ARTICLE IN BRIEF
Pimavanserin, a serotonin inverse agonist, was found to effectively reduce psychotic symptoms compared with placebo in Parkinson's disease patients, without motor worsening or other significant adverse effects.
Psychosis affects half of people with Parkinson's disease (PD) at some point in the course of the disease. It is a major source of distress for both patient and caregiver, and increases the risk for nursing home placement. Clozapine, the only medication proven to work on PD psychosis without worsening motor symptoms, carries significant risks and requires close monitoring. Thus, a safe and effective treatment for psychosis in PD is a major unmet need.
Now, a new study published in the Oct. 31 online edition of The Lancet, shows that pimavanserin, a serotonin inverse agonist, effectively reduces psychotic symptoms compared with placebo in PD patients, without motor worsening or other significant adverse effects, a result one expert not involved in the trial called “a breakthrough.” Based on these results, the drug is likely to be submitted for approval to the United States Food and Drug Administration within a year.
The trial enrolled almost 200 PD patients with documented psychosis across the United States and Canada, and was led by Clive Ballard, MD, professor of medicine at King's College in London. Patients were initially screened for eligibility based on having a combined score on the Neuropsychiatric Inventory of at least a 6, or a score of 4 for either delusions or hallucinations, the two most common manifestations of psychosis in PD. Patients with dementia diagnosed before or concurrent with PD were excluded, as were those with post-surgical psychosis.
All screened patients entered a two-week non-pharmacologic period during which they participated in 10 to 15 minutes of social interactions daily, such as conversation or looking at photographs, with their primary caregiver, based on their interests and abilities. The goal of the intervention was to screen out those individuals whose psychotic symptoms declined in response, in an attempt to reduce the magnitude of the placebo effect during the pharmacologic phase of the trial.
While this intervention may seem too much like normal life to have any effect at all, Dr. Ballard noted, “When patients and caregivers are stressed, they become very illness-focused, and often forget to talk to one another other.” Simply reinstating some element of normalcy was enough to improve symptoms for a small percentage of patients. “The other nice thing about that design is that it mirrors what is in all the best practice guidelines, which is that we should try non-pharmacologic treatment first.”
Final eligibility for the trial was determined by the patient's score on the Scale for the Assessment of Positive Symptoms, adapted for Parkinson's disease (SAPS-PD), a nine-item scale drawn from the hallucinations and delusions domains of the SAPS. It includes seven items assessing individual symptoms, plus a global hallucinations item and a global delusions item. Patients eligible for the trial had to score at least 3 on the hallucinations or delusions global item, and at least 3 on at least one other non-global item. SAPS-PD Scores at baseline were 14.7 for those randomized to placebo, and 15.9 for those randomized to pimavanserin.
Patients received either placebo or once-daily pimavanserin at 40 milligrams for six weeks. The primary outcome was change on the SAPS-PD at day 43. Assessments were performed by live videoconference by blinded raters. “There was quite a lot of rigor in the training, to insure inter-rater reliability,” Dr. Ballard noted.
One hundred ninety-nine patients were randomized, 94 to placebo and 104 to pimavanserin, and about 90 in each group completed the trial; 10 had dropped out due to adverse events. There were more withdrawals due to adverse events in the pimavanserin group, including six who withdrew due to psychosis. The drug also was associated with a slight elongation of the QTc interval, but without any clinical consequence. There was no change in motor function, as assessed by the Unified Parkinson Disease Rating Scale. [For more detail on side effects of the therapy, see “Treatment- Emergent Adverse Events.”]
Treatment with pimavanserin led to a decline in the SAPS-PD of 5.8 points (37 percent improvement from baseline), versus 2.7 points for placebo (14 percent improvement, p=0.001). The scale was designed so that a change of 2.3 points represented a clinically meaningful difference, according to its developers. Treatment benefit was independent of age, sex, and cognitive status. Benefits were also seen on a variety of secondary measures, including clinical global improvement as judged by the investigator, night-time sleep, daytime wakefulness, and caregiver burden.
The results, Dr. Ballard said, indicate that pimavanserin is able to provide an important benefit to PD patients with psychosis, without worsening motor ability or requiring intensive safety monitoring. “I think potentially this provides a first-line pharmacological treatment that is safe and effective,” he said.
Based on these trial results, the sponsor of the trial, Acadia Pharmaceuticals, plans to submit a New Drug Application to the FDA in late 2014. Trials in Alzheimer's disease are being planned.
Two experts in PD psychosis, who were not involved in the trial, found the results very encouraging. “Up until now we have had only one medication, clozapine, that we know works, but it is not commonly used, and another that is frequently used, quetiapine, but we don't have scientific evidence that it works,” said Daniel Weintraub, MD, associate professor of psychiatry and neurology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “So this is a breakthrough in that regard.”
While the SAPS-PD is a novel instrument, he said, making it somewhat harder to gauge the results, the extraction of the PD-specific elements of the well-known SAPS was reasonable.
Christopher Goetz, MD, professor of neurology and pharmacology at Rush University Medical Center in Chicago, concurred. “The results are very exciting,” he said, “because this is a major unmet need in Parkinson's disease.”
The combination of effectiveness and safety seen for pimavanserin “makes a lot of sense,” he said, given the selectivity of the drug for the serotonin system, the same system that clozapine works on. The complexity of the system contributed to the long delay in the development of novel serotonergic agents, he suggested, unlike typical antipsychotics, which exert their effects through the relatively simpler dopamine system.
Based on the results from the trial, Dr. Weintraub concluded, “I see pimavanserin becoming the predominant antipsychotic being used in Parkinson's disease, replacing existing agents as a first-line treatment. I see it as having a very significant impact on psychosis in Parkinson's disease.”