Safety Profile of Adjunctive Pimavanserin in the ENHANCE Study, a Phase 3 Trial for the Potential Treatment of Schizophrenia in Patients With an Inadequate Response to Antipsychotic Treatment

Many patients with schizophrenia do not respond fully to antipsychotic treatment despite adherence. Evidence supporting polypharmacy is limited and adding another antipsychotic is associated with increased risks of adverse events. Pimavanserin is a highly selective serotonin 5-HT2A inverse agonist/antagonist approved for the treatment of Parkinson’s disease psychosis.

ENHANCE was a 6-week, randomized, double-blind, placebo-controlled phase 3 study of adjunctive pimavanserin (starting dose 20 mg daily) in adult patients aged 18–55 years with schizophrenia and inadequate response to prescribed AP (including aripiprazole, olanzapine, and risperidone). Safety was evaluated in all randomized patients who received ≥1 dose of study drug.

All randomized patients in ENHANCE (pimavanserin n=198; placebo n=198) were included in the safety analysis. Treatment-emergent adverse events (TEAEs) were reported in 39.9% pimavanserin and 36.4% placebo patients. The most frequent TEAEs in pimavanserin and placebo patients were headache (6.6% vs. 9.1%), somnolence (6.6% vs. 3.5%), and insomnia (5.1% vs. 3.5%). New-onset parkinsonism (Simpson–Angus Scale total score >3) and akathisia (Barnes Akathisia Rating Scale global clinical assessment of akathisia score ≥2) were reported in 1.7% vs. 2.2% and 2.2% vs 0.5% of pimavanserin and placebo patients, respectively. There were no reports of dyskinesia in either group. Two (1.1%) pimavanserin patients had postbaseline QTcF prolongation >60 msec; there were no cases of QTcF prolongation >500 msec or torsades de pointes in either group. Hypotension was reported in 1 patient in each treatment group. Weight increase ≥7% from baseline was reported for 2.6% pimavanserin and 1.6% placebo patients.