REL-1017 · program

Esmethadone (REL-1017) for Major depressive disorder

DiscontinuedDiscontinuedRelmada Therapeutics, Inc. (RLMD)

Phase 3 RELIANCE program of REL-1017 in MDD, studied both as adjunctive therapy (RELIANCE-I, RELIANCE-II, RELIGHT) for patients with inadequate response to standard antidepressants and as monotherapy (RELIANCE-III), supported by an open-label long-term safety study (RELIANCE-OLS). Following a positive Phase 2a adjunctive study (NCT03051256, 7-day dosing), all three pivotal studies that read out failed the primary MADRS endpoint: RELIANCE-III monotherapy (NCT05081167) missed on 13 Oct 2022 (REL-1017 -14.8 vs placebo -13.9, high placebo response) and RELIANCE-I adjunctive (NCT04688164) missed on 7 Dec 2022 (-15.1 vs -12.9, not statistically significant). On 9 Dec 2024, after a Data Monitoring Committee review of the full RELIANCE-II dataset indicated it was unlikely to meet its primary endpoint, Relmada discontinued the RELIANCE-II (NCT04855747) and RELIGHT (NCT06011577) Phase 3 studies. On 7 Jul 2025 Relmada terminated the esmethadone license and returned the asset to its inventors (Levomecor Inc.), formally ending Relmada's development of REL-1017 in MDD. REL-1017 was consistently safe and well tolerated, with no opioid-like, withdrawal, or psychotomimetic effects.

Data current as of

Development timeline

DiscontinuedDec 2024 – Jul 2025
  1. Relmada terminated the esmethadone license agreement and returned the REL-1017 technology to its inventors (Charles Inturrisi & Paolo Manfredi / Levomecor Inc.), formally ending Relmada's REL-1017 development in MDD.↗
  2. missedRelmada discontinued RELIANCE-II and RELIGHT after a DMC review found RELIANCE-II unlikely to meet its primary endpoint.↗
Phase 3Jan 2021 – Dec 2022
  1. missedRELIANCE-I adjunctive missed its primary MADRS Day 28 endpoint (REL-1017 -15.1 vs placebo -12.9, not significant).↗
  2. missedRELIANCE-III monotherapy missed its primary MADRS Day 28 endpoint (REL-1017 -14.8 vs placebo -13.9).↗
  3. Phase 3 RELIANCE program initiated (RELIANCE-I adjunctive first patient; RELIANCE-II, RELIANCE-III monotherapy, and open-label safety studies followed in 2021).
Phase 2Sept 2019
  1. Phase 2a, 7-day adjunctive proof-of-concept (NCT03051256, n=62, 25 or 50 mg/day) completed; reported rapid, robust, sustained antidepressant signal vs placebo, supporting advancement to Phase 3.

Readouts

  • Date TBDCancelledTopline datamissedNCT04855747

    Relmada discontinued RELIANCE-II and RELIGHT after a DMC review found RELIANCE-II unlikely to meet its primary endpoint. ↗

  • 2022-12-07ReportedTopline datamissedNCT04688164

    RELIANCE-I adjunctive missed its primary MADRS Day 28 endpoint (REL-1017 -15.1 vs placebo -12.9, not significant). ↗

  • 2022-10-13ReportedTopline datamissedNCT05081167

    RELIANCE-III monotherapy missed its primary MADRS Day 28 endpoint (REL-1017 -14.8 vs placebo -13.9). ↗

Clinical trials in Major depressive disorder

NCT06011577RELIGHTPhase 3Discontinuedn=27

Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as Adjunctive Treatment for MDD (RELIGHT)

Started Sept 2023· 📍 36 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline (adjunctive)

Terminated on 9 Dec 2024 alongside RELIANCE-II; only ~27 of a planned cohort had enrolled. No efficacy readout — stopped as part of the program discontinuation following the RELIANCE-II DMC review.

NCT05081167REL-1017-303 (RELIANCE-III)Phase 3Completedn=232

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 Monotherapy for Major Depressive Disorder (RELIANCE-III)

Started Jun 2021· Primary completion Sept 2022· 📍 10 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline to Day 28 (monotherapy) — REL-1017 -14.8 vs placebo -13.9 (~0.9-point difference)

Did not achieve a statistically significant separation from placebo on the primary MADRS Day 28 endpoint amid a higher-than-expected placebo response. A post-hoc 'band-pass' analysis excluding outlier sites showed >4.9-point difference (p<0.05), but this was exploratory. Safety/tolerability favorable.

NCT04855760REL-1017-304 (RELIANCE-OLS)Phase 3Completedn=627

A Phase 3, Multicenter, Open-Label Study to Assess the Long-Term Safety of REL-1017 as a Treatment of Major Depressive Disorder

Started Apr 2021· Primary completion Jul 2023· 📍 9 sites across 1 country (United States)

metprimaryIncidence of treatment-emergent adverse events (long-term safety, open-label)

Open-label long-term safety study (n=627); no placebo comparator and no efficacy primary endpoint. REL-1017 was generally safe and well tolerated over extended dosing.

NCT04855747REL-1017-302 (RELIANCE-II)Phase 3Discontinuedn=236

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment of Major Depressive Disorder (RELIANCE-II)

Started Mar 2021· Primary completion Dec 2024· 📍 70 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline (adjunctive)

Terminated ('Program Discontinued') on 9 Dec 2024 after a DMC review of the full dataset indicated it was unlikely to meet its primary endpoint; no separate efficacy topline with effect sizes was reported. CT.gov lead sponsor now displays 'Levomecor Inc.' following the 2025 asset handover, but the study was conducted by Relmada.

NCT04688164REL-1017-301 (RELIANCE-I)Phase 3Completedn=227

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment of Major Depressive Disorder (RELIANCE-I)

Started Jan 2021· Primary completion Nov 2022· 📍 11 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline to Day 28 (adjunctive) — REL-1017 -15.1 vs placebo -12.9 (2.2-point difference)

Missed the primary endpoint: the 2.2-point MADRS advantage for REL-1017 (n=113) vs placebo (n=114) was not statistically significant. A key secondary response-rate analysis was significant (39.8% vs 27.2%, p<0.05). Results later published in J Clin Psychiatry.

NCT03051256REL-1017-202Phase 2Completedn=62

Phase 2a Multicenter Randomized Double-Blind Placebo-Controlled Study to Assess the Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing of REL-1017 as Adjunctive Therapy in the Treatment of Patients Diagnosed With MDD

Started May 2018· Primary completion Jul 2019· 📍 10 sites across 1 country (United States)

metprimaryTreatment-emergent adverse events (safety/tolerability) over 7-day adjunctive dosing

Primary endpoint was safety/tolerability; REL-1017 (25 or 50 mg/day) was well tolerated with no opioid-like effects. Exploratory efficacy showed a rapid, robust, sustained antidepressant signal vs placebo, supporting Phase 3.

Formulations

FormulationRouteRegimenPharmacokinetics
Esmethadone oral capsule
25 mg once daily maintenance dose, with a 75 mg loading dose on Day 1 (Phase 3 MDD adjunctive regimen)
OralOnce dailyt½ 36.3 h · Tmax 2.5 h

Mechanism of action (compound-wide)

Low-affinity, low-potency, high-trapping uncompetitive NMDA receptor (NMDAR) antagonist that binds the MK-801 (channel) site in an activity- and use-dependent manner. In recombinant human heterodimeric NMDARs in physiological (1 mM) Mg2+, esmethadone is most potent at GluN1/GluN2D (IC50 ~13.5 uM) and least potent at GluN1/GluN2A (IC50 ~63.1 uM), i.e. it preferentially blocks GluN2D-containing receptors (Bettini et al., Pharmaceuticals 2022). As the opioid-inactive (S)-enantiomer of methadone it lacks meaningful opioid activity and showed no abuse potential, no withdrawal, and no psychotomimetic effects clinically. The rapid-antidepressant hypothesis is restoration of physiological plasticity via tonic block of pathologically hyperactive GluN2D NMDARs.

TargetActionAffinity
GluN2DprimaryGRIN2DAntagonistIC50 13.5 uMⓘ
NMDA receptorGRIN1Antagonist—ⓘ

← Full REL-1017 compound page (identity, identifiers, all indications)

Sources

  1. Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism — Clinical Pharmacology in Drug Development (PMC)
  2. Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric NMDA Receptors — Bettini et al., Pharmaceuticals (Basel) 2022;15(8):997 (PMC)
  3. RELIANCE-I: REL-1017 adjunctive Phase 3 in MDD (NCT04688164) — ClinicalTrials.gov
  4. RELIANCE-II: REL-1017 adjunctive Phase 3 in MDD — terminated (NCT04855747) — ClinicalTrials.gov
  5. RELIANCE-III: REL-1017 monotherapy Phase 3 in MDD (NCT05081167) — ClinicalTrials.gov
  6. RELIANCE-OLS: REL-1017 open-label long-term safety Phase 3 in MDD (NCT04855760) — ClinicalTrials.gov
  7. RELIGHT: REL-1017 adjunctive Phase 3 in MDD — terminated (NCT06011577) — ClinicalTrials.gov
  8. Relmada announces RELIANCE-I adjunctive topline results (primary endpoint not met) — Relmada Therapeutics / IR
  9. Relmada announces RELIANCE-III monotherapy topline results (primary endpoint not met) — Relmada Therapeutics / IR
  10. Relmada terminates license agreement for troubled phase 3 depression asset — Fierce Biotech
  11. Relmada to discontinue the RELIANCE-II and RELIGHT Phase 3 studies of REL-1017 — Relmada Therapeutics / IR
  12. Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD — ClinicalTrials.gov