Esmethadone Shows Mixed Results in Phase 3 Trial for Depression

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Esmethadone (REL-1017) did not meet the primary endpoint outcome in the recently published phase 3 trial as an adjunct for major depressive disorder (MDD), despite following on phase 2 results which had been characterized as "robust."¹

However, favorable findings on secondary measures and in subsequent analysis were sufficient to warrant an additional phase 3 trial which is currently underway, Maruizio Fava, MD, department of psychiatry, Massachusetts General Hospital in Boston, MA, and a principal investigator on the phase 2 and 3 trials told Psychiatric Times.

Fava also suggested that the encouraging results in the phase 3 trial, conducted between December 2020 and December 2022, may have reflected some heightened level of response, albeit unintended, in a cohort gathered during the COVID-19 pandemic.

"Not just in this study, but in many other trials during the pandemic we had an unusual, higher than expected placebo response," Fava said.

"A significant proportion of individuals ended up being somewhat isolated from friends, from their families, and unable to travel. So, participation in the trial, where they have a lot of human contact, a lot of human interactions, boosted, in my opinion, the placebo effect. It wasn't just expectation (of antidepressant effect), it was also a therapeutic effect of human interactions," Fava posited.

Although the primary endpoint of the phase 3 trial, greater improvement in symptoms than with placebo, was not met in the Intention-to-Treat (ITT) population, the rate of response, a secondary outcome, was statistically significantly higher and the rate of remission was numerically higher. In addition, post-hoc analysis did reveal that symptom improvement was statistically significantly greater in the most severely affected group than with placebo.

Assessing Esmethadone as Adjunct for Depression

Esmethadone is an orally administered NMDA receptor (NMDAR) uncompetitive antagonist, sharing that action with several drugs, including esketamine—approved by the US Food and Drug Administration for intranasal administration in treatment-resistant depression and depression with suicidal ideation—and dextromethorphan, approved in fixed oral combination with bupropion for MDD.

Fava and colleagues have described possible avenues of action of NMDAR antagonists, including within putative impairment of neural plasticity in the pathogenesis of MDD, thought to be mediated by dysregulation of NMDAR.² An alternative "disinhibition hypothesis" implicates blockade of NMDARs on GABAergic inhibitory interneurons.

Although the activity of NMDAR antagonists in MDD remains to be elucidated, Fava and colleagues remark, "the contemporary understanding of major depressive disorder neurobiology is progressively disengaging from the classic serotonergic hypothesis."²

The phase 3 double-blind, placebo-controlled, randomized clinical trial assessed a 28-day course of esmethadone adjunct over approximately 58 days. Participants were randomized to add placebo to their current antidepressant treatment or esmethadone, in loading dose of 75 mg on day 1 and 25 mg daily thereafter. At baseline, participants had a Montgomery-Asberg Depression Rating Scale (MADRS) total score of greater than or equal to 24 points, and a major depressive episode of 8 weeks to 36 months that was unrelieved by 1 to 3 courses of antidepressant treatment.

The ITT population (n= 227) included all randomized patients, with an estimated 210 treatment completers required to achieve 90% power. Approximately 198 patients did complete treatment without major protocol deviations affecting efficacy measures, and were defined as the per-protocol (PP) population for prespecified supportive analysis.The primary efficacy measure against placebo was statistically greater change in MADRS total score from baseline to day 28. Key secondary outcomes were remission, defined as MADRS score less than or equal to 10, and response, greater than or equal to 50% improvement in MADRS score from baseline.

The investigators reported the mean change from baseline (CFB) MADRS score in the ITT population was 15.1 (SD 11.3) with esmethadone (n=113) and 12.9 (SD 10.4) for placebo, a mean difference of 2.3, but which was not statistically significant (P=0.154). The response rates, however, were 39.8% and 27.2%, which was statistically significantly different (P=0.044). Rates of remission with esmethadone were numerically higher than with placebo, 22.1% and 13.2% (P=0.076).

"If you look at response rates, these were significantly higher in phase 3, and a 2.3 difference would have been statistically significant had we kept the same sample size that we had projected," Fava commented.

The PP (n=198) analysis of CFB was close to significance, with 15.6 (SD 11.2) for esmethadone and 12.5 (SD 9.9) for placebo, with a mean difference of 3.1 (p=0.051). In the most severely affected, with baseline MADRS greater than or equal to 35, the improvement in symptoms from baseline was statistically significantly greater with esmethadone than placebo in both ITT and PP population analyses: mean difference 6.9 (p=0.0059) in ITT; mean difference 7.9 (P=.0015) in PP.

"We hypothesize that in this study, the subgroup of patients with severe depression may have included a lower number of 'professional patients', thus explaining the favorable results seen in the severity-enriched post hoc analysis," the investigators indicated.

Fava is looking forward to following this in the ongoing phase 3 trial. "I think the next step is to do it in a more severe population, but also without the confound of the pandemic," he said.

Dr Fava discloses in the phase 3 trial report that he is a consultant to Relmada Therapeutics on behalf of Massachusetts General Hospital and did not receive any personal compensation.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Fava M, Stahl SM, Pani L, et al. Efficacy and safety of esmethadone (REL-1017) in patients with major depressive disorder and inadequate response to standard antidepressants: a phase 3 randomized controlled trial.J Clin Psychiatry. 2024;85(3):24m15265.

2. Fava M, Stahl SM, de Martin S, et al. Esmethadone-HCL (REL-1017): a promising rapid antidepressant.Eur Arch Psychiatry Clin Neurosci. 2023;273:1463-1476.