138 Efficacy and Safety of SEP-363856, a Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia

Abstract

Background: SEP‐363856 is a novel psychotropic agent that has shown broad efficacy in animal models of schizophrenia and depression. Its antipsychotic effects appear to be mediated by agonist activity at both trace amine‐associated receptor 1 (TAAR1) and 5‐HT1A receptors. Notably, SEP‐363856 does not bind to any dopaminergic, serotonergic (except 5‐HT1A), glutamatergic, or other neuroreceptors thoughtto mediate the effects of currently available antipsychotics. The aim of this study was to evaluate the efficacy and safety of SEP‐363856 in acutely symptomatic patients with schizophrenia. D: Patients aged 18‐40 years meeting DSM‐5 criteria for schizophrenia (PANSS total score >80) were randomized, double‐blind, to 4‐weeks of flexible‐dose SEP‐363856 (50 or 75 mg/d) or placebo. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, and the Clinical Global Impressions‐Severity (CGI‐S) score. Change from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis. RESULTS: Study treatment groups were similar at baseline: SEP‐363856 (N=120; male, 64.2%; mean age, 30.0 years; PANSS total score, 101.4) and placebo (N=125; male, 63.2%; mean age, 30.6 years; PANSS total score, 99.7). Least‐squares (LS) mean reduction from baseline to week 4 was significantly greater for SEP‐363856 vs. placebo on the PANSS total score (‐17.2 vs. ‐9.7; P=0.001; effect size, 0.45), PANSS positive subscale score (‐5.5 vs. ‐3.9; P=0.019; effect size, 0.32), PANSS negative subscale score (‐3.1 vs. ‐1.6; P=0.008; effect size, 0.37), PANSS general psychopathology subscale score (‐9.0 vs. ‐4.7; P<0.001; effect size, 0.51), and the CGI‐Severity score (‐1.0 vs. ‐0.5; P<0.001; effect size, 0.52). Discontinuation rates for SEP‐363856 vs. placebo were similar overall (21.7% vs. 20.8%) and due to an adverse event (8.3% vs. 6.4%). Change in weight, lipids, glucose and prolactin was similar in SEP‐363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP‐363856 or placebo (with SEP‐363856 incidence higher than 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%). The proportion of patients who reported any extrapyramidal symptom was 3.3% on SEP‐363856 and 3.2% on placebo. CONCLUSION: In this placebo‐controlled study, treatment with SEP‐363856, a novel psychotropic agent, was associated with statistically significant and clinically meaningful improvementinschizophrenia symptomsasdemonstrated by endpoint change in PANSS total and subscale scores, and CGI‐Severity scores. Safety and tolerability findings for SEP‐363856 were in general similar to placebo. In particular, SEP‐363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non‐D2 mechanism of action.