Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD

This a Phase 2a, multicenter, randomized, double-blind, placebo controlled 3 arm study to assess the safety and tolerability of multiple oral doses of REL-1017 25 mg and 50 mg as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD). The patients will be adults with MDD who are diagnosed with a current MDE who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication. This population will provide the opportunity to compare the safety and efficacy effects of treatment with an approved antidepressant in conjunction with REL-1017 versus the effects of an antidepressant alone. This study includes in-patient and out-patient periods.

Currently available medications have proven to be useful for the treatment of depression, but also have limitations including low response rates, a significant number of treatment resistant patients, and time-lag for response, which emphasizes a major unmet need for more efficacious and faster-acting antidepressants. Recent studies have demonstrated that ketamine, a non-competitive glutamate-N-methyl-D-Aspartate (NMDA) receptor antagonist, produces rapid onset (2 hours) and long-lasting (7 days) antidepressant actions in treatment resistant patients. This rapid action, by a mechanism completely different from typical monoamine reuptake inhibitors, represents a significant finding in the field of depression.

Racemic methadone, the 50/50 combination of d-methadone and l-methadone, has been in widespread use for decades and has been studied extensively. Methadone is currently approved for use in the management of severe pain, detoxification treatment of opioid addiction, and maintenance treatment of opioid addiction.

The results of a study evaluating the receptor binding profiles of racemic methadone and its stereoisomers suggest that d-methadone does not essentially contribute to the opioid effect of racemic methadone and that it has a 10 times lower affinity for the mu1, mu2, and delta opioid receptors compared to l-methadone. Racemic methadone and its d- and l isomers exhibit similar affinities for the non-competitive binding site of the NMDA receptor and are non-competitive NMDA receptor antagonists.

In the forced swim test, a rodent behavioral model of antidepressant activity, both ketamine and d-methadone at all doses tested significantly decreased the immobility of the rats compared to the vehicle suggesting antidepressant like activity. Neither drug increased spontaneous locomotor activity.

Relmada has conducted 2 clinical studies to identify the dose levels of REL-1017 (d-methadone) that have little to no opioid effects and that are expected to possess NMDA antagonistic properties for the evaluation of oral REL-1017 in the treatment of MDD and neuropathic pain conditions. Initial Phase 1 single ascending dose and multiple ascending dose clinical studies of REL-1017 were designed to evaluate the safety and tolerance of the pure d methadone isomer in healthy opioid-naïve subjects and identify a safe and potentially effective dose range in this population. These studies showed that REL-1017 was safe and well-tolerated at single oral doses up to 150 mg (maximum tolerated dose) and up to 75 mg administered once daily for 10 days in healthy opioid-naïve subjects.

The pre-clinical and previous clinical experience with REL-1017 (d-methadone) provided the basis for the initiation of the present study, which will extend the evaluation of the safety, tolerability, and PK of REL-1017 at 2 doses with repeated administration to depressed patients. Since REL-1017 is proposed for use as adjunctive therapy in the treatment of patients diagnosed with major depressive disorder (MDD), the patients will be male adults with MDD who are diagnosed with a current depressive episode who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication.

Based on the safety data from Protocol REL-1017-111, single doses of 5 mg, 20 mg, 60 mg, 100 mg, and 150 mg of REL-1017 or placebo were well tolerated. The results of Protocol REL-1017-112 evaluated 10 days of dosing with 25 mg, 50 mg and 75 mg of REL-1017 or placebo, and no impact on safety was observed. In spite of the confirmed dose proportionality, the comparison of concentration and exposure between the 50 mg and 75 mg REL-1017 treatment groups demonstrated only slight differences. Consequently, 25 mg and 50 mg doses were chosen for administration in Protocol REL-1017-202 as single daily doses over a period of 7 days.

Thus, as a single isomer of racemic methadone, d-methadone has been shown to possess NMDA antagonist properties with virtually no opioid activity or ketamine-like toxicities at the expected therapeutic doses.

In this study, adult male patients with MDD who are diagnosed with a current MDE and who have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication will be randomized to study drug in a 1:1:1 ratio. Approximately 15 patients each will receive REL-1017 25 mg, REL-1017 50 mg, or placebo once daily for 7 days. Endpoints include assessments of safety, tolerability, efficacy and pharmacokinetics of REL-1017. Patients will be required to stay in the clinic for 10 days and will then be followed as an outpatient for 12 additional days.

Eligibility Criteria:
Inclusion Criteria:

1. Males between 18 and 65 years of age, inclusive; and females between 18 and 65 years of age, inclusive, who are \>1 year postmenopausal.
2. Diagnosed with recurrent MDD as defined by the Diagnostic and Statistical Manual, Fifth Edition (DSM-5), and confirmed by the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI).
3. Diagnosed with a current MDE lasting 8 weeks to 36 months as defined by the DSM-5 and confirmed by the MINI.
4. Treated with an adequate dosage of a SSRI, SNRI, or bupropion during the current MDE for at least 8 weeks prior to Screening with the same, adequate dosage for the last 4 weeks. Minimum adequate doses are defined in the (ATRQ). The maximum dose allowed for paroxetine is 40 mg QD, for fluoxetine is 60 mg QD, and for sertraline is 200 mg QD.
5. Have experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant medication in the current episode, as defined as \<50% improvement with an antidepressant medication at doses listed on the SAFER Interview Criteria: State versus trait; Assessability; Face validity; Ecological validity; and Rule of three Ps (pervasive, persistent, and pathological).
6. Hamilton Depression Rating Scale-17 (HAM-D-17) ≥19 at Screening and Check-in (Day -1).
7. BMI between 18.0 and 35.0 kg/m2, inclusive, and a minimum weight of 50.0 kg.
8. Per the Investigator's judgment, able to meet all study requirements, including the confined/inpatient portion of the study, adherence with both approved ADT and study drug regimen, and completion of all assessments and all scheduled visits.
9. Male patients of reproductive potential must be using and willing to continue using medically acceptable contraception, from Screening and for at least 2 months after the last study drug administration.
10. Must be able to read, speak, and understand English and must provide written informed consent prior to the initiation of any protocol-specific procedures.

Exclusion Criteria:

1. History or presence of clinically significant abnormality as assessed by physical examination, medical history, 12-lead ECG, vital signs, or laboratory values, which in the opinion of the Investigator would jeopardize the safety of the patient or the validity of the study results, including torsades de pointes, any bradyarrhythmias, or uncompensated heart failure.
2. Chronic use of prescribed opioids (i.e., \>120 days in a 6-month period) up to 6 months prior to Screening or any recreational use of opioids.
3. Evidence of clinically significant hepatic or renal impairment, including ALT or AST \>1.5 x upper limit of normal (ULN), bilirubin \>1 x ULN, or endocrine laboratory values (including clinically significant thyroid parameters, i.e., thyroid stimulating hormone \[TSH\], triiodothyronine \[T3\], and thyroxine \[T4\]).
4. History or family history of sudden unexplained death or long QT syndrome (measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle).
5. Any 12-lead ECG with repeated demonstration of QTc ≥450 msec or a QRS interval \>120 msec at Screening.
6. History of clinically diagnosed hypotension requiring treatment.
7. History or presence of any condition in which an opioid is contraindicated (e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, bronchitis, or has/is suspected of having paralytic ileus).
8. No more than 3 prescribed doses of an opioid within the 6 months prior to Screening and no use at all within the last month.
9. Use of an antipsychotic, anticonvulsant, or mood stabilizer, regardless of indication, within the 3 months prior to Screening.
10. History of allergy or hypersensitivity to methadone or related drugs (e.g., opioids).
11. Positive test for hepatitis B or HIV. Patients with a positive hepatitis C test may be considered for inclusion with approval from the Medical Monitor.
12. Any current and primary psychiatric disorder, as defined as a condition that is the primary focus of distress and/or treatment, other than MDD.
13. Any lifetime history of bipolar I or II disorder, any psychotic disorder, post-traumatic stress disorder, borderline personality disorder, antisocial personality disorder, obsessive compulsive disorder, eating disorder, intellectual disability, or pervasive developmental disorder.
14. History in the past 12 months of a primary diagnosis of anxiety disorder or panic disorder not related to the current MDE.
15. Current diagnosis of alcohol or substance use disorder, as defined by DSM-5, at Screening or within the 12 months prior to Screening. Patients with the following diagnoses within the past 12 months, however, may be included at the Investigator's discretion: mild alcohol use disorder, mild cannabis use disorder, and any severity tobacco use disorder.
16. A confirmed positive result on the urine drug/alcohol screen at Screening or Check-in. If the urine drug/alcohol screen is positive at Screening, retesting or rescreening may be scheduled with prior approval from the Medical Monitor.
17. Patients who, in the Investigator's judgment, are at significant risk for suicide. A patient with a Columbia-Suicide Severity Rating Scale (C-SSRS) ideation score of 4 or 5 within the last 6 months or any suicide attempt within the past year must be excluded, as should a patient with an ideation score of 4 or 5 or any suicide attempt at the Check-in or Baseline Visit.
18. Patients with a 20% improvement between Screening and Check-in (Day -1) on the HAM-D-17.
19. Patients who did not safely discontinue medications prohibited.
20. Patients receiving new onset psychotherapy (individual, group, marriage, or family therapy) within 2 months prior to Screening or plans to start at any time during participation in the study.
21. Patients who have received electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or vagus nerve stimulation (VNS) or who have participated in a ketamine study within the last 6 months.
22. Patients with any clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, chronic pain, or gastrointestinal disorder. Medical conditions that are minor or well-controlled may be permitted if they will not increase the safety risk to the patient or compromise interpretation of the safety or efficacy endpoints.
23. Patients taking fluvoxamine or St. John's Wort.
24. Patients who have participated in a clinical study with an investigational medication in the past 6 months, or who have participated in more than 4 clinical studies with investigational medications in the past 2 years.