Adjunctive treatment with the novel oral medication REL-1017 (esmethadone) is effective in adults with major depressive disorder (MDD) who have failed other antidepressants, new research suggests.
REL-1017, from Relmada Therapeutics, is a novel N-methyl-D-aspartate receptor (NMDAR) channel blocker that preferentially targets hyperactive channels while maintaining physiologic glutamatergic neurotransmission.
Results from a phase 2a study showed rapid "therapeutic efficacy," with a statistical difference by day 4, and was "robust," with an effect size of 0.7 to 1. The positive outcome was also sustained for at least 1 week after treatment discontinuation, co-investigator Paolo L. Manfredi, MD, chief scientific officer, Relmada Therapeutics, noted.
"Considering that the available traditional antidepressants have an average effect size around 0.3, this novel, potential rapid-acting antidepressant...holds great promise for millions of patients suffering from depression," Manfredi told Medscape Medical News.
These results were obtained with a "very well-tolerated once-daily oral NMDAR antagonist, without the dissociative effects seen with ketamine," he added.
The findings were published online December 22 in The American Journal of Psychiatry.
"Clear Need" for Better Therapies
It is estimated that more than half of patients with MDD fail to respond adequately following their first standard antidepressant treatment. In addition, responses are often delayed by 4 to 8 weeks after starting an antidepressant.
Therefore, there is a "clear need" to develop drugs for MDD that act quickly and with improved efficacy, the investigators note.
The phase 2a study of REL-1017 enrolled 62 adult patients (45% women) aged 18 to 65 years with moderate to severe MDD and no significant psychiatric comorbidity. All had failed to benefit from one to three standard antidepressant treatments in their current major depressive episode.
The researchers evaluated two doses of REL-1017 (25 mg and 50 mg once daily) vs placebo given as adjunctive treatment. The assigned treatment lasted 7 days.
The primary study objectives were safety and tolerability. Results showed no serious adverse events (AEs), and no patients experienced treatment-emergent AEs that led to the stopping of treatment.
In addition, patients receiving the active drug experienced mild or moderate transient AEs comparable to placebo, with no opioid, dissociative, or psychotomimetic symptoms, or withdrawal effects when treatment ended.
The most common AEs reported were headache, constipation, nausea, and sleepiness.
Significant Efficacy
The primary efficacy endpoint was the Montgomery–Åsberg Depression Scale (MADRS) score.
Mean MADRS score at baseline was 33.8 in the placebo group vs 32.9 in the REL-1017 25-mg group and 35.2 in the REL-1017 50-mg group.
MADRS scores showed improvement on day 4 of treatment in both REL-1017 groups, and the improvement continued through day 7 (last dose) and day 14 (7 days after the last dose), with P ≤ .0308 and effect sizes ranging from 0.7 to 1.0.
Mean change from baseline in MADRS scores showed more improvement at the end of the dosing period for both dosing groups (-16.8 with 25 mg and -16.6 with 50 mg) vs -8.8 with placebo.
Results of the other efficacy endpoints of Symptoms of Depression Questionnaire (SDQ) score and Clinical Global Impressions severity scale (CGI-S) and improvement scale (CGI-I) scores were similar to that of the MADRS.
Remission rates (defined as a MADRS score ≤10) on day 14, the last day of efficacy assessment, were 5% with placebo vs 31% (P = .035) with REL-1017 25 mg and 39% (P = .01) with REL-1017 50 mg.
The number needed to treat to achieve remission on day 14 was four with the 25-mg dose and three with the 50-mg dose.
Phase 3 trials to confirm the efficacy and safety of REL-1017 are in progress, with topline results expected later this year, the investigators report.
The study was funded by Relmada Therapeutics. Manfredi has received personal fees and/or held stock ownership from Relmada. Disclosures for the other investigators are fully listed in the original article.
Am J Psychiatry. Published online December 22, 2021. Abstract
