Relmada Therapeutics Abandons Depression Drug Esmethadone After Multiple Late-Stage Failures

Relmada Therapeutics has officially halted the development of its investigational NMDA receptor blocker esmethadone, marking the end of a tumultuous journey for the once-promising depression treatment. The company announced the decision in a recent SEC filing, citing multiple late-stage clinical trial failures as the primary reason for discontinuation.

A Series of Setbacks

The development saga for esmethadone has been marked by consistent disappointments in clinical trials. In October 2022, the drug failed to show significant efficacy in the Phase III RELIANCE III trial for major depressive disorder (MDD) as a monotherapy. This was followed by another setback in December of the same year when the RELIANCE I study, testing esmethadone as an adjunctive MDD treatment, also failed to demonstrate significant benefits over placebo.

The final blow came in December 2024 when the Phase III RELIANCE II trial was discontinued after an interim analysis revealed a high likelihood of futility. Shortly after, Relmada also terminated the Phase III RELIGHT study in MDD.

Industry-Wide Challenges in Depression Treatment

Relmada's struggles with esmethadone reflect a broader trend of difficulties in developing effective treatments for depression. Other companies have faced similar challenges:

• Alto Neuroscience's ALTO-203 failed to significantly improve mood in MDD patients in a Phase II study.
• Supernus Pharmaceuticals' SPN-820 was unable to improve symptom burden in patients with treatment-resistant depression in a mid-stage trial.
• Even pharmaceutical giant Johnson & Johnson discontinued its late-stage VENTURA program for the kappa opioid receptor blocker aticaprant due to insufficient efficacy signals.

Relmada's Path Forward

With esmethadone now removed from its pipeline, Relmada is shifting its focus to strategic product acquisitions. The company's primary asset is now NDV-01, a Phase II proprietary sustained-release formulation of gemcitabine and docetaxel being tested for non-muscle invasive bladder cancer. Relmada licensed NDV-01 from Trigone Pharma in March, and recent Phase II data showed promising results with an 85% three-month overall response rate.

As the pharmaceutical industry continues to grapple with the challenges of developing effective treatments for depression, Relmada's experience with esmethadone serves as a stark reminder of the complexities involved in addressing mental health disorders.