A new class of antipsychotic drug (SEP-363856) reduced symptom severity in adults with an acute exacerbation of schizophrenia, according to findings of a 4-week trial (NCT02969382) published in the New England Journal of Medicine. This antipsychotic does not bind to dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 and 5-hydroxytryptamine type 1A receptors.
The mechanism of the orally administered drug, which was developed by researchers at Sunovion Pharmaceuticals collaborating with PsychoGenics, is not completely understood. However, its potential is promising given recent findings outlining a decline in treatment effect and increase in placebo response in schizophrenia trials.
The investigators conducted a randomized controlled trial to evaluate the efficacy and safety of SEP-363856 in patients with schizophrenia aged 18 to 40 years who were randomly assigned to receive SEP-363856 (n=120) or placebo (n=125) once daily for 4 weeks. Patients received a starting dose of 50 mg, which could be adjusted to 75 mg per day based on an individual basis and the investigators’ judgment of efficacy and safety. The 2 groups were similar in terms of age, race/ethnicity, gender, and mean time since schizophrenia onset.
At baseline and week 4, the investigators measured mean changes in adjusted Positive and Negative Symptom Scale (PANSS) scores to determine the study’s primary endpoint. They also used 8 secondary endpoints, including changes in scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS).
The mean total PANSS score was 101.4±8.4 in the SEP-363856 group with a mean change of −17.2 points at week 4, compared with 99.7±7.8 at baseline and a mean change of −9.7 points at week 4 in the placebo group (least-squares mean difference, −7.5 points; 95% CI, −11.9 to −3.0; P =.001). Reductions in the BNSS and CGI-S measures were in the same general direction, although the investigators did not adjust for multiple comparisons. There was a PANSS response at week 4 in 64.6% of the SEP-363856 group and 44.0% of the placebo group (odds ratio, 2.6; 95% CI, 1.4-4.9).
The most notable adverse events of SEP-363856 included somnolence and gastrointestinal symptoms, as well as 1 sudden cardiac death in the SEP-363856 group. The incidence of adverse events, including extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin, was generally similar in the SEP-363856 and placebo groups, with a difference of 2.5% or less for each event.
In an open-label extension study of 156 patients that lasted for 26 weeks, PANSS total score decreases were observed in both the SEP-363856 continuity group (n=77; change, -17.1±12.4) and placebo-to-SEP-363856 group (n=79; change, -27.9±16.4). There were 5 cases of adverse extrapyramidal symptoms.
However, the study was limited by the short duration of the trial and enrollment criteria that excluded adults older than 40 years of age and those who had more than 2 prior hospitalizations for exacerbation of schizophrenia.
“Longer and larger trials are necessary to determine the effects and safety of SEP-363856, as well as its efficacy relative to existing drug treatments for schizophrenia,” concluded the investigators.
Koblan KS, Kent J, Hopkins SC, et al. A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia. N Engl J Med. 2020;382:1497-1506.