New Drug Reduced Parkinson's Psychosis

Abstract

A novel selective 5–HT2A inverse agonist in a phase III trial significantly improved psychotic symptoms in Parkinson's disease patients without the worsening of motor symptoms that usually occurs with antipsychotic treatment. The drug is now in a phase II feasibility trial in Alzheimer's patients, according to the manufacturer. Clive Ballard, PhD, professor of age–related diseases at King's College London, reported at the Alzheimer's Association International Conference last year that, in Parkinson's disease, pimavanserin benefited patients and eased caregiver burden. “By 4 weeks into the study, the benefit for caregivers began to appear, and it continued to increase” until the study ended at 6 weeks, said Dr. Ballard. About 50% of Parkinson's patients experience psychosis, “the leading cause of nursing home placement,” he said. The atypical antipsychotics quetiapine and clozapine are the only well–tolerated options, he said. “Quetiapine is ineffective, though, leaving only clozapine. It's well tolerated from a motor point of view, but it has other safety and tolerability issues that limit its use in clinical practice.” As a selective 5–HT inverse agonist, pimavanserin is in a unique drug class. According to Acadia Pharmaceuticals, the company developing the drug, it has the benefits of a 5HT agonist but doesn't affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems. Investigators in the phase III study made a number of study design changes to compensate for a high placebo response in earlier trials. In order to qualify for the trial, for example, patients had to have high baseline minimum scores on the Neuropsychiatric Inventory and the Scale for the Assessment of Positive Symptoms (SAPS). The primary endpoint was antipsychotic efficacy as measured by the SAPS–PD, a nine–item scale adapted from the hallucinations and delusions domains of SAPS. Secondary endpoints included the entire 20–item SAPS, the SAPS hallucinations and delusions subscores, the Clinical Global Impression (CGI) score, Unified Parkinson's Disease Rating Scale (UPDRS) domains I and II, and a measure of caregiver burden. At 6 weeks, patients in the active–treatment group had significantly greater improvement on the SAPS–PD, the primary endpoint. By 15 days, both groups had experienced a significant improvement from baseline. Thereafter, the curves separated, with the placebo group becoming stable. The pimavanserin group, however, continued to improve. By the study's end, there was a mean SAPS–PD decrease of 5.79 points in the active–drug group, significantly better than the mean 2.73–point decrease in the placebo group. This translated to a 37% improvement for the study drug, compared with a 14% improvement for placebo. The scores translated into a meaningful clinical benefit, Dr. Ballard added. By the SAPS–PD measurement, response rates were 42% and 65%, respectively—a significant difference. Changes on the CGI subscores were also significantly different. Patients in the placebo group experienced a mean decrease of less than half a point on the improvement subscale, compared with a decrease of about 1 point in the pimavanserin group. On the severity subscale, the placebo group stayed close to baseline, while the pimavanserin group decreased by about 1 point. About 27% of those taking placebo and 49% of those taking pimavanserin were considered responders. In an exploratory analysis examining pimavanserin's effect on sleep, the drug was associated with improvements in both nighttime sleep and daytime wakefulness on the Scale for Outcomes in Parkinson's Disease sleep measure, Dr. Ballard said. Based on the favorable results, Acadia announced that it had discontinued its work on a planned confirmatory phase III study. A New Drug Application for pimavanserin is in preparation, Dr. Ballard said. Dr. Ballard disclosed that he has received honoraria and consulting fees from the company.