Maurizio Fava1, Stephen Stahl1, Luca Pani1, Sara De Martin1, Marco Pappagallo1, Clotilde Guidetti1, Andrea Alimonti1, Ezio Bettini1, Richard M Mangano1, Thomas Wessel1, Marc de Somer1, Judy Caron1, Ottavio V Vitolo1, Gina R DiGuglielmo1, Adam Gilbert1, Hiren Mehta1, Morgan Kearney1, Andrea Mattarei1, Marco Gentilucci1, Franco Folli1, Sergio Traversa1, Charles E Inturrisi1, Paolo L Manfredi1. 1. Department of Psychiatry, Massachusetts General Hospital, Boston (Fava, Vitolo); Neuroscience Education Institute, University of California, San Diego (Stahl); Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami (Pani); Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy (Martin, Mattarei); Department of Anesthesiology, Albert Einstein College of Medicine, Bronx, N.Y. (Pappagallo); University of Genoa, Genoa, Italy (Guidetti); Catholic University of the Sacred Heart, Rome (Guidetti); Department of Neuroscience, Child and Adolescent Psychiatry Unit, Bambino Gesù Children's Hospital, IRCCS, Rome (Guidetti); Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland (Alimonti); Institute of Oncology Research, Southern Switzerland, Bellinzona (Alimonti); Università della Svizzera Italiana, Bellinzona (Alimonti); Veneto Institute of Molecular Medicine, Padua, Italy (Alimonti); Department of Medicine, Zurich University, Zurich (Alimonti); University of Padua, Padua, Italy (Alimonti); In Vitro Pharmacology Department, Aptuit an Evotec Company, Verona, Italy (Bettini); Drexel University College of Medicine, Philadelphia (Mangano); Relmada Therapeutics, New York (Pappagallo, Wessel, de Somer, Caron, DiGuglielmo, Traversa, Inturrisi, Manfredi); Department of Cardiology, Syneos Health, Morrisville, N.C. (Gilbert, Mehta, Kearney); Department of Medicine, Albert Einstein College of Medicine, Bronx, N.Y. (Gentilucci); and Department of Health Science, University of Milan, Milan, Italy (Folli).
Abstract
Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis. Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0. Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.
Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis. Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0. Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.
Entities:
Keywords:
Depressive Disorders; Major Depressive Disorder; Neurology
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Authors: Ezio Bettini; Stephen M Stahl; Sara De Martin; Andrea Mattarei; Jacopo Sgrignani; Corrado Carignani; Selena Nola; Patrizia Locatelli; Marco Pappagallo; Charles E Inturrisi; Francesco Bifari; Andrea Cavalli; Andrea Alimonti; Luca Pani; Maurizio Fava; Sergio Traversa; Franco Folli; Paolo L Manfredi Journal: Pharmaceuticals (Basel) Date: 2022-08-13