SAN FRANCISCO — The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to a potentially first-in-class psychotropic agent with a completely different mechanism of action of currently available antipsychotic agents.
The drug now known as SEP-363856 is being developed by Sunovion Pharmaceuticals Inc and PsychoGenics Inc.
"Breakthrough Therapy Designation underscores the potential of SEP-363856 as a novel treatment for patients with schizophrenia, for whom few major advances in treatment have occurred since the advent of antipsychotic pharmacotherapy in the 1950s," Antony Loebel, MD, president and CEO at Sunovion, said in a statement.
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 antipsychotic mechanisms.
"I think 60 to 70 years of antipsychotic drug development has focused on D2. The ultimate goal would be to get an antipsychotic that is efficacious but not target the D2 receptor," Robert Goldman, PhD, head of global clinical research and medical affairs at Sunovion, told Medscape Medical News.
"SEP-363856 does not work through direct D2 antagonism and the [phase 2] study showed that it is efficacious and has an adverse event profile similar to placebo," said Goldman.
The FDA granted breakthrough designation based on findings of a pivotal phase 2 trial (SEP 361-201) as well as data from a 6-month, open-label, safety and tolerability extension study (SEP 361-202).
The results of SEP 361-201 were presented here at the American Psychiatric Association (APA) 2019 Annual Meeting.
Clinically Meaningful Improvement
The phase 2 trial was a 4-week, double-blind, placebo-controlled trial involving 245 adults hospitalized with an acute exacerbation of schizophrenia. Patients were randomly allocated to SEP-363856 (50 mg or 75mg once daily) or placebo.
Study treatment groups were similar at baseline. The SEP-363856 group included 120 patients (64% male, mean age 30.0 years, and Positive and Negative Syndrome Scale [PANSS] total score of 101.4). The placebo included 125 patients (63% male, mean age 30.6 years, and PANSS total score of 99.7).
After 4 weeks, patients taking SEP-363856 showed statistically significant and clinically meaningful improvement in the PANSS total score (primary outcome) compared with 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–Severity (CGI-S) score (–1.0 vs –0.5; P < .001; effect size = 0.52), PANSS positive subscale score (–5.5 vs –3.9; P = .019; effect size = 0.32), PANSS negative subscale score (–3.1 vs –1.6; P = .008; effect size = 0.37) and PANSS general psychopathology subscale score (–9.0 vs –4.7; P < .001; effect size = 0.51).
Safety and tolerability of SEP-363856 were generally similar to placebo. Notably, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2-based mechanism of action, Goldman said.
Adverse events occurring with an incidence ≥ 2% (with SEP-363856 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%).
Results of the extension study have not been publicly presented yet.
"The remarkable thing about this drug is that it is not a dopamine antagonist, so it would be the first antipsychotic that doesn't work through the dopamine system," René S Kahn, MD, PhD, chair of the department of psychiatry, Icahn School of Medicine at Mount Sinai, New York City, noted in an interview with Medscape Medical News.
"So far the results are impressive. If it works in phase 3 testing, it's really going to be a game changer," said Kahn, who was not involved in the study.
"Not only will it be good to have a new drug for schizophrenia," added Kahn, "but scientifically this work is also extremely important because we may learn more about the etiology of schizophrenia and what other systems in the brain might be involved and that may lead to other drugs and understanding the illness."
SEP-363856 is also being studied as a potential treatment for Parkinson's disease psychosis.
The study was funded by Sunovion Pharmaceuticals. Goldman is an employee of the company. Kahn has financial relationships with Alkermes, Merck, Minerva Neuroscience, Lundbeck, Otsuka, Teva, and Janssen.
American Psychiatric Association (APA) 2019: Abstract P7-066. Presented May 21, 2019.
Medscape Medical News © 2019
Cite this: Megan Brooks. 'Game Changer' for Schizophrenia on the Horizon? - Medscape - May 22, 2019.