Topline, phase 2 trial results with the antipsychotic drug pimavanserin (Nuplazid, Acadia Pharmaceuticals) in patients with Alzheimer’s disease (AD) psychosis showed a statistically significant reduction in psychosis among those taking pimavanserin vs placebo, the company has announced.
A selective serotonin inverse agonist preferentially targeting 5-HT2A receptors, pimavanserin has a different biological mechanism than other antipsychotics.
Earlier this year, the US Food and Drug Administration (FDA) approved pimavanserin tablets for the treatment of hallucinations and delusions associated with psychosis in Parkinson’s disease (PD).
The new double-blind, placebo-controlled exploratory trial included 181 patients with AD psychosis in the United Kingdom (mean age, 86 years). These patients were randomly assigned to receive 34 mg of pimavanserin or placebo daily.
The primary endpoint was antipsychotic efficacy, as measured by the mean change in the Neuropsychiatric Inventory-Nursing Home (NPI-NH) Psychosis score (combined hallucinations and delusions domains) from baseline to week 6 of dosing. Patients continued dosing to week 12 to provide information on secondary endpoints, including changes in cognition.
At week 6, patients taking pimavanserin had a 3.76-point improvement in the NPI-NH Psychosis score compared with a 1.93-point improvement for placebo, representing a statistically significant (P = .0451) comparative improvement. Baseline mean scores were 9.52 and 10.00 for the pimavanserin and placebo groups, respectively.
Atypical antipsychotics have been associated with worsening of cognitive function in patients with AD. Over the course of 12 weeks of treatment in the current study, pimavanserin did not impair cognition as measured by the Mini-Mental State Examination score and was similar to placebo.
On the secondary endpoint of mean change in NPI-NH Psychosis score at week 12, pimavanserin maintained the psychosis improvement seen at the week 6 primary endpoint. This, however, did not statistically separate from placebo.
Pimavanserin was generally well tolerated, and the safety profile was consistent with that reported in previous studies. A preliminary analysis of safety data found that the most common adverse events were falls, urinary tract infection, and agitation. The mortality rate was similar in two study groups.
In the earlier PD trial, the effectiveness of pimavanserin was shown in a 6-week clinical trial of 199 participants. That study showed the drug to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor PD symptoms.
Hallucinations or delusions occur in as many as 50% of patients with PD at some time during the course of their illness and can be profoundly disturbing and disabling, according to experts in the field.
Despite some concerns about an increased risk for severe adverse events, including death, and the small number of patients tested, members of the FDA’s Psychopharmacologic Drugs Advisory Committee had determined that Acadia had shown its drug to be effective and safe in patients with PD and that its benefits outweigh the risks.
As with other atypical antipsychotic drugs, pimavanserin has a boxed warning alerting healthcare professionals about an increased risk for death associated with the use of these drugs to treat older people with dementia-related psychosis.
Pimavanserin was granted breakthrough therapy designation for the treatment of hallucinations and delusions associated with PD. According to the FDA, this designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint.
The drug was also granted a priority review, which provides for an expedited review of drugs that offer a significant improvement in the safety or effectiveness for the treatment, prevention, or diagnosis of a serious condition.
“Alzheimer’s disease patients suffer from a number of debilitating symptoms, of which psychosis carries a poor prognosis and is associated with earlier placement into nursing homes,” said Steve Davis, Acadia’s president and chief executive officer, in a press release.
The new data, he said, “provide solid evidence that pimavanserin can improve psychosis in another major neurological disorder and provide strategic momentum for the further development of pimavanserin to address the needs of AD psychosis patients.”
March 29, 2016, Washington, D.C. Today, the FDA voted to approve Acadia Pharmaceutical’s new antipsychotic medication, pimavanserin, which will be marketed under the name Nuplazid™. Previously, there was no FDA-approved drug for the treatment of psychosis in Parkinson’s, and expert neurologists and psychiatrists had the option of several atypical antipsychotic medications, none of which were proven effective in Parkinson’s, or one that was proven effective but had a fairly negative safety profile, with patients requiring weekly blood tests to make sure that they were tolerating the drug well.
However, with the lack of an FDA-approved drug for Parkinson’s disease psychosis, this troubling and sometimes terrible symptom is frequently untreated or, worse yet, treated with an antipsychotic medication that is not safe for Parkinson’s patients. Many antipsychotic drugs work by blocking dopamine. Since Parkinson’s is a disease where dopamine producing neurons are lost, blocking dopamine is bad – we think that sometimes it is fatal.
The approval of a drug to treat Parkinson’s disease psychosis will mean that there is a clear option for patients. These are powerful drugs, so there are risks associated with any antipsychotic treatment – an issue presented to the FDA’s panel by Marc Stone, MD, the FDA’s Deputy Director of Safety – and so patients and families need to be careful and talk to their neurologist about all their options. However, with FDA approval, we can hope that most patients with Parkinson’s will have access to a drug designed just for them and for Parkinson’s.
During the public comment period, many patients spoke about the impact of psychosis on their family. These powerful testaments – many of which were from people who had participated in the clinical trial of pimavanserin – described the impact of the drug in a way that went far beyond the numbers from the trial results. Some people told us of the total resolution of hallucinations and delusions in a spouse, parent, or grandparent from taking pimavanserin in the clinical trial and others talked about how their spouse realized that hallucinations were not real, thanks to the treatment.
David Pickar, MD, a key member of the Psychopharmacologic Drugs Advisory Committee, pointed out that he felt that this was not for Parkinson’s disease psychosis, but rather for psychosis in patients being treated for Parkinson’s disease, because every patient in the study was receiving clinically optimized medication to manage their motor symptoms. This is an important point, but also largely an academic one – since psychosis is usually seen later in the disease, use of this drug will be almost exclusively in treated Parkinson’s.
Hopefully, this success of the process for pimavanserin will inspire others to aggressively pursue novel therapies for Parkinson’s. We hope that this approval will lead to better outcomes for people with Parkinson’s today and that this success of the drug approval process will inspire others to pursue the next breakthrough.