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ESMETHADONE (REL-1017) IN PATIENTS WITH ANTIDEPRESSANT TACHYPHYLAXIS: A POST HOC EFFICACY ANALYSIS IN A PRE-RANDOMIZATION–DEFINED SUBGROUP

Clotilde Guidetti — Anna Chiara Frigo2, George I. Papakostas1, Luca Pani3, Sara De Martin2, Giulia Serra4, Massimo Apicella4, Stefano Comai2, Andrea Mattarei4, Franco Folli5, Marco Gentilucci6, Marco Pappagallo6, Paolo L. Manfredi6, Maurizio Fava1 1Massachusetts General Hospital, and Harvard Medical School, 2 University of Padua, 3University of Miami, 4Child Neuropsychiatry Unit, IRCCS Bambino Gesù Pediatric Hospital, 5University of Milan, 6MGGM Inc.

2026 ASCP Annual Meeting

Background

Antidepressant tolerance/tachyphylaxis (AT) is defined as initial response (≥50% improvement) to antidepressant treatment followed by relapse while maintained on the same adequate dose. Research on the prevalence, mechanisms and treatment options for AT remains limited. In a prior phase 3 trial (REL-1017-301; NCT04688164), esmethadone (REL-1017) showed favorable results in a subgroup of patients with AT that was independently adjudicated pre-randomization.

Methods

In a phase 3, double-blind, randomized, placebo-controlled, two-arm trial (REL-1017302; NCT04855747), REL-1017 (75 mg Day 1; 25 mg Days 2–28) or matching placebo was administered to adult outpatients with MDD and inadequate response to first-line antidepressants. Consistent with prior methods used in REL-1017-301, AT was independently assessed pre-randomization by clinicians from the Massachusetts General Hospital (MGH) Clinical Trials Network and Institute using the MGH Antidepressant Treatment Response Questionnaire (ATRQ). Data were analyzed using mean difference (MD) in MontgomeryÅsberg Depression Rating Scale (MADRS) total score from baseline to Day 7 (key secondary endpoint) and Day 28 (primary endpoint). Although AT status was determined prerandomization, efficacy analyses within this subgroup were conducted post hoc. A planned interim analysis (IA) was conducted by an independent Data Monitoring Committee (DMC) at approximately 75% enrollment.

Results

At IA, the DMC recommended early study termination due to low conditional power. The intent-to-treat (ITT) population included 236 randomized patients. In the ITT analysis, statistical significance was reached at Day 7; however, the study did not meet its Day 28 primary endpoint. The AT population, independently adjudicated pre-randomization, included 46 randomized patients. While statistical significance in the AT population was achieved only at Day 7 and was not maintained at later time points, Cohen’s effect sizes (ES) remained in the moderate range at all assessed time points. In both populations, ITT and AT, loss of statistical significance at later time points reflected increased placebo response and not loss of REL-1017 efficacy. ITT population (actual visits) In the ITT population (REL-1017 n=119; placebo n=117), REL-1017 produced a greater reduction in MADRS total score than placebo at Day 7 (mean [SD]: −9.7 [8.23] vs −6.9 [8.58]; mean difference −2.80 [8.41]; Cohen’s d=0.33; p=0.0133). At Days 14, 21, and 28, betweengroup differences were smaller and not statistically significant: Day 14 (−11.8 [9.90] vs −10.9 [9.67]; d=0.10; p=0.4823), Day 21 (−13.8 [10.41] vs −12.9 [10.85]; d=0.08; p=0.5541), and Day 28 (−15.2 [10.99] vs −14.5 [10.46]; d=0.07; p=0.6037). AT population (actual visits) In the AT population (REL-1017 n=25; placebo n=21), REL-1017 demonstrated consistently moderate effect sizes across all time points. At Day 7, REL-1017 was associated with a significantly greater MADRS reduction than placebo (−13.5 [9.54] vs −7.4 [8.09]; mean difference −6.11 [8.91]; Cohen’s d=0.69; p=0.0288). At Day 14, the between-group difference approached statistical significance (−15.0 [11.59] vs −9.2 [6.60]; d=0.59; p=0.0527). Moderate effect sizes persisted at Day 21 (−14.3 [11.28] vs −10.0 [9.07]; d=0.42; p=0.1810) and Day 28 (−17.0 [11.09] vs −12.8 [7.84]; d=0.42; p=0.2004), despite loss of statistical significance.

Conclusions

While this post hoc analysis included only 46 subjects, AT subjects were independently adjudicated pre-randomization and moderate ES were observed across time points. These analyses further suggest that REL-1017 may represent a promising rapid-acting adjunctive treatment for patients with AT.