Relmada Therapeutics Halts Development of Depression Drug Esmethadone After Multiple Trial Failures

Relmada Therapeutics has announced the termination of its esmethadone development program, marking the end of a challenging journey for the investigational NMDA receptor blocker in the treatment of major depressive disorder (MDD). This decision comes after a series of late-stage clinical trial failures, highlighting the ongoing difficulties faced by pharmaceutical companies in the depression treatment space.

Esmethadone's Rocky Development Journey

Esmethadone, originally developed by Charles Inturrisi, a professor at Weill Cornell Medical, has been under Relmada's global rights since January 2018. The company obtained these rights through a licensing agreement, which included an upfront payment of $180,000 to Inturrisi and Paolo Manfredi, followed by quarterly payments of $45,000.

The drug's development history has been marked by repeated setbacks:

• October 2022: Esmethadone failed the Phase III RELIANCE III trial as a monotherapy for MDD.
• December 2022: The RELIANCE I study showed no significant benefit as an adjunctive MDD treatment.
• December 2024: The Phase III RELIANCE II trial was halted due to futility.
• December 2024: Relmada discontinued both RELIANCE II and the Phase III RELIGHT study in MDD.

Relmada attributed the lack of efficacy signals in the RELIANCE I and RELIANCE III trials to an "implausible placebo response."

Industry-wide Challenges in Depression Treatment

Relmada's struggles with esmethadone reflect a broader trend of difficulties in developing effective treatments for depression. Other recent setbacks in the field include:

• 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 aticaprant, a kappa opioid receptor blocker, due to insufficient efficacy signals.

These failures underscore the complexity of developing new therapies for depression and the high bar set for demonstrating efficacy in clinical trials.

Relmada's Strategic Shift and Future Focus

With the termination of the esmethadone program, Relmada has announced a shift in its strategic focus. The company is now prioritizing the exploration of strategic product acquisitions and concentrating its efforts on NDV-01, a Phase II proprietary sustained-release formulation of gemcitabine and docetaxel for non-muscle invasive bladder cancer.

Relmada licensed NDV-01 from Trigone Pharma in March, and recent Phase II data presented in April showed promising results, with an 85% three-month overall response rate. This pivot demonstrates the company's adaptability in the face of setbacks and its commitment to developing innovative treatments in areas of unmet medical need.