Relmada Therapeutics Terminates License Agreement for Failed Depression Drug

Relmada Therapeutics, a Florida-based biotech company, has officially terminated its license agreement for esmethadone, a once-promising depression treatment that failed to demonstrate efficacy in multiple phase 3 clinical trials. This development marks the end of a challenging journey for the drug candidate, known as REL-1017, and signals a shift in the company's strategic focus.

A Series of Clinical Setbacks

Esmethadone's path to termination was paved with a series of disappointing clinical trial results. In October 2022, REL-1017 failed to outperform placebo as a monotherapy for major depressive disorder (MDD) in the phase 3 RELIANCE III trial. This setback was followed by another failure in the RELIANCE I trial, where the drug was tested as an adjunctive MDD treatment. Relmada attributed this failure to "a limited number of high-enrolling sites with unplausible placebo response."

Despite a glimmer of hope from a 2023 open-label trial that showed improvements in depression symptoms, the lack of a placebo arm in this study limited its significance. The final blow came in December 2024 when Relmada announced that the RELIANCE II trial, testing esmethadone as an adjunctive treatment for MDD, was unlikely to meet its primary endpoint. This led to the termination of both RELIANCE II and a related study called RELIGHT.

Licensing History and Financial Implications

Relmada originally licensed esmethadone in January 2018 from Charles Inturrisi, Ph.D., and Paolo Manfredi, M.D., for an upfront fee of $180,000. The licensing agreement included quarterly payments of $45,000 to Inturrisi and Manfredi, which were set to continue until esmethadone was commercialized or its patent expired. With the termination of the license agreement on July 7, 2025, all of Relmada's obligations under the deal will expire on October 5, 2025.

Relmada's Path Forward

Following these setbacks, Relmada is pivoting its focus to strategic asset acquisitions and advancing its remaining pipeline. The company is currently conducting an open-label phase 2 trial of NDV-01 for non-muscle invasive bladder cancer. Additionally, Relmada acquired sepranolone, a phase 2 asset for Tourette syndrome, from Asarina Pharma in February 2025.

As the pharmaceutical industry continues to grapple with the challenges of developing effective treatments for depression, Relmada's experience with esmethadone serves as a reminder of the high risks and potential rewards in drug development, particularly in the complex field of mental health therapeutics.