Acadia Submits Supplemental New Drug Application for Nuplazid to Treat Dementia-related Psychosis, Hallucinations

Nuplazid NDA

Acadia Pharmaceuticals announced it has submitted a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration for a new indication for Nuplazid (pimavanserin) in the treatment of hallucinations and delusions associated with dementia-related psychosis.

Dementia affects approximately 8 million people in the U.S. and is expected to grow as the population ages. An estimated 2.4 million of these people experience dementia-related hallucinations and delusion. There is an unmet need for dementia-related psychosis treatments, as no approved option yet exists.

Positive results in three separate clinical trials support the decision to submit the sNDA, including data from the Phase 3 HARMONY study (NCT03325556), in which 351 patients received either 34 mg or 20 mg of Nuplazid per day, or a placebo. Their progress was followed for up to 26 weeks or until a relapse of psychosis occurred.

Nuplazid was well-tolerated and was not associated with cognitive declines over the entire nine-month testing period. Importantly, Nuplazid significantly reduced the risk of relapse of psychosis by 2.8-fold compared to placebo.

Data from a Phase 2 trial in patients with Alzheimer’s disease-related psychosis (NCT02035553) and from a Phase 3 trial investigating its use in Parkinson’s disease psychosis (NCT01174004) further demonstrated Nuplazid’s positive antipsychotic effectiveness.

Nuplazid is a selective serotonin inverse agonist (SSIA) that specifically targets serotonin 5-HT2A receptors. Evidence suggests these receptors play an important role in psychosis, schizophrenia, depression and other neuropsychiatric disorders. Inverse agonists bind to the same receptors as an agonist, but have the opposite pharmacological effect, blocking the activity of the targeted receptors.

In past studies, Nuplazid was shown to lessen the symptoms of Parkinson’s disease-related psychosis, while minimizing the debilitating side effects that many antipsychotics cause.

Those results and others led the FDA to approve Nuplazid to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease under the FDA’s breakthrough therapy designation, an expedited FDA review program for medications that show substantial improvement over existing treatments in early clinical data.

The new application seeks to expand Nuplazid’s use beyond Parkinson’s disease.

“This is an important step forward for the approximately 2.4 million people in the U.S. who suffer from dementia-related hallucinations and delusions, representing a large unmet need with currently no approved treatment options,” Steve Davis, ACADIA’s CEO, said in a press release. “Our pivotal HARMONY study showed a meaningful reduction of the symptoms and stabilization of psychosis and a nearly three-fold reduction in the risk of relapse of psychosis for patients continuing treatment on pimavanserin compared to placebo. We look forward to working with the FDA as it reviews our submission.”

Should it win supplementary approval, Nuplazid would be the first medication approved for hallucinations and delusions associated with dementia-related psychosis, and would be the second indication for Nuplazid.

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Nuplazid Shows Sustained Easing of Psychosis in Patients in Phase 3 Trial

Nuplazid trial results

Daily use of Nuplazid (pimavanserin) leads to strong and sustained reductions in the frequency and severity of hallucinations and delusions in people with Parkinson’s disease psychosis, according to data from a long-term extension study.

These findings, “Improvement and Durability in SAPS-PD Assessment over 10 Weeks of Pimavanserin Treatment for Parkinson’s Disease Psychosis,” were presented at the at the 2020 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting, which was held virtually due to the COVID-19 pandemic.

Nuplazid, marketed by Acadia Pharmaceuticals, is a selective serotonin inverse agonist that works by blocking the activity of serotonin receptors called 5HT2A. These receptors have been associated with several mental health disorders, including psychosisdepression and schizophrenia.

The medication is currently approved in the U.S. to treat hallucinations and delusions associated with Parkinson’s disease psychosis (PDP).

Nuplazid’s approval was supported by findings in several clinical trials, including a completed Phase 3 study (NCT01174004), that assessed its safety and efficacy compared with a placebo in 199 people with Parkinson’s psychosis.

Patients were randomly assigned to either Nuplazid (34 mg) or placebo tablets, both taken once-a-day for six weeks.

Study findings showed that compared to a placebo, Nuplazid reduced the frequency and severity of hallucinations and delusions without worsening patients’ motor symptoms.

All patients who completed this and earlier Nuplazid studies were then invited to enroll in an open-label extension study (NCT00550238) to either continue or start (previous placebo group patients) treatment with Nuplazid for four weeks.

The prospective analysis presented at ASCP was based on data from 171 patients who completed the original Phase 3 trial and entered in its long-term extension. Of these, 148 (87%) completed the extension study.

Findings showed that Nuplazid’s use led to strong and durable reductions in the frequency and severity of hallucinations and delusions, as measured by the Scale for the Assessment of Positive Symptoms – Parkinson’s disease (SAPS-PD), since the beginning of the original study up until the end of its extension study. This scale is a structured patient interview that consists of five domains: hallucinations, delusions, bizarre behavior, positive formal thought disorder, and inappropriate affect. Higher scores indicate more severe psychosis.

Such benefits were seen both in patients who started treatment in the original trial and were given Nuplazid for a total of 10 weeks (mean reduction of 6.86 points), and in those who only started treatment in the extension study and were on the medication for four weeks (mean reduction of 6.28 points).

In people previously given a placebo, SAPS-PD scores decreased by an average of 3.43 points since the beginning of the extension study until its completion one month later. Among those given Nuplazid in the original trial, SAPS-PD scores remained nearly constant over this trial’s four weeks (slight increase of 0.43 points).

Improvements as assessed by the Clinical Global Impression-Severity and Improvement (CGI-S and CGI-I) scales were also seen, particularly in patients who switched from a placebo in the original trial to Nuplazid in the extension study.

Among these patients, nearly half (46.6%) felt they had very much improved or much improved by the second week of the extension study, and more than half (57.1%) reported the same at week four.

Adverse events observed during the extension study were identical to those reported in the original trial. The most common included falls, hallucinations, urinary tract infections, and swelling.

Most adverse events were only mild or moderate in severity. A total of 14 (8.2%) patients had to stop treatment due to side effects.

“Overall, the sustained improvement in the severity of psychotic symptoms was suggested in patients with PDP [Parkinson’s disease psychosis] receiving treatment with pimavanserin 34 mg daily for 10 weeks,” the researchers wrote.

During the meeting, Acadia also presented data on the long-term safety and tolerability of Nuplazid with Parkinson’s patients, and new findings from trials enrolling people with other central nervous system (CNS; the brain and spinal cord) disorders, including major depressive disorder and schizophrenia.

“Our research presentations at ASCP underscore the potential clinical utility of pimavanserin in serious CNS disorders,” Serge Stankovic, MD, MSPH, president of Acadia, said in a press release.

“Pimavanserin has demonstrated the potential to be an important treatment option for patients [with schizophrenia and major depressive disorder and showed promising] long-term safety and tolerability … in Parkinson’s disease psychosis,” Stankovic added.

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Long-term Nuplazid Safe, Well-tolerated by Parkinson’s Psychosis Patients, Extension Study Shows

Nuplazid extension study

Nuplazid (pimavanserin), an approved therapy for treating hallucinations associated with Parkinson’s disease psychosis, is generally safe and well-tolerated in the long run, and may be associated with reduced mortality in this particular patient population, findings from a long-term extension study suggest.

The results were presented at the 2020 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting, which was held virtually due to the COVID-19 pandemic. The poster was titled “Long-Term Evaluation of Open-Label Pimavanserin Safety and Tolerability in Parkinson’s Disease Psychosis.”

In addition to the motor symptoms of Parkinson’s disease, some patients with the condition experience psychosis, which causes them to experience hallucinations or delusions that affect their quality of life and increase burdens on their caregivers.

Nuplazid, developed by Acadia Pharmaceuticals, was approved by the U.S. Food and Drug Administration (FDA) in 2016 to treat these symptoms of Parkinson’s disease psychosis. It blocks the signaling of certain serotonin receptors in the nervous system, which have been associated with mental disorders such as depression and epilepsy.

Nuplazid has been deemed safe and well-tolerated across a number of randomized clinical trials, but the oral treatment is designed to be taken daily for extended periods and little is known about its safety and tolerability in the long term.

To address that, Acadia designed an open-label Phase 3 extension trial (NCT00550238) that included Parkinson’s disease psychosis patients who completed two prior randomized, six-week Phase 3 trials (NCT00477672 and NCT00658567) and a prior open-label extension Phase 2 study (NCT01518309).

In total, 459 patients were included in extension study, most of whom were men (61.7%), with an average age of 71.2 years. They are receiving once-daily Nuplazid, at an oral dose of 34 mg (the approved dose), with assessments scheduled at two weeks, one month, and three months after entering the trial, every three months thereafter until 12 months, and every six months in the following years.

The study has been going on for more than 10 years, and researchers now are reporting data after a median of 454 days (about 1.2 years) on treatment. Some of these patients have been on Nuplazid for nearly nine years.

Over the follow-up period, 85.4% of patients experienced at least one adverse event (side effect) related to treatment, with most being mild to moderate in intensity. Serious treatment-related adverse events were reported in 41% of patients, and included pneumonia, urinary tract infection, and hip fracture. In total, 29% of patients discontinued treatment due to an adverse event related to Nuplazid.

Findings also demonstrated that disease symptoms remained stable over time, with scores on the Clinical Global Impression (CGI) severity scale and improvements scale being similar at week 192 on treatment (about 3.5 years) compared to study start.

This also was observed among the 43 patients who responded to Nuplazid during the randomized studies — defined as those with a score of zero on the Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis at week 6 — whose mean CGI-S scores were similarly maintained over time through 150 weeks (roughly 2.8 years).

Caregiver burden scores, meanwhile, increased progressively from baseline (28.2 points) to week 192 (32.5 points).

To date of the report, 61 patients have died, amounting to a mortality rate of 6.45 deaths per 100 patient-years. This was similar to the mortality rate seen in Parkinson’s patients of the same age across a Medicare database (7.3 per 100 patient-years), but lower than the mortality usually seen in people with Parkinson’s disease psychosis (28.2 per 100 patient-years), the team noted.

Also, no disease origin or adverse events were consistently associated with deaths in these patients.

This was the largest Parkinson’s disease psychosis study in which patients were followed for long periods, but the team noted that its open-label nature, the lack of a control group, and that the inability to follow patients after treatment discontinuation are clear limitations.

Still, they concluded that “long-term study showed pimavanserin treatment to be generally safe and well tolerated. No new or unexpected safety findings were observed.”

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‘Inappropriate’ Antipsychotics to Treat Depression in Elderly Parkinson’s Patients Linked to Pneumonia Risk


Inappropriate antipsychotic medications — those approved for ills like schizophrenia but used to treat depression — given to elderly people with Parkinson’s disease increase their risk of pneumonia, a study suggests.

The study, “Risk of pneumonia associated with atypical antipsychotic use in nursing home residents with Parkinson’s disease,” was published in the Journal of Psychiatric Research.

Certain antipsychotic medications can be prescribed to help handle some of the behavioral problems evident in Parkinson’s disease (PD). But use of antipsychotics in these patients must be done cautiously, since many affect dopamine signaling — which is dysregulated in PD — and can aggravate other disease symptoms.

According to the 2019 American Geriatrics Society (AGS) Beers criteria, atypical antipsychotics are not appropriate for Parkinson’s patients, with exceptions being Nuplazid (pimavanserin), clozapine (brand names, Clozaril and FazaClo), and quetiapine (Seroquel). (Nuplazid, an oral Parkinson’s psychosis treatment that does not impact motor abilities, was approved in 2016, outside the years of this study.)

Atypical antipsychotics are considered inappropriate due to the risk of worsening Parkinson symptoms, like voluntary movements in general and swallowing abilities in particular.

Researchers in the U.S. investigated the link between inappropriate antipsychotic use and pneumonia, which can be a serious complication when swallowing or breathing are impaired.

Using Medicare data, they identified 16,161 nursing home residents diagnosed with Parkinson’s and depression (mean age, 82; two-thirds female), who were treated with antipsychotic medications between 2007 and 2010. Over a third of these individuals (37.62%; 6,126 people) were given an inappropriate antipsychotic, while the remainder were prescribed an appropriate one, with the most common being quetiapine.

Among these elderly patients, rates of dysphagia (difficulty swallowing), dementia, and levodopa use were similar between groups treated with appropriate and inappropriate antipsychotics.

Rates of pneumonia were significantly higher in patients prescribed inappropriate antipsychotics, 18.78% vs. 16.35%, than in those given appropriate ones over a six-month follow-up. Inappropriate antipsychotic use was also associated with a 20% greater chance of pneumonia, statistical analyses found; this finding was validated through sensitivity analyses that work against uncertainty in given sets of assumption.

Researchers also noted that rates of stopping antipsychotics were higher among those on inappropriate medications (21.17% vs. 15.22%).

“The risk of pneumonia was significantly higher for inappropriate AAP [antipsychotic] users in comparison to the appropriate AAP users,” the researchers wrote.

“The study findings suggest that selection of appropriate antipsychotics in PD is critical to prevent serious adverse events related to antipsychotic use in PD, given that pneumonia is one of the most common causes of mortality in PD patients. Further research is needed to evaluate the risk of pneumonia in PD patients using newer antipsychotic medications,” they concluded.

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Nuplazid ‘Significantly’ Slows Relapses in Dementia-Related Psychosis, Phase 3 Trial Shows

psychosis and Nuplazid

Interim results from the ongoing Phase 3 HARMONY study show that treatment with Nuplazid (pimavanserin) significantly delays time to a psychosis relapse in patients with dementia-related disorders, such as Parkinson’s and Alzheimer’s disease.

Evaluation by an independent data monitoring committee recommended an early stop to this placebo-controlled trial based on the treatment’s “robust” efficacy, Acadia Pharmaceuticals — Nuplazid’s manufacturer — announced in a press release. The study’s primary goal — that of a statistically significant longer time to a psychosis relapse — was met in this early analysis.

Nuplazid was approved by the U.S. Food and Drug Administration (FDA) to treat hallucinations and delusions associated with Parkinson’s disease psychosis in 2016. The therapy is not approved to treat dementia-related psychosis, schizophrenia, or major depressive disorder.

After closing the study in the coming months, Acadia plans to meet with the FDA to explore the possibility of filing a supplemental application in 2020, requesting that Nuplazid’s label be expanded to allow its use as a treatment for dementia-related psychosis based in part on the effectiveness seen in HARMONY.

“We are very excited that today’s results bring us one step closer to the potential of offering patients with dementia-related psychosis a critically needed treatment option,” said Serge Stankovic, MD, MSPH, Acadia’s president.

“We look forward to speaking with the FDA about a supplemental new drug application to support pimavanserin for the treatment of dementia-related psychosis,” Stankovic added. “I want to thank all of the patients, their families, and the investigators for their participation in this important study.”

These and other recent HARMONY results will be discussed at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) meeting set for Dec. 4–7, 2019, in San Diego. The oral presentation, “HARMONY Relapse-Prevention Study: Pimavanserin Significantly Prolongs Time to Relapse of Dementia-Related Psychosis,” will be given by Erin Foff, MD, PhD, clinical director at Acadia Pharmaceuticals.

Nuplazid is a selective serotonin inverse agonist that targets serotonin receptors called 5HT2A. These receptors have been associated with mental disorders such as psychosis, depression, schizophrenia, and other neuropsychiatric disorders. Inverse agonists such as Nuplazid bind to the same receptors as agonists, but induce the opposite pharmacological response, blocking the activity of the targeted receptors.

HARMONY (NCT03325556) was designed to explore Nuplazid’s ability to safely and effectively treat delusions and hallucinations associated with dementia-related psychosis across a broad population of patients, and was scheduled to end in August 2020.

It enrolled people with the most common subtypes of dementia, including Alzheimer’s and Parkinson’s disease, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia spectrum disorders, at sites across the U.S., Europe and in Chile.

For an initial 12 weeks, all were treated with Nuplazid at 34 mg once daily until dementia was stable, or with a reduced 20 mg dose if clinically justified within the first four weeks.

After this stabilization period, patients showing a sustained treatment response were then randomly assigned to continue treatment with Nuplazid (34 mg or 20 mg each day) or to switch to placebo for 26 weeks (six months). About 20% failed to show a sustained response during this early period.

All participants were followed through this double-blind period, or until a relapse of psychosis symptoms. A relapse, or significant disorder worsening, was defined as hospitalization due to dementia-related psychosis, significant deterioration of dementia-related symptoms on clinical scales, or the need to use an off-label antipsychotic medication to treat dementia-related delusions and/or hallucinations.

A “number of these patients” completed the full six months of treatment, as well as the initial three-month stabilization period, showing a sustained response, Acadia said in an investor report. Exact patient numbers were not available, as a rolling enrollment was underway.

The preliminary efficacy analysis revealed that those treated with Nuplazid had significantly longer periods of time without a psychosis relapse compare to the placebo treated group. “The interim analysis results … clearly demonstrates the strong durability of treatment with pimavanserin,” the company said. Analyses are continuing.

Safety was also comparable to what was seen in earlier trials, with no new safety concerns identified.

About 15% of the people in the trial had Parkinson’s dementia; a majority, or about 67%, were Alzheimer’s patients with related dementia.

“With no approved treatment options available today for dementia-related psychosis, the pimavanserin study results represent a meaningful advance that will potentially bring us a much needed therapy for this debilitating disease,” Jeffrey Cummings, MD, ScD, director emeritus of Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, said.

The FDA designated Nuplazid a breakthrough therapy for the treatment of Parkinson’s disease psychosis.

Recent results of a Phase 2 clinical trial showed that treatment with Nuplazid can ease depression and sleep problems in patients with Parkinson’s disease.

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Anavex 2-73 Trial Recruitment Reaches Halfway Mark

Anavex 2-73

A Phase 2 trial evaluating the efficacy and safety of investigational Anavex 2-73 as a treatment for Parkinson’s disease dementia has recruited half of its targeted patients, the therapy’s developer, Anavex Life Sciences, has announced.

The study is still recruiting Parkinson’s disease patients age 50 or older who have been diagnosed with dementia. The Phase 2 trial is being conducted across several clinical sites in Spain, and has received the support of the Michael J. Fox Foundation for Parkinson’s Research and León Research.

“We are encouraged by the rate of patient enrollment in this Phase 2 study and the potential for Anavex 2-73 to become a therapy for this unmet need given that up to 80% of Parkinson’s patients develop dementia,” Christopher U. Missling, PhD, president and chief executive officer of Anavex, said in a press release.

The Phase 2 trial (2017-004335-36expects to enroll 120 patients who will be randomized to receive orally 10 or 20 mg of Anavex 2-73 or a placebo for 14 weeks. Researchers will evaluate the impact of the treatment on cognition, as determined by the cognitive drug research computerized assessment system, as well as patients’ motor function and sleep quality.

The study will also assess genomic precision medicine biomarkers, previously identified to respond to Anavex 2-73 in a Phase 2 trial (NCT02244541) in Alzheimer’s disease.

Anavex 2-73, originally developed as a potential disease-modifying therapy for Alzheimer’s, is given orally to activate a cellular receptor called Sigma-1 (SIGMAR1), known to have neuroprotective effects. Specifically, activation of SIGMAR1 can help reduce neuroinflammation, as well as the accumulation of beta-amyloid and tau proteins and oxidative stress, all known to contribute to the progression of neurodegenerative disorders.

According to a recent study published in the journal Cells, the therapy exerts its neuroprotective effects by re-establishing the normal functioning of cells’ “recycling system,” preventing the accumulation of toxic protein clumps.

Preclinical studies with mouse models of Parkinson’s disease have shown that Anavex 2-73 was able to restore the function of damaged nerve cells and significantly improve motor function.

Currently, only one medicine, Nuplazid (pimavanserin) is approved by the the U.S. Food and Drug Administration (FDA) as a therapy for hallucinations and delusions associated with Parkinson’s disease.

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Lack of Research and Way of Measuring Visual Hallucinations in Parkinson’s Hinders Its Treatment, Study Says

visual hallucinations

Research into the best ways of managing visual hallucinations in patients with Parkinson’s disease over the long term is severely limited and affecting treatment, a review study has found.

In particular, the lack of a universal rating scale renders data interpretation and comparison between studies difficult. To overcome this limitation, researchers propose the creation of a specific scale suitable to monitoring the effects of pharmacological and non-pharmacological treatments for visual hallucinations.

The study, “Management of visual hallucinations in dementia and Parkinson’s disease,” was published in International Psychogeriatrics.

Visual hallucinations — seeing something that is not real — is a common symptom of Parkinson’s and other types of dementia, including Alzheimer’s diseasedementia with Lewy bodies and frontotemporal dementia. These symptoms can be quite disturbing for patients, and are associated with rapid cognitive decline and increased mortality.

Although a large number of pharmacological and non-pharmacological therapies have been proposed to treat such hallucinations, an optimal management strategy is yet to be found.

This systematic review examined the prevalence and risk factors of visual hallucinations, as well as rating scales and therapeutic approaches that have been proposed to monitor and minimize their occurrence.

After a thorough literature search in the PubMed database, a total of 89 relevant studies (11 meta-analyses, 34 randomized controlled trials, six other trials, and a number of relevant review articles) were selected.

Previous studies estimated the prevalence of visual hallucinations for Alzheimer’s disease to range from 3% to 76%, and from 22% to 38% in people with Parkinson’s disease.

The high variability in prevalence, especially in Alzheimer’s disease “may be due to the setting of the study population (clinic vs. nursing home) and differences in who the informant is; whether patient, relative, or professional,” the researchers wrote.

Among Parkinson’s patients, the biggest challenge to determining prevalence of visual hallucinations seems to be separating “the contribution of dopaminergic and anticholinergic drugs from that of the disease.”

In dementia with Lewy bodies and frontotemporal dementia patients, prevalence is estimated to be 15-20% and 14.4%, respectively.

Non-pharmacological strategies have been proposed mainly as a first-line treatment for visual hallucinations. However, solid evidence from controlled trials that might demonstrate therapeutic benefit specifically for visual hallucinations is lacking.

“[R]eviewers have recommended increased socialization, as well as improving lighting and reducing visual triggers, but admit this because they are useful and inexpensive rather than based on trial evidence,” the researchers wrote.

Antipsychotics — both typical and atypical — are commonly used to treat psychosis and depression, but when used in patients with dementia are associated with a series of adverse side effects, including increased risk of stroke and death. Still, these medicines may continue to be prescribed off-label to these patients, mostly due to a lack of better alternatives.

In Parkinson’s disease, several antipsychotic treatments have been tested over the last few years. While some, like melperone and Zyprexa (olanzapine), clearly failed to ease psychosis and delusions, Clozaril (clozapine) and Nuplazid (pimavanserin) were seen to treat psychosis and hallucinations without impairing patients’ motor functions. The effects of others, like Seroquel (quetiapine), vary substantially across studies and are difficult to interpret.

In any case, these medications — even Nuplazid, the only medication approved by the U.S. Food and Drug Administration (FDA) for Parkinson’s delusions and hallucinations — “still carry the same black box warning as other antipsychotics for older people with dementia” and should be used with caution.

One of the key limitations encountered by the researchers that affects not only data interpretation, but also its generation, was the lack of a specific universal rating scale to assess visual hallucinations. Rather, symptoms tend to be “grouped together as all ‘hallucinations’ or ‘psychosis’. This over simplifies symptoms and prevents an understanding of what treatments may or may not work,” they said.

“We recommend the development of a specific scale suitable for natural history and treatment studies of VH, and for larger multi-site studies of both non-pharmacological and pharmacological treatments for VH [visual hallucinations],” the researchers concluded.

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Nuplazid’s Mortality Risk Not Different from Seroquel, Combo Treatment, Study Finds

Treatment with Nuplazid (pimavanserin) does not lead to a different mortality risk compared to the antipsychotic medication Seroquel (quetiapine), or to combination treatment with both medications, in patients with Parkinson’s psychosis, according to results from a large study.
The study, “Mortality in patients with Parkinson disease psychosis receiving pimavanserin and quetiapine” was published in the journal Neurology.
In April 2016, Acadia Pharmaceuticals’ Nuplazid became the first therapy approved by the U.S. Food and Drug Administration (FDA) for hallucinations and delusions associated with Parkinson’s psychosis.
However, two years later, a CNN report cited an analysis by the nonprofit Institute for Safe Medication Practices, which found a total of 700 deaths in the FDA’s Adverse Event Reporting System — including 500 among Parkinson’s patients in which Nuplazid was the only therapy likely involved — in the nine months following Nuplazid’s arrival on the market in June 2016.
Now, researchers at University of California San Diego School of Medicine explored the medication’s safety further. “We wanted to better understand and assess the risks of using pimavanserin (Nuplazid) within our own patient community, either alone or in combination with other commonly prescribed medications,” Fatta B. Nahab, MD, the study’s senior author, said in a press release.
Besides Nuplazid, the team focused on Seroquel, a second-generation antipsychotic (SGA), which is often used to treat Parkinson’s psychosis. Results were mixed. Use of Seroquel and other SGAs led to concerns about increased morbidity and mortality in patients with dementia or those with Parkinson’s, prompting an FDA black box warning.
Unlike Seroquel, Nuplazid does not affect dopamine receptors, so it does not interfere with the effectiveness of Parkinson’s treatments for motor symptoms.
The team conducted a retrospective analysis of 4,478 UC San Diego Health patients with Parkinson’s, of whom 676 were being prescribed Nuplazid, Seroquel, or both, between April 29, 2016 and April 29, 2018.
Results showed that patients treated with Nuplazid alone (113 patients, mean age 75.9 years) had a lower mortality percentage when compared to those treated with quetiapine only (505 patients, mean age 75.2 years), or with both compounds (58 patients, mean age 74.1 years ). However, the differences were not statistically significant.
When compared to 784 Parkinson’s patients not on these medications (mean age 80 years), the results revealed a significantly greater risk (74%) of mortality in the Seroquel-only group and a trend toward increased risk in the combination treatment group.
“It’s reasonable to assume, however, that individuals requiring these medications have greater disease severity and are at a higher risk of complications and death,” Nahab noted.
A subset of the patients receiving both medications exhibited the highest rate of mortality, although not statistically different. Importantly, the team noted that the combination therapy’s safety is not yet established, as the pivotal Phase 3 trial of Nuplazid (NCT01174004) excluded individuals on antipsychotics.
“Our findings provide the largest comparative report of mortality risk in [Parkinson’s psychosis],” researchers wrote.
However, Nahab noted limitations on the study’s design and nature, which precluded the determination of cause of death or duration of antipsychotic treatment.
“While the results pertaining to [Nuplazid] provide some reassurance for clinicians, patients, and families, future studies

Source: Parkinson's News Today

Once-a-day Capsule for Nuplazid and Lower Dose Option Approved for Parkinson’s Psychosis Patients

Nuplazid and FDA

The U.S. Food and Drug Administration has approved a once-a-day capsule formulation and a lower tablet strength for Nuplazid (pimavanserin), a treatment for the hallucinations and delusions associated with Parkinson’s psychosis.

The new formulation — a 34 mg capsule— enables patients to take the recommended oral dose once a day instead of the twice-daily existing 17-mg tablet dose.

Also approved was a 10 mg tablet (a lower-dose strength), for those Parkinson’s patients also being treated with cytochrome 3A4 inhibitors — such as some antibiotics, antidepressants and calcium channel blockers — that can affect how Nuplazid is metabolized.

Both the once-daily capsules and lower-dose tablets will be available by mid-August, Acadia Pharmaceuticals, the treatment’s maker, said in a press release.

“We are very pleased with the FDA approval of the Nuplazid 34 mg capsule and 10 mg tablet, underscoring Acadia’s continued dedication to advancing safe and effective treatment options for patients living with hallucinations and delusions associated with Parkinson’s disease psychosis,” said Steve Davis, the company’s president and CEO.

Nuplazid became the first FDA-approved treatment for hallucinations and delusions associated with Parkinson’s disease in April 2016, but the decision has been controversial.

A selective serotonin inverse agonist, Nuplazid works differently from other anti-psychotic medications in that it does not block dopamine — a brain neurotransmitter crucial to movement and motivation. Instead, it targets a subfamily of serotonin receptors (5 HT2A) of importance to cognition, memory, and the ability to learn.

Recent reports of studies into Nuplazid’s use in real-life settings have shown that the therapy is well-tolerated and can lead to clinical improvement in patients with Parkinson’s psychosis.

Joseph H. Friedman, MD, a Parkinson’s specialist at Butler Hospital and The Warren Alpert Medical School of Brown University, called Nuplazid “a significant advance in our treatments for the hallucinations and delusions in Parkinson’s” in the company release.

Friedman also welcomed the single 34 mg capsule as a “simpler and more straightforward” dosing regimen, important to patients like those he treats “who often also take multiple other medications concomitantly.”

Among the controversy surrounding Nuplazid is a CNN report claiming 244 possibly related patient deaths in the nine months after Nuplazid’s approval, citing an analysis by the Institute for Safe Medication Practices — a nonprofit healthcare group.

The FDA responded by stating that it would “continue to review the drug’s safety profile,” but adding that it recognized the medication’s “complex safety profile” and currently saw no reason to change the existing “black box” warning — the highest possible — placed on Nuplazid.

A recent editorial in The Lancet mentioned that safety concerns in Parkinson’s patients with psychosis were somewhat expected “because these patients are frail, and are usually in the end stages of the disease.” It called for more clinical trials into the medication.

In a related article published about the same time, three neurologists addressed reports of unusual risk linked to Nuplazid’s use, and some mentioned satisfaction with the medication among patients they treat using it while also recommending further study. Safety concerns need to be evaluated fully, “but in a scientific manner,” said Rajesh Pahwa, MD, a professor of neurology at the University of Kansas Medical Center in Kansas City.

Acadia is currently evaluating Nuplazid’s safety and efficacy in a wide range of people with dementia-related psychosis — including Parkinson’s patients — in the Phase 3 HARMONY trial (NCT03325556). This global study — testing pimavanserin at two doses, 34 mg and 20 mg, against placebo — is currently enrolling more than 350 dementia patients with psychosis at 80 sites across the U.S. and Europe. More information is available here.

All enrolled patients will be stabilized with 12 weeks of open-label pimavanserin treatment before being randomized into treatment and placebo groups.

The post Once-a-day Capsule for Nuplazid and Lower Dose Option Approved for Parkinson’s Psychosis Patients appeared first on Parkinson’s News Today.

Source: Parkinson's News Today

#AAN2018 – Real-life Use Supports Nuplazid’s Safety, Efficacy in Treating Parkinson’s Psychosis

Nuplazid studies

Nuplazid (pimavanserin) is well-tolerated and can lead to clinical improvement in people with Parkinson’s disease psychosis (PDP), according to the results of studies into its real-life use.

Acadia will present these data at the 2018 American Academy of Neurology ANN Annual Meeting, taking place in Los Angeles from April 21–27.

Nuplazid is an oral medication, approved by the U.S. Food and Drug Administration (FDA) in 2016 to treat psychosis in Parkinson’s patients. It belongs to a class of compounds known as selective serotonin inverse agonists. Unlike other agonists, which activate the receptors they bind to, inverse agonists induce the opposite response when binding to a cell’s receptors and block or inactivate them.

Specifically, Nuplazid binds to serotonin’s 5HT2A receptors, setting a difference from antipsychotics that interfere with the dopamine system. As loss of dopaminergic neurons is a hallmark of Parkinson’s disease, many experts think it key to avoid antipsychotics that further impair neuronal communication mediated by dopamine.

But reports on patients’ real-world experience using Nuplazid is scarce. To address this gap, researchers evaluated the therapy’s prescribing patterns and clinical efficacy in a large ambulatory group.

The study, “Clinical Experience with Pimavanserin for Treatment of Parkinson’s Disease Psychosis,” to be presented as a scientific poster on April 22, identified patients prescribed with Nuplazid between May 2016 and August 2017.

Researchers performed a retrospective chart review, determining from medical records a patient’s clinical presentation, concomitant medications, medication effectiveness, and side effects.

Nuplazid was prescribed to 70 Parkinson’s patients (76% men, mean age 71), and 59 began using it. The most common indication was visual hallucinations (97%), with 39 patients (66%) also experiencing delusions. Two (3%) had delusions only.

Thirty-nine patients exhibited persistent symptoms despite treatment in a previous trial with other antipsychotics, such as quetiapine and Clozaril (clozapine, HLS Therapeutics). Of these, 10 were able to gradually discontinue these medications after starting Nuplazid, while 18 continued or restarted another antipsychotic while on Acadia’s treatment. Twenty patients received Nuplazid as first-line therapy.

Data shows that 42  patients reported clinical improvement. The treatment was well-tolerated in 50 of the 59 patients, with the most common adverse events being worsening gait instability and weakness, observed in five people.

Of the 37 patients still on Nuplazid, 14 are also taking quetiapine and one is taking olanzapine, the study reports. Of the roughly 20 people who “failed” at treatment with Nuplazid, five found their symptoms eased using a different antipsychotic.

“This study provides relevant clinical data on prescribing patterns of pimavanserin (Nuplazid) in a large [Parkinson’s] cohort. Future studies will assess patient characteristics that predict medication efficacy,” the researchers wrote.

Another study, “Pimavanserin use in a movement disorders clinic: a single center experience,” to be presented April 26 as a scientific poster, also assessed Nuplazid’s clinical use by collecting information on demographics, psychotic features, sleep, and adverse events through telephone interviews with patients and caregivers.

Researchers classified hallucination severity as mild if reported as less than one episode per week, moderate if the range was one per week to less than one per day, and severe if such episodes were daily or continuous.

Of a total of 17 patients, 16 were diagnosed with Parkinson’s psychosis and one with Lewy body dementia. Mean duration of disease was 11.8 years, with 2.6 years as mean duration of psychotic symptoms. At the start of treatment, 93% of the 17 patients reported severe hallucinations, while 7% had moderate hallucinations.

Three had discontinued treatment by the time of the interview.

A total of 71.4% of patients reported improvements in the nature and degree of their hallucinations.

Of six patients taking Nuplazid as a sole or monotherapy, 33.3% had no change in the severity of their hallucinations, 50% improved from the severe to mild on the researchers’ scale, and 16.6% from severe to moderate.

Of the eight patients taking Nuplazid and a dopamine receptor blocker to treat their psychosis, two had no change in severity, 25% reported improvement that moved them from severe to mild hallucinations, 37.5% from severe to moderate, and 12.5% reported hallucination episodes that dropped to mild from moderate.

Of note, five of the nine patients on dopamine receptor blockers — quetiapine and olanzapine — discontinued using these after starting Nuplazid. No major adverse events were reported.

“Our survey, based on real-life experience shows that pimavanserin (Nuplazid) is well-tolerated and efficacious in treatment of PDP. It appears to be effective as both monotherapy and adjuvant treatment for moderate to severe psychosis for most patients,” the researchers wrote.

The post #AAN2018 – Real-life Use Supports Nuplazid’s Safety, Efficacy in Treating Parkinson’s Psychosis appeared first on Parkinson’s News Today.

Source: Parkinson's News Today