A Biomarker-Guided, Randomized, Placebo-Controlled Efficacy and Safety Study of Liafensine in Patients With TRD

Inclusion Criteria:

1. Provide signed informed consent which includes pharmacogenomic (PGx) testing.

2. Have a diagnosis of MDD without psychotic features, according to the Diagnostic andStatistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, based onclinical assessment and confirmed by the Mini International NeuropsychiatricInterview (MINI).

3. Have a history of TRD within the past 5 years as documented by the MassachusettsGeneral Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) (5-year version). That is, within the past 5 years study participants must have hada clinically meaningful inadequate response (estimated < 50% improvement perInvestigator/patient consensus and documented by the Investigator) to at least twotreatment courses with antidepressant regimens. These must involve at least twodifferent pharmacologic treatment classes* and have been given at acceptedtherapeutic doses for an adequate duration (at least 6 weeks). One of thesetreatment failures must have occurred within the current episode.

*Note: Non-pharmacological treatment (eg, cognitive behavioral therapy,electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagus nervestimulation, acupuncture) are not counted as treatment regimen.

4. To be eligible, patients must have DGM4 genotype results obtained from thedesignated Clinical Laboratory Improvement Amendments (CLIA) lab, and all eligibleDGM4-positive patients and about 20% DGM4-negative patients will be randomlyincluded by an IRT system in order to achieve the appropriate randomization ratio ofDGM4-positive vs negative patients.

5. Pregnancy conception limitations

• Female patients must be postmenopausal or surgically sterile or, if ofchildbearing potential and the partner is not vasectomized (6 months minimum),must agree to use a medically acceptable form of contraception from the time ofsigning the informed consent form (ICF) through at least 60 days following thelast administration of study drug. If only the barrier method is used, a doublebarrier must be employed. Postmenopausal women must have had ≥ 24 months ofspontaneous amenorrhea. Surgically sterile women are defined as those who havehad a hysterectomy, bilateral ovariectomy, or bilateral tubal ligation. Allwomen of childbearing potential must have a negative pregnancy test resultbefore administration of study drug.

• Male patients must be biologically incapable of having children (eg,vasectomized) or must agree to use the above forms of birth control forthemselves and their partner from the time of signing the informed consent formthrough at least 120 days following the last administration of study drug.

6. Be fluent in the local language.

7. Male or female aged 18 to 70, inclusive, at time of enrollment.

8. Have a HAMD-17 total score ≥ 21 at screening.

9. Be willing to discontinue the use of antidepressant drugs (includingover-the-counter medications to treat depression [eg, St John's Wort]) at least 5half-lives (or at least 1 week for herbal or other over-the-counter medications fordepression) prior to baseline (Day -1). For fluoxetine, a washout period of at least 3 weeks for ≤ 20 mg/day and at least 4 weeks for > 20 mg/day is required.

Exclusion Criteria:

1. Prior participation in a study with liafensine

2. Used any investigational drug product, device, or biologic within 6 months or fivehalf-lives (whichever is longer) prior to baseline (Day -1).

3. A positive pregnancy test result or currently breastfeeding.

4. Clinically significant illness (including chronic, persistent, or acute infection),medical/surgical procedure, or trauma within 30 days prior to screening or betweenscreening and baseline (Day 1) as determined by the investigator.

5. A history or presence of a clinically significant hepatic, renal, gastrointestinal,cardiovascular, endocrine, respiratory, immunologic, hematologic, dermatologic, orneurologic abnormality, or any other condition, that in the investigator's opinion,represent potential risk to the patient's safety, full participation in the study,or affect the absorption, distribution, metabolism, or excretion of liafensine.

6. Presence of autoimmune hepatitis, primary sclerosing cholangitis, untreatedhepatitis C, active hepatitis B, or any other uncontrolled or unstable liver diseaseaccording to local guidance.

7. Uncontrolled human immunodeficiency virus (HIV) infection according to localguidance.

8. Uncontrolled abnormal thyroid function according to local guidance.

9. One or more clinical laboratory evaluations are outside the reference range, atscreening, that are in the investigator's opinion, of potential risk to thepatient's safety.

10. Has at the Screening Visit:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 1.5x the upper limit of normal (ULN) at screening.

• Total bilirubin (TBL) > 2 mg/dL (34.2 μmol/L) at screening, unless there is anexplained indirect hyperbilirubinemia, eg, Gilbert's syndrome.

• Alkaline phosphatase (ALP) > 1.5x the ULN at screening. Note: Laboratory testscan be repeated to see if values return to normal range, but any suchlaboratory abnormality must be resolved by the Baseline Visit (Day -1).

11. Clinically significant vital sign abnormality at screening. This includes, but isnot limited to, the following, in the supine (after at least 5 min rest) andstanding (after 1 min and 3 min standing): systolic blood pressure ≥ 140 mmHg;diastolic blood pressure ≥ 90 mmHg; or heart rate < 50 or > 90 beats per minute. Ifthe initial blood pressure is ≥ 140/90 mmHg, the lowest value from up to 3additional attempts, which also must not be ≥ 140/90 mmHg, should be used. Patientswith symptomatic orthostatic hypotension, at the discretion of investigator, will beexcluded.

12. Corrected QT interval measurement according to the Fridericia rule (QTcF) > 450 msecfor men and > 470 msec for women during controlled rest at screening, or history oflong-QT syndrome.

13. ECGs containing any of the following readings:

• Left bundle branch block

• Right bundle branch block with QRS duration > 140 ms

• Intraventricular conduction defect with QRS duration > 140 ms

• Long QT syndrome

14. History of seizure, other than childhood febrile seizures.

15. History of clinically significant head trauma, including closed head injury withloss of consciousness, that is, in the opinion of the investigator, likely to affectcentral nervous system function.

16. History of clinically significant symptomatic orthostatic hypotension (ie, posturalsyncope).

17. History of narrow angle glaucoma.

18. History of cancer within 2 years prior to screening or between screening andbaseline (Day -1), except for non-metastatic basal and/or squamous cell carcinoma ofthe skin.

19. Use of prescription or nonprescription medications for attention-deficithyperactivity disorder (ADHD), narcolepsy, or cognitive enhancement (eg,methylphenidate, atomoxetine, modafinil, ginkgo biloba, and huperzine A) within 30days prior to screening or between screening and baseline (Day -1).

20. Regular consumption of (eg, more days than not) excessive quantities ofxanthine-containing beverages (eg, more than five cups of coffee or the equivalentper day) within 30 days prior to screening or between screening and baseline (Day -1).

21. Urine drug screen (UDS) positive for a drug of abuse, with the exception of cannabisin countries where it is legally available (see Table 3 for list of drugs of abuse).Where legal, prior use of cannabis is permitted provided the patient agrees toabstain from smoking or ingesting cannabis or cannabis products during the study.

22. Use of potent inducers of CYP3A4 (eg, rifampin, rifabutin, phenytoin, carbamazepine,or phenobarbital) within 2 weeks prior to baseline (Day-1).

23. Current diagnosis or history of a psychotic disorder, MDD with psychotic features,manic or hypomanic episode of bipolar or related disorders.

24. Current diagnosis of anxiety disorder (if primary), post-traumatic stress disorder,obsessive compulsive disorder (if primary), intellectual disability (DSM-5diagnostic code 319), borderline personality disorder, antisocial personalitydisorder, histrionic personality disorder, or narcissistic personality disorderaccording to the DSM-5 criteria, or any other psychiatric or neurologic disorder orsymptom due to a general medical condition, that, in the judgement of theinvestigator, could pose undue risk to the patient or compromise the study.

25. Hospitalized or discharged from psychiatric ward within 8 weeks prior to thescreening visit and planned hospitalization for any condition(s) during the study.

26. Moderate or severe alcohol use disorder or other substance use disorder (exceptnicotine or caffeine), within 6 months prior to screening, according to the DSM-5criteria.

27. Significant risk of suicide determined by:

28. Acute suicidality as evidenced by answering "yes" to Question 5 ("In the PastYear") on the C-SSRS, indicating active suicidal ideation with specific planand intent for suicide, at screening, or baseline (Day -1); or

29. History of suicidal behavior as indicated by a "yes" response on the SuicidalBehavior section of the C-SSRS ("In the past year") or

30. A score ≥ 5 on Item 10 (suicidal thoughts) of the MADRS at screening orbaseline (Day -1); or

31. Has attempted suicide within 6 months prior to the initial screening visit.

32. Previous allogenic bone marrow transplant.

33. Received non-leukocyte-depleted whole blood transfusion within 4 months prior to PGxtesting at Screening.

34. Currently employed by the sponsor or by a clinical trial site participating in thisstudy, or a first-degree relative of an employee of the sponsor or of an employee ata participating clinical trial site.