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A new class of antipsychotic drug that does not bind to the dopamine D2 receptor significantly reduced symptoms for patients in an acute exacerbation of schizophrenia, researchers reported.

Among 245 adults with schizophrenia, the oral compound SEP-363856 significantly reduced symptoms at week 4 compared with placebo, as measured through mean changes in adjusted Positive and Negative Symptom Scale (PANSS) scores (difference -7.5 points, 95% CI -11.9 to -3.0, P=0.001), reported Kenneth S. Koblan, PhD, of Sunovion Pharmaceuticals in Marlborough, Massachusetts, and colleagues.

A similar portion of patients experienced extrapyramidal symptoms in the intervention and placebo arms (3.3% vs 3.2%), and mean changes in prolactin (-0.037 vs -0.036) and body weight (+0.3 vs -0.1 kg) were also similar, the team wrote in the .

One patient died from sudden cardiac arrest and was found to have coronary artery disease and pulmonary embolism in an autopsy report, the researchers noted.

"In the field of schizophrenia, treatment does work for positive symptoms, but the unmet medical needs ... are with respect to negative symptomatology as well as with respect to cognitive domains," Koblan told 乌鸦传媒 in an interview with a media relations person present.

First-generation and atypical antipsychotics, which work as antagonists to block the dopamine D2 receptor directly, are the standard of care for treating schizophrenia.

In contrast, , which the FDA gave breakthrough therapy designation in May 2019, is a trace amine-associated receptor 1 (TAAR1) and 5-HT type 1A agonist, Koblan said. This novel mechanism of action is thought to reduce negative symptoms as well as cognitive impairment.

The findings from the current mid-stage trial are "very welcome news, given the great need for new pharmacologic treatments for patients with schizophrenia," commented Donald C. Goff, MD, of the New York University School of Medicine in New York City, in an .

If replicated, this new drug class "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," Goff wrote.

It is also possible that SEP-363856 or other TAAR1-targeting drugs will be useful for cognitive impairment, depression, substance abuse, or other diagnosis beyond psychosis, Goff noted. Drugmaker with the agent for schizophrenia as well as phase II studies in Parkinson's disease psychosis.

Study Details, Further Findings

Patients under age 40 with Clinical Global Impression of Severity (CGI-S) scores of at least 4 and PANSS scores of at least 80 were enrolled in the trial. Patients with three or more prior hospitalizations for schizophrenia or who were receiving treatment with depot neuroleptic agents in the last 30 days were excluded.

Across 34 sites in Europe and North America, the 245 participants were assigned to a flexible dose of 50 mg or 75 mg nightly SEP-363856 or placebo for 4 weeks and followed up 1 week after discontinuation. Participants -- 81.6% of whom were white, and 63.7% were male -- had a mean age of 30.3 years. Baseline PANSS scores were slightly higher in the intervention than placebo group (101.4 vs 99.7) but this difference was nonsignificant.

In total, two-thirds of patients in the intervention arm received the higher dose (67.2%) at week 1, and this portion increased at week 2 (70.0%) and week 3 (72.5%), the researchers reported. Patients in the intervention and placebo arms were on some concomitant medications, including anxiolytics (32 vs 30) and hypnotics (10 vs 15).

Patients on SEP-363856 also showed improvements on the CGI-S scale at week 4 versus placebo (-0.5 points, 95% CI -0.7 to -0.2) as well as the Brief Negative Symptom Scale (-4.3 points, 95% CI -6.8 to -1.8) and the Montgomery Åsberg Depression Rating Scale (-4.3, 95% CI -6.8 to -1.8), although these scores were not adjusted for multiple comparisons and "no inferences can be drawn," Koblan and co-authors reported.

After the 4-week treatment period, 156 individuals were enrolled in an extension study. Among 77 patients initially in the intervention arm, PANSS scores were reduced by a mean -17.1 points at week 26, and patients initially on placebo who switched over saw a mean change of -27.9 points, the authors noted.

In this extension period, two patients experienced parkinsonism, whereas one patient each had dyskinesia, tremor, and restlessness, the team added.

One patient in the intervention arm and three in the placebo arm had worsening of schizophrenia in the trial. In the placebo group, one patient attempted suicide and there were two cases of suicidality, but no other serious adverse events occurred in the intervention.

Patients in the intervention arm had higher rates of somnolence (6.7% vs 4.8%), agitation (5% vs 4.8%), and nausea (5% vs 3.2%), although changes in weight parameters like glycated hemoglobin were similar between groups.

Because of the trial's relatively short time period and the exclusion of adults over 40, the generalizability is limited, the authors noted.

Koblan said drug developers are aiming to establish safety across 1 year of exposure through studies in the .

"We believe the benign safety profile of SEP-363856, both with respect to the extrapyramidal and cardiometabolic effects, if confirmed in larger studies, will move it to a very important place in the treatment paradigm," he said.

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