The novel antipsychotic agent SEP-363856 (Sunovion Pharmaceuticals) has a significant and ongoing effect on negative symptoms in patients with schizophrenia, new research shows.
Results of a phase 2 placebo-controlled trial show SEP-363856 significantly decreased total scores on the Brief Negative Symptom Scale (BNSS), and lowered subscale scores for such symptoms as alogia and asociality, compared with placebo.
The active-treatment group also showed significantly lower scores on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). During an open-label extension of the study, both BNSS total scores and PANSS negative symptom scores continued to decrease.
Overall, the results “provide further confirmation of the effectiveness of SEP-363856 in treating schizophrenia,” study investigator Kenneth Koblan, PhD, Sunovion, told Medscape Medical News.
He added that the compound also showed “a favorable safety and tolerability profile that is differentiated from first and second generation antipsychotics, and which is consistent with the absence of D2-receptor binding.”
The findings were presented at the virtual Congress of the Schizophrenia International Research Society (SIRS) 2021.
FDA Breakthrough Designation
SEP-363856 has a completely different mechanism of action from currently available antipsychotics.
In May 2019, it was granted breakthrough therapy designation by the US Food and Drug Administration (FDA) as a novel treatment for patients with schizophrenia.
Phase 2 data published in the New England Journal of Medicine in 2020 showed it achieved significant and clinically meaningful improvements in PANSS total scores after 4 weeks in patients hospitalized with an acute exacerbation of schizophrenia. It also showed durable effects out to 26 weeks.
In the current analysis, the investigators focused on negative symptoms, both in the initial acute treatment phase and an open-label extension.
They analyzed data from the previous phase 2 trial using a validated Uncorrelated PANSS Score Matrix (UPSM) transformation of the PANSS to isolate the effects of the drug on apathy/avolition and deficit of expression. They also used the BNSS.
Patients aged 18 to 40 years with an acute exacerbation of schizophrenia were randomly assigned to receive either 50 mg or 75 mg of SEP-363856 per day (n = 120) or matching placebo (n = 125) for 4 weeks. Completers were eligible for enrollment in a 26-week phase 2 extension study of 25 mg, 50 mg, or 75 mg of SEP-363856 per day.
The mean age of the participants was 30 years, and 64% were men. The treatment groups were balanced in terms of demographics.
The BNSS total score decreased significantly with SEP-363856 over placebo during the 4-week acute treatment period, at a mean reduction of 7.1 vs 2.7, or an effect size of 0.48 (P < .001).
Scores on the PANSS negative subscale also decreased significantly with the active drugs, with an effect size of 0.37 vs placebo (P < .05), as did scores on the UPSM apathy/avolition and deficit of expression subscales (effect size, 0.32; P < .05 for both).
In addition, there were significant reductions with SEP-363856 over placebo for the BNSS alogia, asociality, anhedonia, avolition, and blunted affect subscales (P < .05 for all comparisons) but not for the distress subscale.
During the open-label extension, mean BNSS total scores continued to decrease for the SEP-363856 group, at an average reduction vs extension enrollment across the whole cohort of 11.3.
PANSS negative symptom scores also decreased by an average of 5.2 points, while UPSM apathy/volition scores decreased by 0.4 points on average. UPSM deficit expression scores decreased by 0.5 points.
When the researchers restricted the analysis to those who received SEP-363856 during the acute treatment phase and then continued using the drug during the open-label extension, they found BNSS total scores decreased by an additional 8 points.
Similarly, PANSS negative symptom scores decreased during the open-label extension by an average of 4 points. For UPSM apathy/avolition and deficit of expression, the additional decrease was 0.3 points on average.
In addition, an analysis of the drug’s safety and tolerability showed that, compared with the commonly prescribed antipsychotic lurasidone, it had a significantly lower risk of adverse effects. In addition, the drug was not associated with extrapyramidal symptoms and had no adverse cardiometabolic effects, Koblan reported.
Still in Development
Commenting on the findings for Medscape Medical News, René S Kahn, MD, PhD, chair of the department of psychiatry, Icahn School of Medicine at Mount Sinai, New York City, noted that although the results showed that the drug had a “nice effect” on negative symptoms, it’s still in development.
Kahn, who was not involved in the research, said “we’ve all seen” drugs that were extremely promising in phase 2 trials that have then failed in phase 3 trials. “The proof of the pudding is phase 3, and we have to wait and see,” he added.
“Obviously I hope it’s going to work out, because we are in desperate need of new drugs, especially with a new mechanism of action and not ‘me too’ drugs. And this definitely not a ‘me too’ drug,” Kahn said. However, “we’ll have to wait.”
He noted that psychosis is often the primary focus of schizophrenia management. However, he added, cognitive and negative symptoms are also “very relevant” to the disorder.
“In fact, both of them may be more important in determining the long-term outcome of schizophrenia than psychosis, [and] most of the antipsychotics that we currently have are not very effective against negative symptoms,” he said.
“So it would really be a breakthrough if we have a drug that is really effective not only against positive psychotic symptoms, but also against negative and possibly cognitive, symptoms,” Kahn added.
Commenting on the drug’s safety, Kahn said there is a need for head-to-head studies of active drugs before any firm conclusions can be drawn.
However, he noted the exploratory analysis suggests it has a different side effect profile compared to other medications on the market.
The study was supported by Sunovion Pharmaceuticals Inc. Koblan and his co-investigators are employees of Sunovion Pharmaceuticals.
Congress of the Schizophrenia International Research Society (SIRS) 2021: Abstracts S96 and M1. Presented April 18, 2021.