A novel drug that helps reduce hallucinations, delusions, and other psychotic symptoms experienced by some patients with Parkinson's disease (PD), without affecting motor symptoms, has been given the green light by the US Food and Drug Administration's (FDA's) Psychopharmacologic Drugs Advisory Committee.
Despite some concerns about an increased risk for severe adverse events (SAEs), including death, and the small number of patients tested, committee members determined that Acadia Pharmaceuticals Inc had shown that its oral drug, pimavanserin (Nuplazid), is effective and safe and that its benefits outweigh the risks.
The committee voted 12 to 2 that the sponsor provided sufficient evidence of efficacy, 11 to 3 that safety was sufficiently characterized, and 12 to 2 that the drug's benefits outweigh its risks.
"Although we would have liked to have seen a bigger trial and a stronger effect, in the context of this disease and the lack of other readily available treatments that are easy to use, this represents a step forward," said committee chair, David A. Brent, MD, academic chief, Division of Child and Adolescent Psychiatry, University of Pittsburgh School of Medicine, in summing up the day-long discussion.
Pimavanserin is an inverse agonist at serotonin receptor subtype 5-HT2A. Unlike other antipsychotics, it doesn't produce dopamine blockade and so has the potential to reduce symptoms of hallucinations, delusions, and agitation without adversely affecting motor symptoms of PD.
There are currently no FDA-approved drugs for Parkinson's disease psychosis (PDP), which can occur in up to 40% of patients with PD at some time during their illness. The condition can severely affect quality of life and place huge stresses on families and has been associated with nursing home placement.
Acadia applied for, and was granted, breakthrough therapy designation by the FDA. A priority review is underway for the product.
For the advisory board meeting, Acadia submitted a single positive 6-week phase 3 trial (ACP-103-020) that evaluated the efficacy, tolerability, and safety of pimavanserin (40 mg daily) in 199 patients with PDP. They also submitted results of three other randomized controlled trials as supportive information, although none was statistically positive on the primary endpoint.
As explained by Mitchel Mathis, MD, director, Division of Psychiatry Products, Department of Health and Human Services, Public Health Service, FDA Center for Drug Evaluation and Research, it's within the authority of the Division to rely on only one robustly positive trial, especially when there is supportive evidence.
To establish efficacy, the pivotal trial used the 9-item Scale for the Assessment of Positive Symptoms–Parkinson's Disease (SAPS-PD). The scale measures various forms of hallucinations (visual, somatic, and auditory) and delusions (including jealousy, which many patients with PDP seem to develop).
The study showed that the mean difference in change from baseline on this scale, assessed by independent raters, was 3.1 points (–5.79 for the treatment group vs –2.73 for the placebo group; P = .001).
There was also a significant improvement (P = .001) in the secondary efficacy measure, the Clinical Global Impressions Scale assessed by investigators blinded to the SAPS-PD.
Secondary outcomes were motor symptom changes. The study used the combined score of the Unified Parkinson's Disease Rating Scale Part II (Activities of Daily Living) and Part III (Motor Examination). Here, the study found that pimavanserin met the endpoint for noninferiority to placebo.
The risk for SAEs, including death, was 2.38 (95% confidence interval, 1.00 - 5.73; P = .05) for the drug vs placebo. SAEs occurred in 7.9% of patients taking pimavanserin vs 3.5% of those taking placebo.
In the ensuing long-term open-label trial, 51 treated patients with PDP died (11.1%).
During the public hearing session of the committee meeting, caregivers (or treating physicians) told heart-wrenching stories about a loved one (or patient) seeing animals in the bedroom or intruders in the night, being convinced their spouse was having an affair, or speaking to a dead relative.
An emerging theme from these speakers was that patients had tried every drug imaginable, with each being either poorly tolerated, lacking efficacy, or raising safety concerns, but when they tried pimavanserin, they "got their freedom back."
Stanley Fahn, MD, professor, neurology, Columbia University, and director emeritus, Movement Disorders Division, Neurological Institute, New York, stressed that "there is really nothing out there," for this condition, and that the drug does not worsen Parkinson's, which was "a key factor" for him.
While Dr Fahn was "disappointed" that the efficacy seemed "less robust than I would have liked" and that the drug didn't have an immediate effect, taking about 4 weeks to provide some degree of benefit, he concluded that "it's certainly better than nothing, and does help people."
What was compelling to John E. Duda, MD, director, Parkinson's Disease Research Education & Clinical Center, Philadelphia Veterans Affairs Medical Center, and associate professor, neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, was that patients had an average 3 years of psychosis going into the study.
"This suggests that the typical management strategies, including using [the antipsychotics] clozapine and Seroquel [quetiapine], which are effective in many patients, were probably tried and probably failed in a lot of them, making it an even more convincing argument that this [newer drug] was effective," he said.
Dawn F. Ionesco, MD, Depression Clinical and Research Program, Massachusetts General Hospital, and Harvard Medical School, Boston, said she "can completely understand how needed new medications are for these difficult to treat conditions."
She added that she wanted to "applaud the company" for including external raters in the study design. "That's really important and cuts down on bias; they have nothing to gain by saying your patients are getting better or worse."
There was some discussion about the wording of the question on efficacy. At least one member felt it should have asked whether the company had provided substantial evidence of the effectiveness of pimavanserin for the treatment of "psychosis associated with drug treated PD" rather than of "psychosis associated with PD." Various members pointed out that it's most likely PD drugs, not the disease itself, that cause psychosis, although almost all patients with PD in the United States are treated with some kind of dopaminergic agent.
Members voted 11 to 3 that Acadia adequately characterized the safety profile of pimavanserin, but they voiced several concerns about safety, including the rates for SAEs and deaths.
Dr Brent noted that safety might have differed according to Mini-Mental State Examination status. "In the group with some evidence of dementia, it looked like the rate of serious adverse events was similar between the drug and placebo, and this needs to be characterized better."
In the third and final vote of 12 to 2, members determined that the benefits of the drug outweigh its risks.
"I have plenty of patients who would tell me that if they had moderate to severe psychosis in PD, they would gladly take a medication that had a 1 in 10 chance of completely resolving their symptoms even if it had a 1 in 100 chance of killing them," said Dr Duda.
Dr Brent said he was persuaded by the "really terrible quality of life" of some patients. "As long as they can be given an informed choice about the risks, I think they ought to have the option."
Many members stressed the importance of postmarketing commitments, such as a robust observational program. Almut Winterstein, RPh, PhD, professor and interim chair, pharmaceutical outcomes & policy, University of Florida, Gainesville, however, said a controlled phase 4 trial is needed because "there is a statistically significant difference between the two treatment groups when SAEs are considered."
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Cite this: FDA Panel Gives Thumbs Up to Parkinson's Psychosis Drug - Medscape - Mar 30, 2016.