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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.

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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.

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Source: Parkinson's News Today

FDA Continuing to Monitor Nuplazid Use, But Sees No Shift from Expected, Agency Says

Nuplazid

The U.S. Food and Drug Administration is keeping close watch on the use of Nuplazid (pimavanserin) by Parkinson’s patients with disease-related psychosis, but at present sees no reasons to change the existing warnings placed on the medication — sold by Acadia Pharmaceuticals — when first approved.

The FDA stated its position, given in response to a recent CNN report on patient deaths allegedly linked to the Parkinson’s medication, in an email sent April 16 to Parkinson’s News Today.

“We are aware of adverse events associated with Nuplazid and continue to review the drug’s safety profile,” said the statement, sent byb a press officer in the FDA’s Office of External Affairs.

The FDA said it has recognized the medication’s “complex safety profile” ever since Nuplazid was approved in April 2016 under its Breakthrough Therapy designation— one of four expedited FDA review programs that apply to medications showing substantial improvement over existing treatments in early clinical data.

This recognition, it said, “led to the inclusion of a Boxed Warning and the addition of other important Warnings and Precautions in the product labeling, so that healthcare professionals could have the risk/benefit information needed to make prescribing decisions.”

Nuplazid is aimed at treating Parkinson’s disease psychosis, a condition characterized by hallucinations and delusions that affects about 40 percent of the one million or so Americans with the disease. According to CNN, Nuplazid generated $125 million in 2017 sales for Acadia, a San Diego-based company.

The April 9 article on the cable network’s website cited an analysis by the Institute for Safe Medication Practices — a nonprofit healthcare group — finding that 244 deaths had been reported to the FDA in the nine months between Nuplazid’s June 2016 appearance on the market and March 2017. The day the story broke, shares of Acadia nosedived by 23 percent.

But the CNN article did not show any evidence that Parkinson’s patients on Nuplazid were more likely to die than patients not taking the medication. In fact, the network quoted an Acadia statement noting that Parkinson’s patients using Nuplazid had a much lower death rate than those with psychosis but not taking the therapy.

“We have noted that the cases typically involve geriatric patients with advanced-stage Parkinson’s disease, as well as numerous medical conditions, who are frequently taking concomitant medications with risks for serious adverse events, including death,” the FDA noted in its statements.

The Parkinson’s Foundation, in statement posted on April 10 that referred to the CNN article, said it’s “closely monitoring” the recent reports on Nuplazid.

“At this time, we are recommending that patients on this drug consult with their neurologists about the risks and benefits of the treatment,” it said. “The FDA will continue to monitor the drug’s use and safety, but they have not identified a specific safety issue that isn’t already described in the drug’s label.”

The Michael J. Fox Foundation, in a similar posted statement, also said it “will continue to monitor and report any new developments around the status of Nuplazid.”

MJFF added as a disclaimer that while it didn’t fund Acadia’s development of this therapy, “our clinical trial search engine, Fox Trial Finder, helped to increase the flow of participants into clinical trials of the drug” and that the foundation “has also granted funding to Acadia for studies of a different Parkinson’s therapy.”

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Source: Parkinson's News Today

Nuplazid and Clozaril Are Most Reliable Parkinson’s Psychosis Therapies, Review Finds

Parkinson's psychosis therapies

The antipsychotics Nuplazid (pimavanserin) and Clozaril (clozapine) are the only therapies shown to improve Parkinson’s disease psychosis (PDP) symptoms without impairing motor function, in double-blind, placebo-controlled clinical trials, according to a review.

The study, “Pharmacological interventions for psychosis in Parkinson’s disease patients,” was published in the journal Expert Opinion on Pharmacotherapy. 

Parkinson’s disease psychosis is a non-motor symptom that causes patients to experience hallucinations and delusions. More than half of Parkinson’s patients will develop psychosis over the course of their disease.

While hallucinations — seeing, hearing, or feeling things that do not exist — are usually harmless, with no associated emotion, delusions — distorted interpretations of reality — are usually paranoid, creating stressful situations.

Researchers believe the risk factors of Parkinson’s disease psychosis include medication, disease duration, dementia, and delirium — a short-term, reversible symptom usually caused by abnormalities in metabolism, medical conditions, or reactions to medication.

In most cases, Parkinson’s-related psychosis is believed to be a side effect of the medication to treat Parkinson’s. For that reason, treatment involving medication reduction, which can result in aggravated motor symptoms, is only performed when psychosis symptoms become a problem for the patient or caregivers.

In his report, the author argues that before doctors evaluate medication reduction, medical conditions — specially infections — that can cause psychosis should be treated, and psychoactive medication — such as antidepressants, pain killers, and anti-anxiety medication — reduced, if possible.

There is no consensus on the order in which Parkinson’s medications may be reduced, or the speed at which they should be reduced. Clinicians must make those decisions based on the specifics of each patient and their reaction to therapy.

After reducing Parkinson’s medication towards lower levels that can be tolerated by patients, doctors may recommend the use of antipsychotic drugs, such as Nuplazid (pimavanserin), Clozaril (clozapine), or Seroquel (quetiapine, or QTP), to balance abnormal chemical levels in the brain.

Nuplazid and Clozaril are the only therapies which have seen their efficacy supported by double-blind, placebo-controlled clinical trials. Both were shown to reduce psychosis symptoms without impairing motor function.

Nuplazid, the only FDA-approved treatment for PDP, takes four to six weeks to show benefits. On the other hand, Clozaril takes only one week to show responses, but requires frequent blood tests, which makes it inconvenient for elderly patients.

These tests are meant to monitor neutropenia, or reduced levels of neutrophils — a type of white blood cell. This adverse event is reported in some patients under Clozaril.

As for Seroquel, double-blind, placebo-controlled clinical trials showed that it does not improve psychotic symptoms in PDP, even though it does not affect motor function. The author noted that, interestingly, despite the non-positive results in those trials, he and other Parkinson’s experts often use it and find it useful to treat PDP.

Two other antipsychotics, Zyprexa (olanzapine) and Melperone, were also subject to trials. However, none showed benefits for psychosis symptoms. And Zyprexa was shown to induce harmful motor effects, making it a therapy to be avoided.

Dementia drugs, such as cholinesterase inhibitors, showed potential improvements in psychosis features, but additional studies are required to confirm those effects.

As of January 2018, the current position of the International Parkinson Disease and Movement Disorders Society on psychosis, which has not yet been updated to include the positive Nuplazid results, recommends Clozaril over Seroquel. Additional clinical trials are needed to clarify the benefits of other antipsychotic drugs to treat PDP.

The author, Joseph H. Friedman of the Department of Neurology, Warren Alpert Medical School, of Brown University, has received research funding from the National Institutes of Health and the Michael J. Fox Foundation.

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Source: Parkinson's News Today

Safety Watchdog ISMP Issues Alert on Acadia’s Nuplazid Therapy for Parkinson’s

Nuplazid alert

The Institute for Safe Medication Practices (ISMP) questions the approval of Acadia Pharmaceuticals’ antipsychotic therapy Nuplazid (pimavanserin) in the face of reports that it is ineffective in treating Parkinson’s disease and leads to severe adverse effects, including death.

Researchers shared these concerns in an article, “Safety Signals for Two Novel Drugs,” that appeared in the ISMP publication QuarterWatch. In it, the Pennsylvania-based ISMP issued a safety alert for the medication, and cautioned against combining Nuplazid with Seroquel (quetiapine) or other antipsychotics. It cautioned that such treatments are not recommended for older people, nor are they approved for use in Parkinson’s.

Unlike traditional antipsychotic medications — which mainly block dopamine signaling in the brain, Nuplazid blocks certain types of serotonin receptors. Blocking dopamine using other antipsychotics may trigger worsened movement symptoms in Parkinson’s patients, as these medications essentially counter the effect of levodopa and similar Parkinson’s treatments.

The U.S. Food and Drug Administration (FDA) approved Nuplazid in 2016, despite limited evidence of its effectiveness, ISMP noted.

The institute has access the all adverse events data, best known as MedWatch reports, sent to the FDA. The team noted that Nuplazid was among the 66 medications for which the FDA received 1,000 or more adverse events reports.

ISMP examined four main groups of adverse events for the treatment over the course of a year since Nuplazid’s approval. While the medication intends to treat psychotic symptoms — hallucinations and delusions — the main reported adverse event was hallucinations.

Nearly 22 percent of all reported adverse events were hallucinations. On second place were reports of lack of effectiveness, making up 15 percent of all reports. Confusion and death were the other two frequently reported issues.

This indicates that either the treatment is ineffective, or it worsens psychotic symptoms in some patients, ISMP said. Moreover, the data is consistent with that from the Phase 3 clinical trial (NCT01174004), which led to the medication’s approval.

In that study, both hallucinations and confusion were more common in treated patients compared with patients getting a placebo. An FDA medical reviewer had also underscored that Nuplazid treatment more than doubled the risk of death and serious adverse events in this trial, the ISMP underscored.

The reviewer had recommended against the approval of the treatment, based on this finding and the fact that Nuplazid was minimally effective — an effect assessed with an unvalidated tool. In addition, three earlier trials had failed to show a benefit from the treatment.

These facts made the ISMP side with the cautious reviewer, stating that “We found that pimavanserin was FDA-approved on limited scientific evidence that its benefits outweighed its risks.”

In addition to the adverse events reports, ISMP researchers also noted that many patients used Nuplazid together with Seroquel or other antipsychotics that block dopamine signaling. In addition to not being recommended or approved for the treatment of Parkinson’s psychosis, a recent review noted that there is no evidence that such combinations are effective.

The ISMP, however, gave Nuplazid’s maker, Acadia, a chance to comment on the observations.

The large numbers of adverse event reports, Acadia said, could partly be explained by the company’s extensive contact with health professionals and consumers through a specialty pharmacy network that distributes Nuplazid. Acadia also run a patient support program, which may improve reporting.

But the company also said that reports of hallucinations may reflect the slow onset of Nuplazid’s treatment effect — it takes four weeks for the treatment to be fully effective. Reported hallucinations may, therefore, have occurred before the drug became fully effective, it claimed.

“We share the FDA medical officer’s concerns about the approval of pimavanserin in the face of weak evidence of effectiveness, on the basis of a single small trial, and with increased rates of serious adverse events including death. The early but substantial adverse event data further support these concerns,” the ISMP concluded.

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Source: Parkinson's News Today

Nuplazid Review Endorses Treatment, But Pinpoints Additional Study Needs

Nuplazid Review

Even though 60 percent of Parkinson’s Disease patients develop psychotic symptoms, it was only in 2016 that a treatment for the condition was approved.

Nuplazid (pimavanserin) employs an entirely different mechanism to control psychotic symptoms compared to the bulk of antipsychotic medications on the market.

The review, Pimavanserin, a novel antipsychotic for management of Parkinson’s disease psychosis,” took a look at the drug’s specific features, and its potential to early on prevent psychotic symptoms from bringing on more severe disease and premature death among Parkinson’s patients.

Researchers from Feinberg School of Medicine at Northwestern University, published the review in the journal Expert Review of Clinical Pharmacology.

Why not common antipsychotics?

Treatments capable of treating hallucinations and delusions have existed since the 1950s. So, why then do people with Parkinson’s disease require a specific type of medication?

People with Parkinson’s disease suffer neurodegeneration, particularly affecting neurons producing the neurotransmitter dopamine; medications aim to replace lost dopamine signaling by adding more of the substance.

The problem is that the majority of antipsychotic treatments work to block dopamine receptors. Using such drugs, therefore, would worsen motor symptoms. Moreover, some studies show that antipsychotics may increase the risk of death among Parkinson’s patients, although the issue is a topic of debate.

The brain, however, is complex and some newer compounds exist that target other signaling substances to treat psychosis.

Clozapine is considered the most effective antipsychotic on the market. But its widespread use, in Parkinson’s as well as other patients, is prevented by severe and potentially fatal side effects linked to the treatment. Patients need to be closely monitored with blood cell counts because a loss of neutrophil cells can be life-threatening.

Another so-called atypical antipsychotic, quetiapine, is sometimes used in Parkinson’s psychosis. But clinical trials have failed to prove the treatment is more effective than a placebo.

Moreover, both clozapine and quetiapine cause sedation and postural hypotension, which can be difficult to tolerate for someone with Parkinson’s disease, and may increase the risk of falls and worsen cognition, researchers underscored.

The novelty of Nuplazid

Unlike these medications, Nuplazid blocks brain receptors for the neurotransmitter serotonin. The drug has been studied in five Phase 2 or 3 clinical trials, and a sixth is ongoing. So, there is plenty of data showing the safety and effectiveness of this approach.

An analysis of pooled data from four of these trials showed that Nuplazid effectively reduced hallucinations and delusions in patients with Parkinson’s disease psychosis. It also has a good benefit-safety balance, researchers say.

While the side effects of earlier antipsychotics often made doctors delay treating Parkinson’s patients until the hallucinations and delusions became more severe, Nuplazid’s safety profile allows early treatment, the Feinberg researchers underscored.

Studies show that psychotic symptoms in Parkinson’s disease are linked to worsening disease and early death. Moreover, a psychotic Parkinson’s patient is extremely difficult to manage for family caregivers, often making early nursing home placements necessary.

Early treatment, researchers argued, may prevent this development. Since it takes several weeks for the drug to be fully effective, it also is important to start treatment early to prevent a potential exacerbation, they said.

More studies are needed, however, to explore if early treatment really does change the course of negative outcomes linked to psychosis in Parkinson’s disease.

Future directions

Nevertheless, although Nuplazid is approved for use in Parkinson’s disease, it carries a boxed warning that patients with dementia taking antipsychotics are at an increased risk of death.

Many patients with Parkinson’s psychosis also develop dementia, so more information is needed to assess the safety and effectiveness of Nuplazid in this patient group, the reviewers noted.

Acadia Pharmaceuticals, Nuplazid’s developer, recently launched a Phase 3 trial (NCT03325556) testing the drug in patients with dementia-related psychosis. The study enrolls patients with Parkinson’s disease, among others.

The review, however, pointed out that further studies examining the drug are necessary. For instance, the treatment is available in one dose only. Studies should explore other doses, and assess the safety of combining Nuplazid with atypical antipsychotics for people who fail to respond to Nuplazid alone.

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Source: Parkinson's News Today