dextromethadone (REL-1017) / Relmada Therapeutics - LARVOL DELTA

Long-Term Safety and Efficacy of Esmethadone in Patients With Major Depressive Disorder: Findings From a 12-Month Open-Label Study. (PubMed, J Clin Psychiatry) - P3 | "The antidepressant efficacy of esmethadone was sustained over 12 months. Trial Registration: ClinicalTrials.gov identifier: NCT04855760."

Clinical • Journal • Cardiovascular • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

New Synthesis and Pharmacological Evaluation of Enantiomerically Pure (R)- and (S)-Methadone Metabolites as N-Methyl-d-aspartate Receptor Antagonists. (PubMed, J Med Chem) - "(S)-Methadone (esmethadone), has recently shown promising efficacy for the treatment of major depressive disorder. Strikingly, N-demethylated (6R)-methadol metabolites retain the higher NMDAR uncompetitive antagonism of (R)-methadone, while presenting lower opioid receptor affinity compared to (S)-methadone. These compounds could represent novel candidates for drug development in CNS disorders."

Journal • CNS Disorders • Depression • Developmental Disorders • Major Depressive Disorder • Mood Disorders • Psychiatry

REL-1017-305: A Study to Evaluate the Efficacy and Safety of REL-1017 As Adjunctive Treatment of Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: MGGM LLC | N=146 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RELIGHT: Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as Adjunctive Treatment for MDD (clinicaltrials.gov) - P3 | N=27 | Terminated | Sponsor: Relmada Therapeutics, Inc. | N=340 ➔ 27 | Recruiting ➔ Terminated; Program Discontinued

Enrollment change • Trial termination • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RELIANCE-II: A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=236 | Terminated | Sponsor: Relmada Therapeutics, Inc. | N=340 ➔ 236 | Recruiting ➔ Terminated; Program Discontinued

Enrollment change • Trial termination • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

REL-1017-305: A Study to Evaluate the Efficacy and Safety of REL-1017 As Adjunctive Treatment of Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=146 | Recruiting | Sponsor: MGGM LLC

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Glu-REST: A Proof of Concept, Phase 2, Double-blind, Randomized Trial With d-Methadone Product Versus Placebo (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Mauro Manconi | Trial completion date: Jul 2025 ➔ Dec 2025 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression. (PubMed, Eur Arch Psychiatry Clin Neurosci) - "Specifically, here we focus on substances beyond (es)ketamine, for which meaningful data from clinical trials are available, including arketamine, esmethadone, nitrous oxide and other glutamate receptor modulators. Molecules only successful in preclinical settings and case reports/series are only marginally discussed. With this review, we aim underscore the critical role of glutamatergic modulation in advancing antidepressant therapy, thereby possibly enhancing clinical outcomes but also to reducing the burden of depression through faster therapeutic effects."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment. (PubMed, Drugs R D) - "Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis."

Journal • PK/PD data • Chronic Kidney Disease • CNS Disorders • Depression • Hepatology • Major Depressive Disorder • Mood Disorders • Nephrology • Psychiatry • Renal Disease

RELIGHT: Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as Adjunctive Treatment for MDD (clinicaltrials.gov) - P3 | N=417 | Recruiting | Sponsor: Relmada Therapeutics, Inc. | N=300 ➔ 417

Enrollment change • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

RELIANCE-II: A Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment for Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=300 | Recruiting | Sponsor: Relmada Therapeutics, Inc. | Trial completion date: Jun 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Controlled Trial. (PubMed, J Clin Psychiatry) - P3 | "Esmethadone was well tolerated, consistent with prior studies. Trial Registration: ClinicalTrials.gov identifier: NCT04688164."

Clinical • Journal • P3 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Effect of Time From Onset of Major Depressive Disorder on the Therapeutic Response to Esmethadone (REL-1017). (PubMed, J Clin Psychiatry) - P2a | " Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset. Trial Registration: ClinicalTrials.gov identifier: NCT03051256."

Clinical • Journal • P2 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice. (PubMed, Front Neurol) - "REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles. In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Depression • Major Depressive Disorder • Psychiatry • CLSPN, • DLG4

Long-Term Safety and Efficacy of Esmethadone in Patients with Major Depressive Disorder: Findings from a 12-Month Open-Label Study (ASCP 2024) - "Long-term treatment with esmethadone was well tolerated with no signal for meaningful neurological, cardiovascular, metabolic or sexual side effects. No new safety concerns were identified. Patients showed a mean CFB in MADRS scores of approximately -20 points, with consistent improvements in CGI-S, CGI-I, and HAM-A scores."

Clinical • Late-breaking abstract • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

A Critical View on New and Future Antidepressants. (PubMed, Clin Psychopharmacol Neurosci) - "Neurosteroids have been recently approved and their rapid benefit may extend from postpartum depression to anxious depression and bipolar depression, dextromethorphan and bupropion combination may prove useful in major depression but also in treatment resistant depression, dextromethadone is a possible augmentation in partial antidepressant response, psychedelic drugs have the potential of long lasting benefits after a single administration, though are still experimental treatments. Further potentially interesting new antidepressant mechanisms include new drug targets, drug repurposing and genetic or epigenetic manipulations. It is therefore important that clinicians are kept up to date with new evidence so that new evidence can be rapidly translated into clinical practice."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Postpartum Depression • Psychiatry

Clinical management of treatment-resistant depression (PubMed, Nervenarzt) - "For example, esketamine is already an established treatment method that is fast-acting and well tolerated, while psychedelics or esmethadone are currently still undergoing clinical trials. Compounds that can be used off-label, such as dextromethorphan or anti-inflammatory strategies are also presented. Pharmacological approaches that focus on the modulation of the glutamatergic system or belong to the class of psychedelics, appear to be of particular importance for current research and development. These particularly include substances that rapidly exert clinical effects and have a favorable side-effect profile."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

Glu-REST: A Proof of Concept, Phase 2, Double-blind, Randomized Trial With d-Methadone Product Versus Placebo (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Mauro Manconi | Trial completion date: Jul 2024 ➔ Jul 2025 | Trial primary completion date: Jul 2024 ➔ Jul 2025

Trial completion date • Trial primary completion date • Movement Disorders • Restless Legs Syndrome • Sleep Disorder

Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants: A Phase 3 Randomized Placebo-Controlled Trial (ACNP 2023) - "In this Phase 3 study of REL-1017 as an adjunctive treatment in patients with MDD, efficacy results were more favorable in the PP analysis compared to the ITT analysis. Favorable outcomes were also observed in the two prespecified PP subgroup analyses of females and in patients >50 years of age, and in two post hoc analyses of PP subgroups of patients with baseline MADRS >35 and patients with AT determined pre-randomization by MGH-CTNI clinicians. REL-1017 was safe and well tolerated with mostly mild and moderate transient AEs no treatment related serious AEs."

Clinical • P3 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

No Indication of Abuse or Withdrawal Potential with Esmethadone (REL-1017): Results From Two Phase 3 Randomized Placebo-Controlled Trials in Patients With Major Depressive Disorder (ACNP 2023) - "These Phase 3, double-blind, placebo-controlled MDD studies of REL-1017 showed no indications of meaningful abuse or dependence potential. The results of these Phase 3 trials were consistent with the favorable tolerability and safety profile of REL-1017 seen in Phase 1 and Phase 2 studies, and were consistent with earlier abuse liability studies showing no meaningful abuse potential for REL-1017."

Clinical • P3 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism. (PubMed, Drugs R D) - "In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • CYP2D6 • CYP3A4

RELIANCE-OLS: Safety of REL-1017 for Major Depressive Disorder (clinicaltrials.gov) - P3 | N=627 | Completed | Sponsor: Relmada Therapeutics, Inc. | Recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Review on the Use of NMDA Receptor Antagonist Therapy and Its Potential for Use in Adolescent Treatment-Resistant Depression (AACAP 2023) - "This review focuses on NMDAR antagonists dextromethorphan/bupropion (ASX-05) and esmethadone-HCl and their potential for adolescent treatment-resistant depression...A recent phase 3 RCT looking at AXS-05 treatment in 327 adults found an average drop in the MADRS score of 22.2 within 2 weeks of initiation of treatment...With the recent development of lower-potency medications in the NMDAR antagonist class, there appears to already be a safer alternative that could be just as efficacious. Given the better safety profile compared to ketamine, further research should be conducted looking at using these lower-potency NMDAR antagonists in the adolescent population."

Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

Efficacy of esmethadone in patients with major depressive disorder and antidepressant tolerance (antidepressant tachyphylaxis) (ECNP 2023) - "In this Phase 3 trial, efficacy outcomes favored the PPS over the FAS analyses, with the discrepancy not attributable to treatment-related AEs affecting treatment adherence. It is hypothesized that the PPS may have included a lower proportion of either “professional patients” or patients with transient reactive depression, potentially linked to COVID-19 pandemic stress, exhibiting diminished motivation to complete treatment and assessments. The favorable efficacy outcomes observed in the AT subgroup could suggest REL-1017 effects on antidepressant tolerance reduction, potentially mediated via NMDAR uncompetitive antagonism."

Clinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

No indication of abuse potential and absence of withdrawal from esmethadone in patients with major depressive disorder (ECNP 2023) - "In this safety analysis from two Phase 3 contemporary studies of REL-1017 for MDD, there were no indications of abuse potential, and abrupt discontinuation resulted in no withdrawal signs or symptoms. AEs were predominantly mild or moderate and transient. These results support the favorable safety profile and lack of meaningful abuse potential observed in Phase 1 and Phase 2 studies."

Clinical • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry