Treatment with an investigational non-D2-receptor-binding agent led to significant reductions in psychosis and negative symptoms in adults with an acute exacerbation of schizophrenia, researchers reported.
In a 4-week, flexible-dose trial done in the U.S. and Europe, 120 patients given the oral agent SEP-363856 started with a mean baseline total score on the Positive and Negative Symptom Scale (PANSS) of 101.4 and saw a mean change of −17.2 points at week 4. Among 125 patients assigned to placebo, the mean baseline total score on PANSS was 99.7, and they saw a mean change of −9.7 points at week 4 (least-squares mean difference −7.5 points, 95% CI −11.9 to −3.0, P=0.001), according to Kenneth S. Koblan, PhD, of Sunovion Pharmaceuticals in Marlborough, Mass., and co-authors.
SEP-363856 “does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT) receptors,” the authors explained in the New England Journal of Medicine, and “may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia.
Koblan and co-authors also found that treatment with the agent in patients who met the DSM-5 criteria for schizophrenia for at least 6 months, and at study screening had an acute exacerbation of psychotic symptoms with a duration of ≤2 months, experienced reductions in Clinical Global Impressions Severity (CGI-S) and Brief Negative Symptom Scale (BNSS) scores at week 4, although those “results were not adjusted for multiple comparisons.”
And there were some adverse events (AEs) with the study agent, including one case of sudden cardiac death, they noted.
Still, the study findings offer a promising therapeutic compound, “along with more evidence… that TAAR1 is a promising target. This is very welcome news, given the great need for new pharmacologic treatments for patients with schizophrenia,” stated Donald C. Goff, MD, of the Nathan Kline Institute at the New York University School of Medicine in New York City, in an editorial accompanying the study.
He explained that TAAR1 modulates “dopaminergic, serotoninergic, and glutamatergic transmission in the brain and regulation of metabolic and immune function in the periphery,” adding that a selective TAAR1 agonist improved cognitive function on tests of executive functioning in an animal model, and pointed to a potential benefit in patients with psychosis, negative symptoms, and depression.
The trial was designed by the commercial developer of SEP-363856, which provided the agent and the placebo. Included patients (mean age 30.3 years; 81.6% white; 63.7% male; 5 years for mean time since onset of schizophrenia) had a CGI-S score of at least 4 and a total PANSS score of at least 80. Exclusion criteria were three or more prior hospitalizations for treatment of an acute exacerbation of schizophrenia and receiving treatment with depot neuroleptic agents that had not been discontinued 30 days before screening.
The study agent or placebo were given once daily at an oral dose of 50 mg/day at bedtime on days 1 to 3. A dose adjustment to a maximum of 75 mg/ day of either was an option on day 4 and at subsequent regularly scheduled weekly trial visits. A dose reduction back to 50 mg/day also was permitted at any time, generally because of unacceptable AEs, the authors explained.
Additionally, treatment with anticholinergic agents or propranolol was allowed for akathisia and movement disorders. Lorazepam, temazepam, eszopiclone, or their equivalents were permitted as needed for anxiety or insomnia, but not within 8 hours before any trial assessment, according to Koblan’s group.
At trial completion, patients had the option to enroll in an outpatient study and receive open-label treatment with SEP-363856 in flexible doses of 25 mg, 50 mg, or 75 mg per day for 26 weeks, which is when the final assessment was done. The authors reported that the mean duration of exposure to SEP-363856 or placebo was about 25 days.
They also reported the following for the secondary endpoints:
- CGI-S score: −1.0 for SEP-363856 (50 mg or 75 mg) and −0.5 for placebo for least-squares mean change from baseline at week 4 (−0.5 least-squares mean difference, 95% CI −0.7 to −0.2).
- BNSS total score −7.1 and −2.7 (−4.3, 95% CI −6.8 to −1.8).
However, the authors once again stressed that “No inferences can be made from the results for the secondary end points because there was no plan for adjustment for multiple comparisons,” although Goff stated that “the moderate effect size of 0.45 (SEP-363856 versus placebo) for a reduction in overall symptoms compares favorably with that of second-generation antipsychotic drugs (0.51).”
Severe AEs occurred in 5.8% in the SEP-363856 arm and in 1.6% in the placebo arm, while the incidence of insomnia was 3.3% in the former group and 10.4% in the latter. Concomitant hypnotics were used by 8.3% and 12.0%, respectively.
“Treatment with SEP-363856, as compared with placebo, was associated with an improvement in sleep quality,” the authors noted.
As for the two serious AEs that occurred in the study agent arm, they were worsening of schizophrenia and acute cardiovascular insufficiency that resulted in sudden death 7 days after the first 50-mg dose of SEP-363856. But the woman (age 37 years) “had a history of essential hypertension and was found on autopsy to have coronary artery disease and pulmonary embolism,” the authors stated.
According to scores on the Columbia-Suicide Severity Rating Scale, no suicidal ideation or behavior was seem among patients taking the study agent versus two instances of suicidality among placebo patients.
Short-term treatment with the study agent was linked with a mean increase in body weight of 0.3 kg, Koblan’s group found, but weight gain is also a problem AE with some newer, second-generation dopamine D2-receptor blockers, Goff noted.
Finally, around 21% of patients in both groups discontinued treatment, but over 80% of the patients enrolled in the extension trial, and they continued to see benefits in PANSS scores with similar incidence of AEs, the authors reported.
Study limitations included its short duration, and exclusion of people over age 40 years, as well as those with more than two prior hospitalizations for exacerbation of schizophrenia, which ultimately limits how generalizable the findings are.
“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,” the authors concluded. SEP-363856 has been tested in schizophrenia in numerous other trials, and is slated for testing in currently recruiting trials in Japan and the U.K.
SEP-363856, a non–D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the Positive and Negative Symptom Scale total score than placebo.
The investigational agent had a moderate effect size versus placebo for a reduction in overall symptoms but still compared favorably with that of second-generation antipsychotic drugs.
Shalmali Pal, Contributing Writer, BreakingMED™
The study was funded by Sunovion Pharmaceuticals.
Koblan reported relationships with Sunovion Pharmaceuticals and a pending patent for methods of treating schizophrenia (WO 2018/151861).
Goff reported grants and support from Avanir Pharmaceuticals and Takeda.
Cat ID: 146
Topic ID: 87,146,730,130,192,146,57,921,925
Koblan KS, et al “A non–D2-receptor-binding drug for the treatment of schizophrenia” N Engl J Med 2020; 382: 1497-1506.
Goff DC “Promising evidence of antipsychotic efficacy without dopamine D2-receptor binding” N Engl J Med 2020; 382: 1555-1556.