On 20 September, Relmada Therapeutics announced positive efficacy and safety data from a long-term, open-label, non-comparative, registrational Phase III trial (NCT04855760) for its antidepressant REL-1017 (esmethadone hydrochloride) in patients who had not previously been treated with the drug. There is a significant unmet need within the major depressive disorder (MDD) space for pharmacotherapies that can demonstrate a rapid antidepressant effect, an issue that REL-1017 is looking to address. In the trial, 26.6% of patients achieved a clinical response, defined as a ≥50% improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, by Day 7, increasing to 51.0% by Month 1. Additionally, 12.1% of patients were in clinical remission, defined as MADRS total score ≤10 by Day 7, increasing to 30.1% at Month 1. Combined with its rapid onset of action, REL-1017 demonstrated sustained antidepressant effects, with 77.2% of patients achieving clinical response by Month 12 and 54.5% of patients achieving clinical remission by Month 12.

In general, the side-effect burden is high with currently available antidepressants. According to key opinion leaders interviewed by GlobalData, significant weight gain and sexual dysfunction are the most undesirable side effects of standard-of-care antidepressants such as selective serotonin reuptake inhibitors (SSRIs). By demonstrating favourable long-term tolerability without these side effects, REL-1017 could be a more appealing long-term option for patients. This could help improve treatment compliance compared with other antidepressants, potentially boosting its overall efficacy as a result.

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While these positive results are important for Relmada Therapeutics in demonstrating the efficacy of REL-1017 as an adjunctive therapy for MDD, they have come in an open-label trial. The drug will still need to demonstrate efficacy in a placebo-controlled trial, following a previous Phase III trial where the primary endpoint was missed due to a high placebo response rate (RELIANCE I: NCT04688164). Therefore, demonstrating efficacy compared to placebo in two ongoing Phase III trials that are due to be completed in 2024, RELIANCE II (NCT04855747) and RELIGHT (NCT06011577), will be crucial to REL-1017’s prospects.

If REL-1017 does enter the MDD market, it will face significant competition from Axsome Therapeutics’s Auvelity (dextromethorphan + bupropion), which was the first oral, rapidly acting antidepressant to be approved by the FDA in 2022. Like REL-1017, Auvelity demonstrated statistically significant efficacy from Week 1 of treatment and the drug was not associated with weight gain. Since Auvelity has had time to establish itself in the MDD market, if REL-1017 can demonstrate greater efficacy than Auvelity in RELIANCE II and RELIGHT, it could enhance REL-1017’s uptake despite its later start.

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