Novel Agent Safe, Effective for Parkinson's Psychosis

Caroline Cassels

April 17, 2013

San Diego, California — A novel, first-in-class, nondopaminergic agent that selectively blocks serotonin 5-HT2A is safe and effective for the treatment of Parkinson's disease psychosis (PDP), new research suggests.

Confirming previously released topline results and reported by Medscape Medical News at that time, the phase 3 placebo-controlled trial showed that the selective nondopaminergic 5-HT2A receptor agonist pimavanserin was significantly better than placebo at reducing PDP.

"There was consistent efficacy across different analyses…If we look at change from baseline there was a 37% improvement on SAPS-PD [Scales to Assess Positive Symptoms in Parkinson's Disease] in the pimavanserin group and 14% in the placebo group," principal investigator Jeffrey Cummings told delegates here attending the American Academy of Neurology (AAN) 65th Annual Meeting.

"The results of this study suggest that a selective, non-dopaminergic-based therapy has the potential to transform the standard of care by providing an effective, safe and well tolerated treatment for patients suffering from this large unmet medical need," Dr. Cummings noted in a release.

A common and distressing symptom, PDP is a leading cause of institutionalization in patients with Parkinson's disease. According to investigators, it complicates disease management and has been linked to increased morbidity, incident dementia, and mortality.

Current antipsychotics, they add, lack efficacy and/or have considerable tolerability and safety concerns.

The researchers point out that pimavanserin has demonstrated antipsychotic effects and good tolerability in previous phase 3 trials. However, they add that a robust placebo effect precluded statistical separation.

For the current trial, known as the -020 study, investigators recruited 199 nondemented outpatients who were stable on PD medication and who had moderate to severe PDP. After a 2-week screening period in which brief psychosocial therapy adapted for PD (BPST) was offered, study patients were randomly assigned to receive 40 mg of pimavanserin once daily or placebo for 6 weeks.

The study's primary endpoint was change from baseline in SAPS-PD, as assessed by independent raters. Secondary endpoints included the Clinical Global Impression Severity (CGI-S) scale, the Clinical Global Impression Improvement (CGI-I) scale, and a CGI-I responder analysis.

In addition, motor tolerability was measured by change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) parts 2 and 3.

At study conclusion there was a 3.06-point treatment difference in SAPS-PD scores between the 2 study groups, indicating a "highly significant and clinically meaningful antipsychotic effect" for pimavanserin, said Dr. Cummings.

He noted that these findings in the primary endpoint were supported by similar, significant improvements in secondary outcomes, including CGI-S, and in measures of caregiver burden, night-time sleep, and daytime wakefulness.

"Importantly, regardless of whether assessments were performed by independent blinded raters, site investigators or caregivers, clear benefits were observed and clinical measures were well aligned," said Dr. Cummings.

The most common adverse events were urinary tract infections (11.7% placebo vs 13.5% pimavanserin) and falls (8.5% placebo vs 10.6% pimavanserin).

Importantly, the researchers note that pimavanserin met the secondary endpoint of motor tolerability, with both groups showing improvements in combined UPDRS 2 and 3 scores (-1.69 for placebo and -1.40 for pimavanserin).

The investigators report that more than 90% of patients who completed the 6-week trial opted to roll over into the ongoing open-label safety extension study.

Since these findings were presented, the drug's manufacturer has announced that it has met with the US Food and Drug Administration. It has been agreed that the data supporting the pimavanserin as a potential treatment for PDP are sufficient to support a new drug application for this indication.

According to a company release, this means the company will no longer conduct a phase 3 trial to confirm these results.

"This represents another important step toward our goal of bringing pimavanserin to the market as an innovative therapy for Parkinson's patients who suffer from the psychosis frequently associated with this disease," Acadia's chief executive officer, Uli Hacksell, PhD, said in a statement.

American Academy of Neurology (AAN) 65th Annual Meeting. Emerging Science Session Abstract 004. Presented March 15, 2013.