BOSTON – A novel 5-HT2A receptor inverse agonist significantly improved psychotic symptoms in Parkinson’s disease patients without the worsening of motor symptoms that usually occurs with antipsychotic treatment, according to the results of a randomized, placebo-controlled phase III trial.*
In addition to benefiting patients, the drug eased caregiver burden, Dr. Clive Ballard said at the Alzheimer’s Association International Conference 2013.
Dr. Clive Ballard
"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, professor of age-related diseases at King’s College London.
Parkinson’s psychosis is a common manifestation of the disease, and about 50% of patients will experience it, he said. "It’s not just frequent. It’s impactful. It’s distressing for patients and for those caring for them. It’s also associated with more impairment, with mortality, and it’s the leading cause of nursing home placement."
Sadly, he noted that there are not many medical options for the problem. Most antipsychotics produce extrapyramidal symptoms, which worsen parkinsonism. Atypical antipsychotics may be well tolerated, but are not very effective against the delusions and hallucinations that can occur in Parkinson’s patients.
"The situation in Parkinson’s is even worse than it is in Alzheimer’s. At least we do have some options for Alzheimer’s psychosis, even if they’re not great," Dr. Ballard 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-HT2A inverse agonist, pimavanserin is in a unique drug class. According to Acadia Pharmaceuticals, the company developing the drug, it has the benefits of a 5HT2A agonist but doesn’t affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems.
"Previous studies suggested that it was well tolerated and had some signal of potential benefit in psychosis," Dr. Ballard said. But those trials posted an unusually large placebo effect as well, making the results "difficult to interpret."
Investigators in the pimavanserin phase III study made a number of study design changes to compensate for the placebo response. 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).
They also took part in a brief psychosocial intervention before randomization. "In this intervention, the caregiver spends about 10 minutes each day with the patient, enabling the patient to do an activity they enjoy." This reduces the placebo response rate when the study medication commences, Dr. Ballard said.
The study also centralized any robust key findings, which were interpreted by independent, blinded raters.
The primary endpoint was antipsychotic efficacy as measured using 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.
The patients were randomized to 40 mg of pimavanserin daily (n = 105) or to placebo (n = 94) for 6 weeks. They were assessed at baseline and at 2, 4, and 6 weeks. After the randomization period, they could join a long-term, open-label extension study at the 40-mg/day dose. Most of the patients completed the trial protocol (87 in the placebo group and 89 in the pimavanserin group). Seven placebo patients dropped out, including two because of an adverse event. Of 15 patients in the pimavanserin group who dropped out, 10 did so because of adverse events. One patient randomized to pimavanserin did not take the medication.
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; Dr. Ballard said this indicated that the study design compensated for a large placebo response. 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 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 also translated into a meaningful clinical benefit, Dr. Ballard added. By the SAPS-PD measurement, response rates were 42% and 65%, respectively – a significant difference.