Efficacy and Safety of SEP-363856, a Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia: A 4-Week, Randomized, Placebo-Controlled Trial

Background: SEP-363856 is a novel trace amine associated receptor-1 (TAAR1)/5-HT1A agonist with no dopamine-D2/5-HT2A antagonist activity which has shown efficacy in animal models of psychosis. The aim of this study was to evaluate the efficacy and safety of SEP-363856 for schizophrenia.

Method: Patients aged 18-40 years with an acute exacerbation of schizophrenia were randomized, double-blind, to 4-weeks of flexible-dose treatment with SEP-363856 (N=120) given once daily (50 or 75 mg) or placebo (N=125). The primary efficacy endpoint was week 4 change in the Positive and Negative Symptom Scale (PANSS) total score. Secondary efficacy endpoints included the Clinical Global Impressions-Severity (CGI-S) score, and Brief Negative Symptom Scale (BNSS) total score.

Results: The primary analysis showed a significant reduction in LS mean PANSS total score for SEP-363856 vs. placebo at week 4 (-17.2 vs. -9.7; P=0.001; effect size = 0.45). Significant reduction for SEP-363856 was also observed on the CGI-S and BNSS total score. Effects on weight, lipids, glucose, prolactin, ECG and extrapyramidal symptoms were similar to placebo. Adverse events occurring with an incidence ≥2% on SEP-363856 vs. placebo were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%).

Conclusion: In this study, SEP-363856, a novel, non-D2 binding agent, demonstrated significant antipsychotic effects at primary and secondary efficacy endpoints in patients with schizophrenia. The safety and tolerability profile of SEP-363856 was similar to placebo and was notably devoid of D2-related pattern of adverse effects characteristic of current antipsychotic agents.

This poster was presented at the 32nd annual Psych Congress, held Oct. 3-6, 2019, in San Diego, California.