No Indication of Abuse or Withdrawal Potential with Esmethadone (REL-1017): Results From Two Phase 3 Randomized Placebo-Controlled Trials in Patients With Major Depressive Disorder

Authors: Pappagallo M, Shram M, Henningfield J, Gorodetsky C, De Martin S, Vocci F, Sapienza F, Kosten T, Guidetti C, O’Gorman C, Folli F, Traversa S, Inturrisi C, Manfredi P

Background: Esmethadone (REL-1017) is a promising adjunctive antidepressant candidate currently in Phase 3 development as an N-methyl-D-aspartate receptor uncompetitive antagonist. It is the dextro-isomer of racemic methadone; however, it does not have meaningful mu opioid agonism and may antagonize the respiratory depression and euphoria of levomethadone, the opioid active enantiomer in racemic methadone. REL-1017 did not show evidence of meaningful abuse potential in animal studies predictive of abuse and in human abuse potential studies. Because of the substance misuse vulnerability of patients with major depressive disorder (MDD), we further evaluated the abuse and dependence potential of REL 1017 in two Phase 3 trials of patients with MDD.

Methods: Studies-301 and -303 were 28-day, outpatient, Phase 3, randomized, double-blind, placebo-controlled trials of once-daily oral 25 mg REL-1017 (Day-1 loading dose 75 mg) in patients with MDD. In study 301 REL-1017 was administered as adjunctive to standard antidepressant therapy. In study 303 REL-1017 was administered as monotherapy. We performed a safety analysis of all adverse events (AEs) and collected narratives for predefined AEs potentially related to abuse. We assessed “drug liking,” “drug high,” and “desire to take the drug again” with a 100-point visual analogue scale (VAS) and used the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®) to assess potentially abuse-related events. We assessed withdrawal after abrupt treatment discontinuation with the Physician Withdrawal Checklist (PWC), Clinical Opiate Withdrawal Scale (COWS), and Subjective Opiate Withdrawal Scale (SOWS). We also assessed potential dissociative effects with The Clinician-Administered Dissociative States Scale (CADSS).

Results: Among the 459 patients receiving any study drug, AEs were predominantly mild or moderate, and transient. There were no serious treatment related AEs. AEs potentially related to abuse were not correlated with elevated VAS scores and did not differ between REL-1017 and placebo. Further, VAS scores for drug liking, high and desire for repeated use, as well as CADSS scores for potential dissociative effects did not differ between REL-1017 and placebo. Also, the MADDERS® showed no indicators of abuse. Among 354 patients who participated in the safety withdrawal assessment, change from baseline on the withdrawal indicators, PWC, COWS, and SOWS were not clinically meaningful and did not differ between REL-1017 and placebo groups.

Conclusions: These Phase 3, double-blind, placebo-controlled MDD studies of REL-1017 showed no indications of meaningful abuse or dependence potential. The results of these Phase 3 trials were consistent with the favorable tolerability and safety profile of REL-1017 seen in Phase 1 and Phase 2 studies, and were consistent with earlier abuse liability studies showing no meaningful abuse potential for REL-1017.

To be presented at the 62nd Annual Meeting of the American College of Neuropsychopharmacology

Wednesday, December 6, 2023 at 5 PM – 7 PM