Acadia’s Pimavanserin Narrowly Hits Primary Endpoint in Schizophrenia Study

ACADIA Pharmaceuticals, based in San Diego, announced positive top-line data from its Phase III ADVANCE trial of pimavanserin in schizophrenia. The trial studied the efficacy and safety of adjunctive pimavanserin dosages in patients with predominantly negative symptoms of schizophrenia who had adequate control of positive symptoms with their current antipsychotic treatment.

The drug showed a statistically significant improvement in the trial’s primary endpoint, the change from baseline to week 26 on the Negative Symptoms Assessment-16 (NSA-16) total score compared to placebo. A greater improvement in the NSA-16 total score was 53.8% in the pimavanserin cohort compared to placebo. However, the drug did not hit the key secondary endpoint, the Personal and Social Performance (PSP) scale.

Company shares were down 2% after the announcement, likely because expectations for greater efficacy were high.

The company indicates it will start a second pivotal trial with the 34 mg dose of the drug in the first half of next year. More results from the ADVANCE study will be presented at future scientific meetings.

“The negative symptoms of schizophrenia such as social withdrawal, apathy, anhedonia, loss of motivation, blunted affect, and restricted speech contribute significantly to low function levels, long-term disability, and increased caregiver burden,” said Henry A. Nasrallah, professor of Psychiatry, Neurology, & Neuroscience, and director of Neuropsychiatry and Schizophrenia Programs at the University of Cincinnati College of Medicine. “Historically, it has been a challenge for clinicians to treat and significantly improve the negative symptoms of schizophrenia. There are no FDA-approved treatments indicated for the treatment of the negative symptoms of schizophrenia and there remains a serious and significant unmet need.”

The drug was well-tolerated with high completion rates. About 86% of patients in both the pimavanserin and placebo cohorts had similar rates of adverse events, with 39.8% in the pimavanserin group and 35.1% in the placebo group. There were no clinically significant differences observed in vital signs, weight, metabolic syndrome or extrapyramidal symptoms between the two groups. Serious side effects were reported in 2.0% of patients on the drug and 0.5% in the placebo group. Discontinuation of the trial from adverse events was low, 5.0% for pimavanserin and 3.0% for placebo.

Pimavanserin is a selective serotonin inverse agonist and antagonist that preferentially targets 5-HT2A receptors. These receptors are believed to play an important role in psychosis, schizophrenia, depression and other neuropsychiatric disorders.

About 1% of the U.S. population develops schizophrenia in their lifetimes, according to the National Mental Health Institute. The disease is chronic, debilitating, and can be progressive. It is marked by disturbances in thinking, emotional reaction, and behavior. The symptoms may include hallucinations and delusions. Negative symptoms include loss of interest, emotional withdrawal, and cognitive disturbances.

Between 40 and 50% of schizophrenics have predominant negative symptoms. Currently available antipsychotic therapies target positive symptoms, but the patients typically stay functionally impaired as the result of negative symptoms, cognitive problems and social function.

“The positive efficacy results and favorable tolerability profile of pimavanserin observed in the ADVANCE study represents an important step forward for patients and their families, given the lack of currently approved treatment options for the negative symptoms of schizophrenia,” said Serge Stankovic, Acadia’s president. “We are pleased with the positive efficacy findings in this difficult to treat patient population and identified the 34 mg dose as demonstrating greater efficacy with favorable tolerability. We look forward to initiating a second pivotal study with the 34 mg dose during the first half of 2020.”