Conference Coverage
SAN DIEGO—Pimavanserin provides statistically significant and clinically meaningful benefit on measures of Parkinson’s disease psychosis, according to data from two phase III trials presented at the 19th International Congress of Parkinson’s Disease and Movement Disorders. In addition, two open-label trials suggest that pimavanserin may offer long-term benefit with a safety and tolerability profile that is appropriate for chronic use.
Studies have shown that Parkinson’s disease psychosis is a risk factor for premature nursing home placement and mortality. Antipsychotics used to treat Parkinson’s disease psychosis may worsen motor symptoms, lack consistent efficacy, or require regular blood monitoring. With these concerns in mind, researchers developed pimavanserin, a small-molecule selective serotonin 5-HT2A inverse agonist, for the treatment of Parkinson’s disease psychosis.
Pooled Data Show a Clinically Relevant Change
To evaluate the drug’s efficacy and tolerability, Roger Mills, MD, Executive Vice President of Development and Chief Medical Officer at Acadia Pharmaceuticals in San Diego, and his research colleagues analyzed pooled data from two studies. The integrated data set included a six-week, placebo-controlled study that was conducted entirely in North America. In that study, a centralized rater who was masked to treatment assignment assessed patients by live video feed. Pimavanserin demonstrated highly significant antipsychotic efficacy, as measured using the nine-item Parkinson’s disease-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD). The researchers also observed highly significant improvement in the Clinical Global Impression (CGI) Improvement and Severity scales, and significant improvements in nighttime sleep, daytime wakefulness, and caregiver burden. The study was published in Lancet.
The integrated data set also included data from the North American subgroup of an international phase III study. In that study, a robust placebo response precluded statistical separation, said Dr. Mills. The data contained signals of efficacy for the 40-mg dose of pimavanserin, however, particularly in the North American subgroup. In the North American subgroup, centralized raters assessed the 20-item SAPS Hallucinations and Delusions domains by live video feed, whereas site-based raters assessed patients in other parts of the world. The different assessment methods likely caused a treatment-by-region interaction, said Dr. Mills.
In the combined sample of 268 patients, 133 received placebo and 135 received pimavanserin. Participants who received 40 mg of pimavanserin per day demonstrated a 6.21-point improvement in psychosis at Day 43, as assessed using the SAPS-PD, compared with a 3.34-point improvement for those who received placebo. The difference of 2.87 points was highly significant and clinically meaningful. “Importantly, treatment effect was seen on each of the hallucination and delusion symptom domains, as demonstrated by statistically significant improvements on the SAPS-H and SAPS-D domain scores,” said Dr. Mills.
In addition, the proportion of subjects who achieved a decrease in the SAPS-PD score of at least three points was significantly greater among those who received pimavanserin, compared with those who received placebo (64% vs 41%). The literature has established a 2.33-point change on this scale as clinically relevant. Across studies, pimavanserin did not worsen motor symptoms, as measured using the Unified Parkinson’s Disease Rating Scale, and was otherwise safe and well tolerated.
Evaluation of Long-Term Use Shows a Durable Effect
A separate analysis of two open-label studies examined the durability of pimavanserin’s antipsychotic effect, as well as the drug’s tolerability. Stuart Isaacson, MD, Director of the Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida, and Clinical Associate Professor of Neurology at Herbert Wertheim College of Medicine in Miami, and his research colleagues analyzed data from two studies that included 498 patients with Parkinson’s disease psychosis who were evaluated for a median period of approximately 15 months.
After completing placebo-controlled trials, patients were eligible to enter open-label studies and receive pimavanserin once daily for as long as the investigators considered it beneficial. In a phase II open-label study with 39 participants who received 20, 40, or 60 mg of pimavanserin, CGI-Severity improved through Week 24, and improvement was maintained through Week 72, when 55% of subjects remained in the study. The 34% of subjects who continued through Week 96 had further improvement in CGI-Severity.
In an ongoing phase III open-label study, 459 subjects who enrolled at 114 international sites received 40 mg of pimavanserin once daily. SAPS-PD was assessed at Week 4, and CGI-Severity, CGI-Improvement, and caregiver burden score were assessed at all follow-up visits. Subjects who had been receiving 40 mg of pimavanserin had sustained improvement on the SAPS-PD at Week 4 (ie, 10 weeks from core study baseline). Subjects who had been receiving placebo or 10 mg of pimavanserin had improvement during the first four weeks of the extension trial that was similar in overall magnitude to that seen for patients receiving a 40-mg dose during the randomized controlled trial. Subjects who switched from 20 mg of pimavanserin to 40 mg of pimavanserin did not show further improvement in the extension trial.
