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

Inclusion Criteria

• Provide signed informed consent which includes pharmacogenomic (PGx) testing.
• Have a diagnosis of MDD without psychotic features, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, based on clinical assessment and confirmed by the Mini International Neuropsychiatric Interview (MINI).
• Have a history of TRD within the past 5 years as documented by the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) (5-year version). That is, within the past 5 years study participants must have had a clinically meaningful inadequate response (estimated 20 mg/day is required.

Exclusion Criteria

• Prior participation in a study with liafensine
• Used any investigational drug product, device, or biologic within 6 months or five half-lives (whichever is longer) prior to baseline (Day -1).
• A positive pregnancy test result or currently breastfeeding.
• Clinically significant illness (including chronic, persistent, or acute infection), medical/surgical procedure, or trauma within 30 days prior to screening or between screening and baseline (Day 1) as determined by the investigator.
• A history or presence of a clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, respiratory, immunologic, hematologic, dermatologic, or neurologic 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.
• Presence of autoimmune hepatitis, primary sclerosing cholangitis, untreated hepatitis C, active hepatitis B, or any other uncontrolled or unstable liver disease according to local guidance.
• Uncontrolled human immunodeficiency virus (HIV) infection according to local guidance.
• Uncontrolled abnormal thyroid function according to local guidance.
• One or more clinical laboratory evaluations are outside the reference range, at screening, that are in the investigator's opinion, of potential risk to the patient's safety.
• 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 an explained indirect hyperbilirubinemia, eg, Gilbert's syndrome.
• Alkaline phosphatase (ALP) > 1.5x the ULN at screening. Note: Laboratory tests can be repeated to see if values return to normal range, but any such laboratory abnormality must be resolved by the Baseline Visit (Day -1).
• Clinically significant vital sign abnormality at screening. This includes, but is not limited to, the following, in the supine (after at least 5 min rest) and standing (after 1 min and 3 min standing): systolic blood pressure ≥ 140 mmHg; diastolic blood pressure ≥ 90 mmHg; or heart rate 90 beats per minute. If the initial blood pressure is ≥ 140/90 mmHg, the lowest value from up to 3 additional attempts, which also must not be ≥ 140/90 mmHg, should be used. Patients with symptomatic orthostatic hypotension, at the discretion of investigator, will be excluded.
• Corrected QT interval measurement according to the Fridericia rule (QTcF) > 450 msec for men and > 470 msec for women during controlled rest at screening, or history of long-QT syndrome.
• 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
• History of seizure, other than childhood febrile seizures.
• History of clinically significant head trauma, including closed head injury with loss of consciousness, that is, in the opinion of the investigator, likely to affect central nervous system function.
• History of clinically significant symptomatic orthostatic hypotension