Relmada Therapeutics Abandons Depression Drug Esmethadone After Three Failed Phase III Trials
核心洞察
Relmada Therapeutics has officially halted development of esmethadone, an investigational NMDA receptor (搜索) blocker for major depressive disorder (搜索), following three consecutive Phase III trial failures.
The company terminated its January 2018 licensing agreement for the drug after the RELIANCE III, RELIANCE I, and RELIANCE II trials all failed to demonstrate significant efficacy versus placebo.
Relmada is now shifting focus to strategic product acquisitions, with primary emphasis on NDV-01, a Phase II sustained-release formulation of gemcitabine and docetaxel for non-muscle invasive bladder cancer (搜索).
Relmada Therapeutics has officially ended development of its investigational depression drug esmethadone, marking the conclusion of a troubled development program that suffered three consecutive Phase III trial failures. The company announced the decision in an SEC filing on Friday, stating it will terminate the January 2018 licensing agreement that granted global rights to the NMDA receptor (搜索) blocker.
Three Consecutive Trial Failures
Esmethadone's development history has been marked by repeated late-stage disappointments. In October 2022, the drug failed the Phase III RELIANCE III trial in major depressive disorder (搜索) (MDD), unable to significantly ease the severity of depressive symptoms as a monotherapy versus placebo. Two months later, esmethadone delivered another setback in December 2022 when the RELIANCE I study showed no significant benefit as an adjunctive MDD treatment.
For both RELIANCE I and RELIANCE III trials, Relmada attributed the lack of significant efficacy signals to an "unplausible placebo response." The company's struggles continued into 2024, when the Phase III RELIANCE II trial also ended in failure following an interim analysis that found a high likelihood of futility. Weeks later, Relmada discontinued both RELIANCE II and the Phase III RELIGHT study, also in MDD.
Financial Impact and Licensing Terms
Under the original licensing agreement, Relmada paid a nonrefundable sum of $180,000 upfront to the drug's developers, Charles Inturrisi, a professor at Weill Cornell Medical, and Paolo Manfredi. The company also made quarterly payments of $45,000 that were intended to continue until certain conditions were met, including the first market sale of esmethadone or the expiration of its patent. None of these events occurred during the partnership.
The molecule was originally developed by Inturrisi and later licensed to Medeor (搜索), co-founded by Manfredi. Medeor subsequently merged with Relmada in 2013.
Strategic Pivot to New Assets
With esmethadone removed from its pipeline, Relmada has "made the exploration of strategic product acquisitions our primary focus," according to a note to investors on its website. The company is now concentrating efforts on NDV-01, a Phase II proprietary sustained-release formulation of gemcitabine and docetaxel being trialed for non-muscle invasive bladder cancer (搜索).
Relmada licensed NDV-01 from Trigone Pharma (搜索) in March, and Phase II data presented in April showed an 85% three-month overall response rate, representing a potential bright spot in the company's repositioned pipeline.
Broader Depression Development Challenges
Relmada's setback reflects the broader difficulties facing biotechnology companies in depression drug development. Last month, Alto Neuroscience's ALTO-203 failed to significantly boost mood in patients with MDD in a Phase II study, forcing the California company to examine exploratory endpoints and EEG biomarkers for efficacy signals. Similarly, in February, Supernus Pharmaceuticals experienced a mid-stage failure when its asset SPN-820 failed to improve symptom burden in patients with treatment-resistant depression (搜索).
The abandonment of esmethadone underscores the persistent challenges in developing effective treatments for major depressive disorder (搜索), despite significant unmet medical need in this therapeutic area.