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 troubled 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 History of Setbacks

Esmethadone's development has been fraught with challenges for several years. The drug failed to demonstrate significant efficacy in three consecutive Phase III trials:

1. RELIANCE III (October 2022): Failed as a monotherapy for major depressive disorder (MDD).
2. RELIANCE I (December 2022): Showed no significant benefit as an adjunctive MDD treatment.
3. RELIANCE II (December 2024): Terminated early due to a high likelihood of futility.

Following these setbacks, Relmada also discontinued the Phase III RELIGHT study in MDD.

Financial Implications and Licensing Agreement

The termination of esmethadone's development has significant financial implications for Relmada. The company will end its January 2018 licensing agreement, under which it obtained global rights to the molecule. This agreement involved:

• A nonrefundable upfront payment of $180,000 to the original developers, Charles Inturrisi and Paolo Manfredi.
• Quarterly payments of $45,000, which were to continue until certain conditions were met.

Industry-Wide Challenges in Depression Treatment

Relmada's struggle with esmethadone reflects broader challenges in the pharmaceutical industry's efforts to develop effective treatments for depression. Several other companies have faced similar setbacks in recent months:

• Alto Neuroscience's ALTO-203 failed to significantly improve mood in MDD patients in a Phase II study.
• Supernus Pharmaceuticals' SPN-820 did not improve symptom burden in treatment-resistant depression during mid-stage trials.
• Johnson & Johnson discontinued its late-stage VENTURA program for kappa opioid receptor blocker aticaprant due to insufficient efficacy signals.

These collective failures underscore the complexity of developing successful treatments for depression and the ongoing need for innovation in this therapeutic area.