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T35

EFFICACY AND SAFETY OF ESMETHADONE (REL-1017) IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER AND INADEQUATE RESPONSE TO STANDARD ANTIDEPRESSANTS: FINDINGS FROM TWO EARLY-TERMINATED PHASE 3 TRIALS

Clotilde Guidetti — Anna Chiara Frigo2, George I. Papakostas1, Sara De Martin2, Andrea Mattarei2, Stefano Comai2, Luca Pani3, Charles Gorodetzky4, Frank Vocci5, Thomas Kosten6, Franco Folli7, Marco Pappagallo8, Paolo L. Manfredi8, Stephen M. Stahl9, Maurizio Fava1 1Massachusetts General Hospital, and Harvard Medical School, 2University of Padua, 3University of Miami, 4Consultant in Pharmaceutical Medicine, 5Friends Research Institute, 6Baylor College of Medicine, 7University of Milan, 8MGGM Inc.; Levomecor Inc., 9University of California, San Diego and Riverside

2026 ASCP Annual Meeting

Background and

Objective

Up to 50% of patients with MDD do not respond to first-line therapy. There is an unmet need for safe, effective, oral rapid acting adjunctive antidepressants. We evaluated the efficacy and safety of esmethadone (REL-1017) in patients with MDD and inadequate response to first-line therapy.

Methods

These were two prematurely terminated near-identical Phase 3 randomized, double-blind, placebo-controlled trials: REL-1017-302 (NCT04855747) and REL-1017-304 (NCT06011577). REL-1017 (75 mg on Day 1 followed by 25 mg daily from Day 2 to Day 28) or matching placebo was administered as adjunctive therapy to adult outpatients with MDD and inadequate response to first line antidepressants. Data were analyzed using mean difference (MD) in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to Day 7 and to Day 28, key secondary endpoint and primary endpoint, respectively. The planned sample size was 280 subjects (140 per treatment arm). A planned interim analysis (IA) for sample size re-estimation was conducted by an independent Data Monitoring Committee (DMC) at approximately 75% enrollment.

Results

At IA the DMC recommended early termination for study REL-1017-302 due to low conditional power for meeting the primary endpoint at Day 28. Following the DMC recommendation, both studies were terminated by the former sponsor. Neither trial met the primary endpoint at Day 28. Study REL-1017-302 — ITT population (actual visits) REL1017 n=119; placebo n=117, changes in MADRS total score from baseline were as follows. Day 7: REL-1017 (n=114) showed a mean (SD) change of −9.7 (8.23) compared with −6.9 (8.58) for placebo (n=110), corresponding to a mean difference of −2.80 (8.41), Cohen’s d (ES)=0.33, p=0.0133. Day 14: REL-1017 (n=106) had a mean (SD) change of −11.8 (9.90) versus −10.9 (9.67) for placebo (n=109), with a mean difference of −0.94 (9.79), ES=0.10, p=0.4823. Day 21: REL-1017 (n=110) demonstrated a mean (SD) change of −13.8 (10.41) compared with −12.9 (10.85) for placebo (n=106), yielding a mean difference of −0.86 (10.63), ES=0.08, p=0.5541. Day 28: REL-1017 (n=102) showed a mean (SD) change of −15.2 (10.99) versus −14.5 (10.46) for placebo (n=100), corresponding to a mean difference of −0.79 (10.73), ES=0.07, p=0.6037. However, study REL-1017-302 (N=236) showed statistically significant rapid antidepressant efficacy at Day 7 (prespecified key secondary endpoint). Day 7 statistical significance was lost at later time points due to improvement in the placebo arm. Within-group improvements in the REL-1017 arm continued across time points. Prespecified MMRM and prespecified per protocol analyses supported Day 7 rapid antidepressant effects. Study REL-1017-304 (N=27) showed a similar trend for rapid antidepressant efficacy at Day 7 (MADRS MD REL-1017 vs placebo: -3.8 points) but did not achieve statistical significance due to the small sample size. Exploratory pooled data from both studies (N=263) also supported Day 7 antidepressant effects. Consistent with prior trials, totaling over 1000 participants exposed to REL-1017, treatment emergent adverse events were mostly mild or moderate, with no serious adverse events, no meaningful opioid-like effects or dissociative effects, and no signal for metabolic, neurological, cardiovascular, or sexual side effects.

Conclusions

With the limitations of early study termination, Day 7 statistically significant antidepressant effects and favourable safety results, consistent with prior results, support the development of REL-1017 as a rapid-acting, safe and well-tolerated, oral, once daily adjunctive antidepressant.