Scientific Poster Session II - Original Research

Original Research
  Sunday, November 12, 2023
  12:45 PM–02:15 PM

Abstract

Introduction: Esmethadone (REL-1017) is a promising uncompetitive N-methyl-D-aspartate receptor antagonist in development for adjunctive treatment of major depressive disorder (MDD).

Research Question or Hypothesis: REL-1017 is efficacious, safe, and well tolerated.

Study Design: Phase 3, double-blind, placebo-controlled randomized trial of oral 25 mg REL-1017 (75 mg loading dose on Day 1) or placebo for 28 days in patients with MDD and inadequate response to standard antidepressants.

Methods: Pre-randomization, clinicians from the Massachusetts General Hospital Clinical Trials Network and Institute assessed prior antidepressant response and antidepressant tolerance/tachyphylaxis (initial response followed by relapse on the same antidepressant) using the Antidepressant Treatment Response Questionnaire. Montgomery-Åsberg Depression Rating Scale (MADRS) score >35 at Day 1 (baseline) was categorized as severe depression. The primary efficacy endpoint was the change in the MADRS from baseline to Day 28. Modified intent-to-treat (mITT): patients randomized and dosed, irrespective of protocol deviations or discontinuation. Per-protocol (PP): subjects completing treatment without major deviations affecting efficacy assessments.

Results: Table: N=number of subjects; R=REL-1017; P=placebo; CFB=MADRS change from baseline; AT=antidepressant tachyphylaxis

	Mean (SD) CFB R	Mean (SD) CFB P	Mean (SD) CFB R vs P	P value	Effect size
mITT N 227: 113 R; 114 P	15.1 (11.3)	12.9 (10.4)	2.3 (10.9)	0.1537	0.21
PP N 198: 100 R; 98 P	15.6 (11.2)	12.5 (9.9)	3.1 (10.6)	0.0510	0.29
PP AT N 79: 43 R; 36 P	17.5 (10.4)	11.4 (9.0)	6.1 (9.8)	0.0101	0.62
PP MADRS >35 N 98: 43 R; 55 P	19.2 (13)	11.3 (10.1)	7.9 (11.6)	0.0015	0.68

Adverse events (AEs) were mild or moderate and transient. Seven patients discontinued the study due to AEs (5 placebo and 2 REL-1017).

Conclusion: Efficacy outcomes favored PP analyses. Favorable efficacy outcomes were observed in post hoc analyses of PP AT subgroup and of PP subgroup with baseline MADRS >35. Esmethadone was safe and well tolerated.

Presenting Author

Marco Pappagallo MD
Relmada Therapeutics

Authors

Andrea Alimonti MD
David Bushnell MS
Paolo Manfredi MD
Andrea Mattarei PhD
Fava Maurizio MD
Massachusetts General Hospital

Clotilde Guidetti MD
Charles Inturrisi PhD
Cedric O'Gorman MD, MBA
Luca Pani MD
Stefano Comai PhD
Sara De Martin PhD
Franco Folli MD, PhD
Sergio Traversa PharmD, MBA
Stephen Stahl MD, PhD, DSc (Hon)