SEP-363856 for Treatment of Schizophrenia

Rob Goldman, PhD

A new study has found that a novel compound, which has already received a Breakthrough Therapy Designation from the FDA, appears to be a safe and effective treatment for schizophrenia in adults.

Investigators presented the results of 4-week, double-blind trial that examined the efficacy of SEP-363856 at the 2019 Annual Meeting of the American Psychiatric Association in San Francisco, CA.

“We put it to the test. Would this compound, this novel molecule, work for the treatment of patients who are acutely ill and would it have a safety profile that would be consistent with a non-D2 mechanism of action,” explained Rob Goldman, PhD, head of global clinical research and medical affairs with Sunovion. “Essentially the results of that study at a high level that, yes, it was efficacious. It separated on the primary end point, which is positive and negative symptoms of schizophrenia. As well as secondary endpoints.”

SEP-363856 is a novel psychotropic agent, with a non-D2 mechanism, that had previously shown broad efficacy in animal models of schizophrenia and depression. Additionally, SEP-363856 does not bind to dopaminergic, serotonergic (except 5-HT1A), glutamatergic, or other neuroreceptors that are believed to mitigate the effects of available antipsychotics.

Investigators examined the efficacy of SEP-363856, in once-daily doses of 50 or 75 mg) on hospitalized patients with schizophrenia in a randomized, double-blind trial that lasted 4 weeks. The primary measure of efficacy was a patient’s Positive and Negative Syndrome Scale (PANSS) score.

Secondary measures of efficacy included the Clinical Global Impressions-Severity (CGI-S) score, PANSS sub scale scores, and the Brief Negative Symptom Scale (BNSS) total score. Changes from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis.

In order to be included within the study, patients had to meet multiple eligibility criteria. The criteria included being between 18 and 40 years of age, number of hospitalizations for schizophrenia cannot exceed 2, and must have been experiencing an acute exacerbation of psychotic symptoms at the time of the study. Additionally, patients must have had a CGI-S score of 4 or more at baseline and screening, a PANSS total score of 80 or greater, and a PANSS item score of 4 or more on 2 of the following: delusions, conceptual disorganization, hallucinatory behavior, or unusual thought content.

A total of 245 patients were involved in the study. Of the 145, 120 of them received SEP-363856 and 125 received placebo.). 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), 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 BNSS total score (-7.1 vs. -2.7; P<0.001; effect size, 0.48).

Authors noted that study completion rates between both groups were similar, with the placebo group retaining 79.2% of patients and SEP-363856 group retaining 78.3%. Adverse events occurring with an incidence of 2% or greater and at a higher rate than placebo include 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%).

This study, titled “Efficacy and Safety of SEP-363856 in the Treatment of Schizophrenia: A Four-Week, Randomized, Placebo-Controlled Trial of a Novel Compound with a Non-D2 Mechanism of Action,” was presented at APA 2019.