed trial or other trials under the direction of theinvestigator or trial site, or is a family member of an employee or of theinvestigator.

20. Subject has a history of human immunodeficiency virus (HIV), hepatitis B surfaceantigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinicallyactive liver disease, or tests positive for HIV, HBsAg, or anti-HCV at screeningvisit.

21. Subject has CS ECG abnormalities at screening or predose on Day 1.

22. Subject has received vagal nerve stimulation (VNS) or has received deep brainstimulation (DBS) in the current episode of depression.

23. Subject has a current or past history of seizures (uncomplicated childhood febrileseizures with no sequelae are not exclusionary).

24. Subject is taking a total daily dose of benzodiazepines greater than the equivalentof 6 mg/day of lorazepam at the start of the screening phase.

25. Subjects with any underlying medical conditions where elevation of blood pressuremay pose a risk (including severe cardiovascular disease, recent cerebral injury,increased intracranial pressure, intracranial bleeding, or acute stroke, unstableheart failure, untreated glaucoma) are excluded.

26. Subjects have a current or history of significant pulmonary insufficiency/conditionor with a peripheral blood oxygen saturation (SpO2) of < 93% at screening visit orprior to the SC administration on Day 1.

27. Subject has uncontrolled diabetes mellitus, as evidenced by HbA1c > 9% at screeningvisit or history in the prior 3 months prior to screening of diabetic ketoacidosis,hyperglycemic coma, or severe hypoglycemia with loss of consciousness.

28. Subjects have a history of interstitial cystitis or bladder inflammation.

29. Subject has any factors that might increase the risk of an injection site reactionprogressing to subcutaneous necrosis under the investigator's discretion (e.g.,immunocompromised patients, subjects have a history of severe skin disorder orinjection site reaction at abdomen, or the subject whose abdominal area isunsuitable for SC injections (e.g., nodules, lesions, excessive pigment, infected,scarring)).

30. Significant symptoms, medical conditions, or other circumstances which, in theopinion of the investigator, would preclude compliance with the protocol, adequatecooperation in the trial or obtaining informed consent, or may prevent the subjectfrom safely participating in trial.

31. Subjects receiving psychotherapy of any type that began, or was changed in frequencyor focus, less than 3 months before the Screening Visit.