Daniel M. Keller, PhD

June 29, 2015

SAN DIEGO — A new antipsychotic with a novel mechanism of action maintains benefit over 15 months for treating Parkinson's disease (PD) psychosis (PDP), two long-term open-label extension studies of short-term randomized, controlled trials (RCTs) show.

The drug, pimavanserin (Nuplazid, ACADIA Pharmaceuticals), has no dopaminergic, histaminergic, adrenergic, or muscarinic activity.

"It's really a serotonin inverse agonist, or it blocks serotonin receptors — the 5-HT2A receptor — and this seems to stop the psychosis symptoms in Parkinson's disease," lead investigator Stuart Isaacson, MD, director of the Parkinson's Disease and Movement Disorders Center of Boca Raton, Florida, told Medscape Medical News. An inverse agonist not only blocks activation of a receptor but also reduces any constitutive activity associated with the receptor.

Patients who completed the short-term 4- to 6-week phase 2 or phase 3 RCTs could continue in an open-label extension study (OLS, n = 498). The extension of the phase 2 trial (n = 39) using 20, 40, or 60 mg of pimavanserin has been completed, and the phase 3 of pimavanserin, 40 mg (n = 459), is ongoing.

Investigators reported findings from the OLS of the former trial and interim data from the latter here at the 19th International Congress of Parkinson's Disease and Movement Disorders (MDS).

Study participants were as expected for patients with PDP: elderly, mostly male, with PD for a mean of 110 months and PDP for about 28 months. During the two open-label studies, patients were evaluated for a mean of 15 months. Individuals discontinued the studies mainly for withdrawal of consent, adverse events, or lack of efficacy/PDP progression. Only about 20% of discontinuations were for lack of efficacy.

Long-Term Efficacy

"We were able to demonstrate ongoing efficacy, both on the SAPS-PD [Scale for Assessment of Positive Symptoms-PD] at 4 weeks into the open-label extension... as well as in caregiver burden scale out to 9 months, and the overall global impressions of the investigators out to 15 months," Dr Isaacson reported.

The Scale for Assessment of Positive Symptoms (SAPS) in schizophrenia was adapted for PD (SAPS-PD) to assess hallucinations and delusions in PDP. All patient groups improved in the randomized trial, achieving a relatively dose-dependent reduction in SAPS-PD of about 4 to 6 points from core baseline by week 6. However, even the placebo group had just over a 4-point reduction at week 6.

Going from the randomized trials to the open-label extension, groups that started on placebo or 10 mg of pimavanserin and transitioned to 40 mg showed further improvement, with about a 2.5-point decrease from extension baseline in the SAPS-PD score by extension week 4 (P < .001 for placebo; P < .002 for 10 mg).

Even patients who were receiving 40 mg in the RCT improved with a further 1- to 2-point reduction in SAPS-PD by extension week 4. Interestingly, patients who transitioned from 20 mg to 40 mg did not show any better response by extension week 4, having about a 4-point decrease from core baseline at extension week 4.

Scores on the Clinical Global Impression of Severity (CGI-S) in the phase 2 open-label study showed that patients derived continuous benefit through week 24, which persisted to weeks 48, 72, and 96.

Similarly, in the phase 3 open-label extension, CGI-S and CGI-Improvement (CGI-I) scores reflected continued efficacy of pimavanserin through week 96. Absolute CGI-I scores of about 2.5 to 2.7 (between minimally improved and much improved from baseline) were maintained for patients who stayed on study for up to 2 years.

In the open-label extension of the phase 3 trial patients, the Caregiver Burden Score (CBS) was persistently improved through week 36, at which time it was back to baseline and then steadily worsened above baseline. The investigators said it was unclear whether there was a loss of efficacy or for example, the patients had increasing dementia or worsening of underlying PD or other comorbidities.

PDP "primarily impacts care givers, both in terms of caregiver distress, caregiver's ability to live and feel well, and in agitation that can occur as well," Dr Isaacson said. "Demonstrating that it stayed improved out to 9 months was, I think, a very important finding."

The open-label study of pimavanserin did not reveal any safety or tolerability issues that were not seen in the 6-week pivotal trials, Dr Isaacson said. The most common adverse effects leading to drug discontinuation were hallucinations (2% of patients), confusional state, PD, falls, psychotic disorder, myocardial infarction, or urinary tract infection (1% each).

New Insight Into PDP

This the first drug in a new class that has antipsychotic activity without blocking dopamine. "It really goes to a shifting paradigm of how we understand psychosis, at least in Parkinson's disease and probably in other disorders as well," Dr Isaacson postulated. He said it is probably more an intrinsic problem involving serotonin that leads to psychosis, which can be triggered by dopamine drugs, other drugs, systemic infections, dehydration, or other conditions.

Without available effective treatments, PDP may be ignored or inadequately treated, the authors say. Many of the current antipsychotics worsen Parkinson's mobility, so doctors may not use them. And they may hesitate to increase dopamine drugs to improve mobility for fear of worsening psychosis.

Having an antipsychotic that does not require blood monitoring (as does clozapine); does not produce somnolence; and has demonstrated efficacy, safety, and tolerability "would be a real change in how we treat these patients," he predicted. "If we could treat [psychosis] earlier, we'd be able to treat Parkinson's mobility better and hopefully have patients have a longer time where they can have good mobility, quality of life, and stay out of nursing placement."

 
If we could treat [psychosis] earlier, we'd be able to treat Parkinson's mobility better and hopefully have patients have a longer time where they can have good mobility, quality of life, and stay out of nursing placement. Dr Stuart Isaacson
 

Mark Stacy, MD, professor of neurology, division chief for Parkinson's disease and movement disorders, and vice dean for clinical research at Duke University in Durham, North Carolina, thinks pimavanserin may be just such a drug.

It "represents a major advance both in terms of the use of the drug and increasing awareness of these symptoms in Parkinson's disease and in fact that there is a treatment," he commented to Medscape Medical News.

"Traditional antipsychotics work by blocking dopamine receptors, which is a horribly unsafe thing to do in patients with Parkinson's disease because the mobility in Parkinson's disease is improved by increasing dopaminergic stimulation," he said. "So this mechanism is theoretically much safer than traditional antipsychotics, and it appears in these early studies to be very well tolerated."

Dr Stacy felt the measurement of caregiver burden was an important aspect of the study. Caregiver burnout "would lead to nursing home placement," he said. "I think that reducing [psychosis] symptoms would allow a family to continue better as a family" as well as delay nursing home placement.

Maurizio Facheris, MD, MSc, senior associate director for research programs at the Michael J. Fox Foundation for Parkinson's Research, called the work "a great study" and "promising" and commended the investigators for customizing their scales to measure factors that are important in PDP, such as hallucinations.

"I actually can't wait for that drug to be out because it will be one of the very few new drugs for Parkinson's that are not dopaminergic," he said.

He noted that another unmet need in PD is anxiety; there are no randomized clinical trials for anxiety in PD.

The study was funded by ACADIA Pharmaceuticals. Dr Isaacson has received honoraria for continuing medical education, consulting, research grants, or promotional speaker on behalf of Abbvie, Acadia, Addex, Allergan, Allon, AstraZeneca, Biotie, Britannia, Chelsea Therapeutics, Civitas, Eisai, GE Healthcare, GSK, Impax, Ispen, Kyowa, Lilly, Lundbeck, Merck Schering-Plough, Medtronic, Merz, Michael J. Fox Foundation for Parkinson's Research, Novartis, Neurocrine, NIH, Novartis, Orion, Parkinson Study Group, Pfizer, Phytopharm, Purdue, Roche, Santhera, Serono, Shire, Teva, UCB, US World Meds, Vanda, and Xenoport. Dr Stacy participated in the pimavanserin clinical trials but is still blinded to the results and has not received any compensation from ACADIA. (funding for research participation has gone to Duke University.) He is a consultant to Acorda, Allergan, Biotie, Chelsea, General Electric, Genzyme, Eli Lilly, Merz, Osmotica, Pfizer, ProStraken, SK Life Sciences, UCB, and Vanda and has received royalties from Informa Press. Dr Facheris is an employee of the Michael J. Fox Foundation for Parkinson's Reearch.

19th International Congress of Parkinson's Disease and Movement Disorders (MDS). Abstract 149. Presented June 15, 2015.

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