First-in-Class Schizophrenia Drug Safe,
Effective, Durable

Megan Brooks

April 16, 2020

A novel first-in-class antipsychotic that has a completely different mechanism of action than other currently available agents shows long-term efficacy and a good safety profile in patients with schizophrenia.

SEP-363856 (Sunovion Pharmaceuticals) was described as a potential "game changer" for schizophrenia after initial results were presented at the American Psychiatric Association 2019 Annual Meeting. The drug has been granted breakthrough therapy designation by the US Food and Drug Administration (FDA).

Additional data from this study, as well as results from a 6-month open-label extension trial were published online April 15 in The New England Journal of Medicine

"This is the first safety and effectiveness data for 6 months on therapy," lead author Kenneth Koblan, PhD, chief scientific officer at Sunovion, told Medscape Medical News.

To be able to show "durable" benefit and that the drug is "benign with respect to weight gain, lipids, and extrapyramidal side effects really provides us with a view of what could be a whole new class of molecules with respect to safety and efficacy," Koblan said.

Clinically Meaningful Improvement

Although the exact mechanism of action is unknown, SEP-363856 is thought to activate trace amine-associated receptor 1 (TAAR1) and serotonin 1A (5-HT1A) receptors. It does not bind to dopamine 2 (D2) or serotonin 2A (5-HT2A) receptors, which are thought to mediate the effects of currently available antipsychotics.

The original SEP 361-201 study was a phase 2, 4-week, double-blind, placebo-controlled trial comprised of 245 adults hospitalized with an acute exacerbation of schizophrenia. Patients were randomly allocated to receive SEP-363856 (50 mg or 75 mg once daily) or placebo.

Demographics of the treatment groups were similar at baseline. The SEP-363856 group included 120 patients (64% men; mean age, 30.0 years; Positive and Negative Syndrome Scale [PANSS] total score, 101.4). The placebo group included 125 patients (63% men; mean age, 30.6 years;
PANSS total score, 99.7).

After 4 weeks of treatment, patients taking SEP-363856 showed statistically significant and clinically meaningful improvement in PANSS total scores (the primary outcome) compared with patients taking placebo (–17.2 vs –9.7;
P = .001; effect size = 0.45).

SEP-363856 also led to significant improvement in several secondary outcomes, including overall illness severity as judged by the Clinical Global Impression of Severity score, PANSS positive subscale score, PANSS negative subscale score and PANSS general psychopathology subscale score.

A total of 156 patients, representing 81% of those who completed the 4-week trial, were enrolled in an extension study. They received treatment with SEP-363856 for 26 weeks.

Among 77 patients who had initially been assigned to SEP-363856 in the double-blind trial and then continued to receive treatment in the open-label extension, the mean change in PANSS total score from extension-study baseline to week 26 was −17.1 points.

Among 79 patients who had initially been assigned to placebo and then switched to open-label SEP-363856, the mean change in PANSS total score was −27.9 points.

Safety and tolerability of SEP-363856 were generally similar to placebo.

The active treatment and placebo arms were similar in number of patients who reported extrapyramidal symptoms (3.3% vs. 3.2%, respectively) and who used medications to treat extrapyramidal symptoms. The findings were also similar on movement disorder scales.

In addition, the novel drug had minimal effects on the protein hormone prolactin. "These findings are consistent with the absence of D2-receptor binding for SEP-363856," the investigators write.

Adverse events (AEs) occurring with an incidence of at least 2%, and with a higher incidence in SEP-363856 than placebo, were somnolence (6.7% vs 4.8%, respectively), agitation (5% vs 4.8%), nausea (5% vs 3.2%), diarrhea (2.5% vs 0.8%), and dyspepsia (2.5% vs 0%).

Two serious AEs that occurred in the SEP-363856 arm were worsening of schizophrenia and acute cardiovascular insufficiency in a 37-year-old woman, which led to her death 1 week after taking the first 50-mg dose of treatment.

However, the woman had a history of essential hypertension and at autopsy was found to have coronary artery disease and pulmonary embolism.

A large phase 3 program is now underway to confirm safety and efficacy of SEP-363856 for schizophrenia, Koblan said. It includes four studies that are open and enrolling.

Benefit Beyond Psychosis?

In an accompanying editorial, Donald Goff, MD, Nathan Kline Institute, NYU School of Medicine, New York City, writes that if the findings are replicated in future trials with more patients and of longer duration, "this class of drugs may provide a valuable new therapeutic option for psychosis and the negative symptoms of schizophrenia, possibly without the adverse effects associated with direct D2-receptor antagonism."

It is also possible that SEP-363856 will have effects "beyond D2-receptor antagonists and hence beyond the treatment of psychosis. Other potential therapeutic indications, including cognitive impairment, depression, and substance abuse, remain to be explored," Goff writes.  

This study "not only introduces a promising therapeutic compound but also provides additional evidence, on the basis of an agnostic drug-discovery process, that TAAR1 is a promising target," he adds.  

"This is very welcome news, given the great need for new pharmacologic treatments for patients with schizophrenia," Goff concludes.

The study was funded by Sunovion Pharmaceuticals. Koblan is an employee of the company. Disclosures for the other authors are listed in the original article. Goff reports having received grants and nonfinancial support from Avanir Pharmaceuticals and from Takeda.

N Engl J Med. Published online April 15, 2020. Abstract, Editorial

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