O12.5. 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

Abstract

Background SEP-363856 is a novel psychotropic agent with broad efficacy in animal models of schizophrenia and depression. In vitro and in vivo studies suggest that SEP-363856 may have antipsychotic effects in schizophrenia mediated by its 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 thought to mediate the effects of available antipsychotics. The aim of this Phase 2 study was to evaluate the efficacy and safety of SEP-363856 in patients with schizophrenia. Methods Hospitalized patients aged 18–40 years of age meeting DSM-5 criteria for schizophrenia and experiencing an acute exacerbation of psychotic symptoms (PANSS total score ≥80; item score ≥4) were randomized, double-blind, to 4-weeks of flexible-dose SEP-363856 (50 or 75 mg) or placebo treatment given once daily in the evening. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, the Clinical Global Impressions-Severity (CGI-S) score, and the Brief Negative Symptom Scale (BNSS) total score. Change from baseline in primary and secondary efficacy 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; primary endpoint), the PANSS positive subscale score (-5.5 vs. -3.9; P=0.019; effect size, 0.32), the PANSS negative subscale score (-3.1 vs. -1.6; P=0.008; effect size, 0.37), the PANSS general psychopathology subscale score (-9.0 vs. -4.7; P<0.001; effect size, 0.51), the CGI-Severity score (-1.0 vs. -0.5; P<0.001; effect size, 0.52), and the BNSS total score (-7.1 vs. -2.7; P<0.001; effect size, 0.48). Overall discontinuation rates were similar for SEP-363856 vs. placebo (21.7% vs. 20.8%) and for discontinuations due to an adverse event (would prefer the %'s here for consistency). The mean daily dose of SEP-363856 was 64.3 mg. Change in weight, lipids, glucose and prolactin was similar in SEP-363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP363-856 or placebo (with SEP363-856 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. Discussion SEP-363856 is a novel psychotropic agent with a novel mechanism of action that does not involve dopamine or serotonin receptor antagonism and is therefore distinct from currently available antipsychotic agents. In this placebo-controlled study, SEP-363856 treatment was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms, as demonstrated by change in PANSS total, positive, negative, and general psychopathology subscale scores at the 4-week study endpoint. Significant improvement in overall illness severity (based on CGI-S assessment) was also observed in SEP-363856 vs placebo-treated patients. 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.