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Adjunctive treatment with the atypical antipsychotic pimavanserin (Nuplazid) succeeded in treating negative symptoms of schizophrenia, according to the ADVANCE study.

In the 26-week phase II study, people on pimavanserin added to a main antipsychotic saw a significant improvement in the Negative Symptom Assessment-16 (NSA-16) total score (least squares mean -10.4 vs -8.5, P=0.043, effect size 0.21), reported Dragana Bugarski-Kirola, MD, of Acadia Pharmaceuticals in Princeton, New Jersey, at the virtual Psych Congress 2020 meeting.

By the end of the trial, those receiving the final dose of 34 mg of pimavanserin on top of their antipsychotic saw significant improvement in negative symptoms (least squares mean -11.6 vs -8.5 with placebo, unadjusted P=0.0065, effect size 0.34).

However by week 26, difference in the Personal and Social Performance scale score was not significant between the two groups.

"Treatment of negative symptoms of schizophrenia remains a high unmet need as there are no currently approved treatments," Bugarski-Kirola noted during her presentation.

She explained that pimavanserin acts as a selective inverse agonist of the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor, with lower activity at the 5-HT2C receptor. The drug received FDA approval in 2016 for hallucinations and delusions associated with Parkinson's disease psychosis.

The ADVANCE study randomized 403 patients 1:1 from North America and Europe with predominant negative symptoms of schizophrenia for at least 1 year to either pimavanserin or placebo in addition to their main antipsychotic. All participants had a sum score of at least 20 on the Positive and Negative Syndrome Scale (PANSS) Marder negative factor items at baseline. About 93% of the participants were white, and the majority were male.

The main antipsychotics used were oral or long-acting injectable aripiprazole (Abilify, Aristada), asenapine (Saphris), brexpiprazole (Rexulti), cariprazine (Vraylar), lurasidone (Latuda), olanzapine (Zyprexa), and oral or long-acting injectable risperidone (Risperdal). Those on a long-acting injectable had no dose changes 16 weeks prior to screening, while those on oral agents had no dose changes 4 weeks before screening. The most popular main antipsychotics were risperidone, aripiprazole, and olanzapine.

For the initial 8 weeks, those in the treatment group were started on 20 mg of daily pimavanserin, which was subsequently titrated up to 34 mg or down to 10 mg daily after 2 weeks. From weeks 8 through 26 of the trial, participants were on a fixed dose of pimavanserin. By the final dosing, a little more than half of the participants were on a 34 mg dose of pimavanserin, while 44% were on a dose of 20 mg. Only three participants were on a dose of 10 mg.

There were slightly more treatment-emergent adverse events reported in the pimavanserin group versus the placebo group (39.8% vs 35.1%), with the most common events being headache and somnolence.

"No new safety signals were observed with additional pimavanserin to other antipsychotics," Bugarski-Kirola concluded.

Acadia previously tested pimavanserin for schizophrenia in the phase III , which included patients with both positive and negative symptoms who had persistent inadequate response to existing therapy. The study failed to meet its primary endpoint, but did show improvements for negative symptoms.

The company has also investigated pimavanserin for , and the FDA accepted a supplemental new drug application for this indication in July 2020. The drug is also currently investigated as an add-on for the treatment of major depression.

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