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Parkinson’s Foundation’s ‘Care Partner Summit’ Online Only This May 16

caregiver summit

With a focus on the unpredictable path often facing caregivers, the Parkinson’s Foundation is again hosting a free-of-charge, English-Spanish bilingual summit for those helping Parkinson’s patients with their daily needs.

But the Care Partner Summit (Cumbre Para Cuidadores) on Saturday, May 16, will be exclusively online — due the coronavirus, COVID-19, “viewing parties” planned nationwide for that day are postponed for one year.

The live Miami program and its assorted coast-to-coast viewing parties are now set for May 15, 2021.

Sponsored by Acadia Pharmaceuticals, the May summit will feature a series of expert-led panels, welcoming questions submitted by anyone caring for someone living with Parkinson’s, including spouses, partners, children, or friends. Panel topics will focus on cognitive changes, mental health, self-care, and practical planning.

Sessions will take place that day from noon to 3:30 EST (11 a.m. to 2:30 p.m. CST, 10 a.m. to 1:30 p.m. MST, and 9 a.m. to 12:30 p.m. PST).

With its theme “Planning for the Unpredictable Path of Parkinson’s Caregiving,” this summit’s goal is to provide encouragement, education, and resources to help caregivers better manage those unexpected bumps. Parkinson’s is a complex condition, and its symptoms and their progression can be different for each patient. This affects caregiving.

“The Parkinson’s Foundation Care Partner Summit helps to prepare care partners with tools and resources to make life better for themselves and their loved one with PD,” John L. Lehr, president and CEO of the Parkinson’s Foundation, said in a press release. “This event also allows us to address the needs and priorities of our care partner community, and support them throughout every stage of their PD journey.”

Go here to register in English or Spanish. A video of the Foundation’s first bilingual summit, which focused on self-care and caregiving, is available here.

“Acadia is proud to be the presenting sponsor of this important initiative to support Parkinson’s disease caregivers and the development of educational tools and resources for the patient community,” said Ponni Subbiah, MD, Acadia senior vice president, global medical affairs and chief medical officer.

Parkinson’s disease affects an estimated one million U.S. residents — 60,000 new cases diagnosed annually— and 10 million individuals globally.

Acadia is focused on developing and commercializing treatments addressing unmet medical needs in diseases of the central nervous system, including Parkinson’s.

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

antipsychotics

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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Safety and Efficacy of Oral Cannabidiol in Treating Parkinson’s Psychosis Focus of Phase 2 Study in UK

cannabidiol

A planned Phase 2 clinical trial will assess the safety and effectiveness of pharmaceutical-grade cannabidiol (CBD) in treating Parkinson’s-related psychosis.

The trial was announced by Parkinson’s UK, which is investing £1.2 million (roughly $1.5 million) to support the study, due to begin enrolling patients in 2020.

Psychosis is estimated to affect more than half of people with Parkinson’s disease. It is characterized by hallucinations (seeing, hearing, or feeling things that are not really there) and delusions (fixed beliefs that are demonstrably untrue).

These symptoms are typically managed by reducing or stopping the use of medications used to treat Parkinson’s, but such choices have the obvious drawback of arresting any benefits those treatments provide. Antipsychotics are sometimes also used, but they can carry side effects or worsen motor symptoms.

Nuplazid (pimavanserin, by Acadia Pharmaceuticals) is the only medicine currently approved to treat Parkinson’s-related psychosis in the United States; no approved therapies for this condition are available in the United Kingdom.

“Current treatments prescribed by clinicians for psychosis typically work by blocking dopamine receptors, which can increase the problems people with Parkinson’s experience with movement and other symptoms of the condition,” Sagnik Bhattacharya, a professor at King’s College London who will help lead the trial, said in the press release.

This trial will “will determine, for the first time, whether CBD can correct the abnormal functioning of the brain that is causing symptoms such as hallucinations and delusions,” Bhattacharya added.

Cannabidiol is a non-psychoactive component of the cannabis plant, meaning it is found in cannabis, but unlike tetrahydrocannabinol or THC does not induce a feeling of being “high.” CBD is currently undergoing a renaissance of interest for its potential medical uses.

“We know from a recent survey we carried out, that people with Parkinson’s would continue to use, or start using, cannabis-derived products if robust evidence became available that they are safe and effective in treating Parkinson’s symptoms,” said Arthur Roach, PhD, the director of research at Parkinson’s UK. “One of the key questions this clinical trial will address is if CBD is safe to use for Parkinson’s-related psychosis, which has never been done before.”

The two-part study will begin with a six-week pilot phase to evaluate the safety, tolerability and effectiveness of CBD in people with Parkinson’s-related psychosis. Participants will be given daily oral CBD capsules at doses up to 1 gram per day to find the optimum dose. Then, 120 patients will be randomized to treatment with either CBD or a placebo for 12 weeks.

In addition to safety, trial goals (endpoints) will include a detailed assessment of psychotic, motor and non-motor symptoms, as well as brain imaging.

“We will be assessing how safe CBD is for people with Parkinson’s, what the correct dosage is and how it is tolerated alongside the different medications someone with the condition may already be on,” Bhattacharya said. “The study will also look at the effect of CBD on other symptoms which will pave the way for scientists to investigate the potential of the compound in treating these in future studies.

“We hope that this will progress to large-scale clinical trials — the final step towards becoming a new treatment that will improve the lives of people with Parkinson’s,” Bhattacharya added.

If successful, this study “could result in a regulated cannabinoid-based medicine being prescribed and used in the clinic, as opposed to self-administration of expensive supplements that have not been monitored for their composition or effects,” Roach said.

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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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Phase 2 Trial of SEP-363856, Potential Oral Treatment of Parkinson’s Psychosis, Enrolling in US

SEP-363856 psychosis trial

A Phase 2 clinical trial of SEP-363856, an oral treatment candidate for people with Parkinson’s psychosis, is now recruiting patients across the U.S.

SEP-363856 is a candidate therapy being developed by Sunovion to treat schizophrenia, and the hallucinations and delusions linked to Parkinson’s disease. It is designed to act as an antipsychotic agent, but through a mechanism distinct from currently available antipsychotics. Specifically, it does not bind to dopamine 2 (D2) or serotonin 2A (5-HT2A) receptors, as current antipsychotics are thought to do.

The 21-week, multi-part Phase 2 SEP361-203 trial (NCT0299369) is expected to enroll up to 36 patients, ages 55 and older, at 24 sites. Among them, 24 people will initially be randomized to SEP-363856 treatment and 12 will be given a placebo.

Eligible patients must have been diagnosed at least one year before study’s start, and have been experiencing such psychosis symptoms as visual hallucinations or paranoia (delusions). Participants also need to have a caregiver able to attend an estimated 13 on-site visits.

Following an initial screening, patients will be randomly assigned to either SEP-363856 oral capsules at 25, 50, or 75 mg once daily, or to a matching placebo, for six weeks. This treatment period will be followed by 12 weeks of an open-label extension phase, during which all participants will be given SEP-363856.

Researchers will evaluate the safety, tolerability, and effectiveness of the candidate therapy.

They will assess changes in the Scale for Assessment of Positive Symptoms–Parkinson’s Disease (SAPS-PD) total score, which addresses manifestations of hallucinations and delusions. Researchers will also evaluate, as secondary trial goals, disease severity and patients’ cognitive function.

The roughly five-month study is expected to expected to conclude in May 2020.

SEP-363856 was designated a breakthrough therapy as a potential treatment of schizophrenia by the U.S. Food and Drug Administration in May, based largely on results from a Phase 2 trial and an open-label extension study. The designation offers FDA guidance to the company in developing the potential treatment, and priority review should a request be filed for approval.

Currently, Nuplazid (pimavanserin), by Acadia, is the only FDA-approved medication for treating hallucinations and delusions associated with Parkinson’s disease.

More information on the SEP361-203 study is available on its website.

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Nuplazid Eases Depression in Parkinson’s Patients, Phase 2 Trial Shows

Nuplazid

Treatment with Nuplazid (pimavanserin), approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s psychosis, eased depression and sleep problems in patients with Parkinson’s, according to results from a Phase 2 clinical trial.

The research, “Open-Label Study of Pimavanserin Patients With Comorbid Parkinson’s Disease and Depression,” was presented at the 2019 International Congress of Parkinson’s Disease and Movement Disorders in Nice, France.

Depression is one of the most frequent non-motor symptoms of Parkinson’s. While its severity and duration typically increase with disease progression, easing depression has been linked with greater quality of life and less disability.

An eight-week, open-label, study (NCT03482882) assessed Acadia Pharmaceuticals’ Nuplazid either as a stand-alone therapy, or as an add-on to a selective serotonin reuptake inhibitor (SSRI, a type of antidepressant) or a selective norepinephrine reuptake inhibitor (SNRI) for Parkinson’s patients with depressive symptoms. The 47 participants, all 50 or older, received two 17 mg oral tablets per day of Nuplazid.

Nuplazid is a selective serotonin inverse agonist that targets serotonin receptors called 5HT2A receptors. Inverse agonists bind to the same receptors as agonists, but induce the opposite pharmacological response. Serotonin receptors are found throughout the nervous system. Specifically, 5HT2A has been associated with mental disorders such as depression and epilepsy.

The results found significant benefits as early as week 2 assessed with the 17-item Hamilton Depression Rating Scale (HAMD-17) — the study’s primary goal. At week 8, 60% of the participants showed an improvement of at least 50% on the HAMD-17 score, with 44.4% of patients reaching remission (HAMD-17 score up to 7).

The study also showed improvements on the Clinical Global Impression-Severity scale (a measure of disease severity) and the Clinical Global Impression-Improvement — a 0.5 lower score from week 2 to week 8, as rated by clinicians.

Sleep measures, namely the SCOPA-nighttime sleep and SCOPA-daytime sleepiness scales, also revealed benefits from week 4 to week 8. Likewise, the SCOPA-Global Sleep Quality scale showed significant improvements comparing week 8 to baseline.

“Results of this open-label study suggest that pimavanserin may be a potential treatment to be further investigated for depression associated with Parkinson’s,” Gus Alva, MD, a co-author of the study, and founder and medical director of ATP Clinical Research, said in a press release.

Treatment with Nuplazid was well-tolerated, with treatment emergent adverse events (TEAE) being in line with other studies of this therapy. Reported TEAEs included falls (8.5%), nausea (6.4%), diarrhea (4.3%), edema, or swelling (4.3%), skin abrasion (4.3%), and urinary tract infection (4%).

“Pimavanserin [Nuplazid] as adjunctive or monotherapy is associated with early sustained improvement of depressive symptoms in patients with [Parkinson’s] and is well tolerated,” the scientists wrote.

“We are pleased with the exploratory study results which show a positive treatment effect with pimavanserin [Nuplazid] for depression in patients with Parkinson’s,” said Serge Stankovic, MD, Acadia’s president.

Stankovic commented that the results are consistent with those of the 10-week CLARITY Phase 2 study (NCT03018340). Using Nuplazid as an add-on led to improved HAMD-17 scores, while also easing disability and sleepiness,  and improving sexual function in patients with major depressive disorder with inadequate response to standard SSRI/SNRI treatments.

Nuplazid is currently being tested in two six-week Phase 3 studies named CLARITY-2 (NCT03968159) and CLARITY-3 (NCT03999918), each with approximately 280 patients. Patients who complete these trials will be able to participate in a 52-week open-label extension study (NCT04000009) to assess long-term safety and tolerability. These three studies are currently enrolling. (For more information, follow the links on the NCT identifiers.)

“We are committed to continued research for pimavanserin [Nuplazis] to address unmet medical needs in central nervous system disorders, including our ongoing Phase 3 clinical program in major depressive disorder,” Stankovic said.

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Benefits of Acadia’s Nuplazid Outweigh Risks for Parkinson’s Psychosis Patients, FDA Reports

Nearly half a year after news reports surfaced about deaths allegedly linked to Nuplazid (pimavanserin) — a therapy for Parkinson’s patients with disease-related psychosis — the U.S. Food and Drug Administration says it could not find any new or unexpected safety concerns with the controversial treatment.
The agency said in a Sept. 20 press release that “after a thorough review, the FDA’s conclusion remains unchanged that the drug’s benefits outweigh its risks for patients with hallucinations and delusions of Parkinson’s disease psychosis.”
San Diego-based Acadia Pharmaceuticals, which produces Nuplazid, welcomed the announcement.
“As the only drug currently approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, Nuplazid is filling an important and previously unmet need,” Doral Fredericks, Acadia’s vice president for U.S. medical affairs, said in a statement emailed to Parkinson’s News Today.
She added that “we remain confident in the efficacy and safety of Nuplazid that supported its approval by the FDA and the reaffirmation the agency has given for the positive benefit-risk profile of Nuplazid in its most recent review.”
In that review, the FDA said it considered the fact that patients with Parkinson’s psychosis are more likely to die in the first place due to their older age, advanced disease, and other medical conditions.
“Moreover, Nuplazid is primarily distributed through a patient support program and a specialty pharmacy network, which increases the likelihood that deaths will be reported to the manufacturer,” said the agency, referring to its FDA Adverse Event Reporting System (FAERS). “In FAERS reports that included a cause of death (many reports did not provide sufficient information to assess drug cause and effect), there was no evident pattern to suggest a drug effect.”
It added that “overall, the postmarketing data were consistent with the safety data obtained from the premarketing controlled clinical trials of Nuplazid for Parkinson’s disease psychosis.”
The recommended dosage is 34 mg, taken orally as two 17 mg tablets once daily, with or without food.
The FDA’s recognition of Nuplazid’s complex safety profile after the medication’s April 2016 approval, the agency said in an April 2018 statement, “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.”
Concern over Nuplazid first surfaced following a CNN report in April. An article on the network’s website cited an analysis by the nonprofit Institute for Safe Medication Practices, which found that FAERS showed a total of 700 deaths — including 500 among Parkinson’s patients in which Nuplazid was the only treatment likely involved — in the nine months following Nuplazid’s June 2016 appearance on the market.
Nuplazid is targeted at treating Parkinson’s psychosis, which affects about 40 percent of the 1 million Americans believed to have the disease. According to CNN, the therapy — Acadia’s only product — generated $125 million in 2017 sales for the company.
The New York-based Michael J. Fox Foundation for Parkinson’s Research posted a bulletin about the FDA’s review on its website but offered no independent

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

Nuplazid’s Risks in Treating Parkinson’s Psychosis Don’t Appear Exceptionally High, Experts Say

Nuplazid and Parkinson's psychosis

The controversy surrounding Nuplazid (pimavanserin), Acadia Pharmaceuticals‘ approved treatment for psychosis in Parkinson’s patients, has made its way to scientific journals. But experts appear to take a more questioning view of the medication’s risks than that aired by general media.

A clinical trial comparing the effectiveness and benefits of Nuplazid to other antipsychotics used to treat these patients would be warranted, and ideally pit the medication against clozapine, an editorial in The Lancet said. But the piece also noted that clozapine, a schizophrenia treatment, is not approved for Parkinson’s disease and is used off-label, complicating matters.

The editorial, “Difficult choices in treating Parkinson’s disease psychosis,” was published on May 29.

Focusing on the “relative risk of pimavanserin” in comparison to psychosis medications like clozapine and quetiapine, it also noted that “it is important to remember that safety concerns were expected and deaths can occur commonly in patients with Parkinson’s disease psychosis — a fact acknowledged by the FDA during its assessment — because these patients are frail, and are usually in the end stages of the disease.”

Still, the editorial recommended that a randomized clinical trial assessing Nuplazid’s risks and benefits in Parkinson’s patients be pursued, and research “continue into novel drugs for psychosis in frail populations.”

In the journal Neurology Todaymeanwhile, three neurologists questioned reports of an unusual risk to Parkinson’s patients being treated with Nuplazid for psychosis.

“In my personal experience with pimavanserin, it is effective in a majority of PD [Parkinon’s] psychosis patients,” said Rajesh Pahwa, MD, a professor of neurology and chief of the Parkinson & Movement Disorders Division at the University of Kansas Medical Center in Kansas City. “We need to further study the reports of increased mortality, but in a scientific manner.”

The journal’s “Article in Brief,” published June 7, recounted the controversy concerning Nuplazid, the first medication approved by the U.S. Food and Drug Administration to treat Parkinson’s psychosis, or disease-related hallucinations and delusions, in 2016.

Nuplazid works differently from other anti-psychotic medications in that it does not block dopamine — a brain neurotransmitter crucial to movement and motivation, and the target of treatments for Parkinson’s movement difficulties — focusing instead on a subfamily of serotonin receptors (5 HT2A) of importance to cognition, memory, and the ability to learn.

The news channel CNN reported in April that the FDA’s Adverse Event Reporting System (FAERS) showed a total of 700 deaths, including 500 in Parkinson’s patients in which the medication was the only agent likely involved.

The FDA initially responded by noting that “FAERS data by themselves are not an indicator of the safety profile of the drug or biologic,” and emphasizing it had placed a “boxed warning” on Nuplazid highlighting its risks. A boxed warning is the strictest warning on product labeling that can be given an approved medication, but one — warning of an increased risk of mortality and morbidity in people with dementia — given on all antipsychotics, The Lancet commentary noted.

Later, the FDA acknowledged that is was continuing to keep close watch on Nuplazid and its use in Parkinson’s patients. The CNN report led to a 20 percent drop in Acadia’s stock in the days after its airing.

But, as Pahwa argued, the U.S. Medicare database show that mortality rates (per 100 patient years) are 7.3 for Parkinson’s patients without psychosis, and 28 for patients with psychosis — with a mortaility rate of 18.6 for those using quetiapine off-label, compared to 12.4 in post-marketing data for pimavanserin.

Joseph Jankovic, MD, director of the Parkinson’s Disease Center at Baylor College of Medicine in Houston, told Neurology Today that his patients largely have responded well to Nuplazid treatment.

“While not all patients are completely satisfied, many of my patients have experienced marked improvement in their visual hallucinations, paranoia, and other psychotic symptoms,” Jankovic said. “I suspect that the death rates in elderly patients with advanced PD and psychosis are higher than in a control population without these problems, so it’s not surprising to see deaths in such patients who are taking pimavanserin, but the cause-effect relationship has not been established.”

He preferred to recommend that physicians simply continue to closely monitor their patients.

A similar view was voiced by Cynthia Comella, MD, a professor of neurology at Rush University Medical Center’s Parkinson’s Disease and Movement Disorders Section in Chicago.

“I think it is too soon to be concerned specifically about this drug,” Comella said. “I feel that we need to be cautious with all of these drugs. I especially have concerns prescribing them in elderly patients because they are more fragile and usually have additional disorders and health conditions.”

According to the Neurology Today article, Pahwa has received consulting fees from about a dozen pharmaceuticals and government agencies including Acadia, but no research grants from Acadia. Jankovic and Comella reported no conflicts of interest.

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Source: Parkinson's News Today

Better Understanding of Parkinson’s Psychosis Needed to Develop New Therapies, Study Suggests

psychosis

Improved understanding of Parkinson’s disease psychosis (PDP) and a unified approach for its clinical evaluation are key for developing new therapeutics, a review study suggests.

The research, “Treating Hallucinations and Delusions Associated With Parkinson’s Disease Psychosis,” was published in the journal Current Psychiatry Reports.

PDP has been increasingly recognized as a distinct clinical symptom linked with Parkinson’s progression, dementia, and medications. Both its diagnosis and symptom management remain challenging.

PDP is a non-motor symptom that causes patients to experience hallucinations and delusions, with more than half of Parkinson’s patients developing psychosis over the course of their disease.

PDP involves diverse neurotransmitter systems. Altered functioning of serotonin 5-HT2A receptors may affect how PDP patients process what they see.

Visual hallucinations — seeing, hearing, or feeling things that do not exist — are the most frequent feature in PDP patients, but non-visual hallucinations also may occur. Delusions  — distorted interpretations of reality — are more often paranoid and related to persecution or infidelity.

Both visual hallucinations and delusions are risk factors for nursing home placement, which has been associated with a 100 percent mortality rate in a two-year follow-up study. This underscores “the severity with which psychosis correlates with the disease state,” authors wrote. PDP also may impact caregivers, who have shown greater risks for chronic illnesses, depression, and mortality.

As for risk factors underlying the development of psychotic symptoms, dementia and cognitive impairment have been demonstrated extensively. Older age, Parkinson’s duration and severity, and sleep disturbances also are associated with greater risk of PDP.

Regarding treatment, non-pharmacological approaches are an important initial option. Potential reversible medical problems and patients’ non-Parkinson’s related medications — in particular antidepressants, sedatives, and narcotics — should be assessed carefully. Clinicians should then focus on Parkinsonian medications with the greatest risk of inducing psychosis, and always be on the lookout for worsening of motor symptoms.

Regarding pharmacological options, until recently patients had no approved treatments, leading to off-label use of atypical antipsychotics, which may worsen motor symptoms. These medications differ from typical antipsychotics because they induce fewer extrapyramidal symptoms, which are drug-induced movement disorders that include acute and late symptoms.

Pharmacological approaches should be considered if non-pharmacologic strategies and reducing doses of anti-parkinsonian medications are not able to reduce PDP symptoms without affecting motor function, the authors noted.

Several studies demonstrated the safety and tolerability of low-dose Clozaril (clozapine, HLS Therapeutics), an atypical antipsychotic, in PDP patients, without worsening their motor symptoms. Supporting research included multi-center, double-blind trials, which reported benefits with doses ranging between 6.25–50 mg/day. However, patients’ white blood cell counts should be monitored.

Seroquel (quetiapine, AstraZeneca) is a more potent blocker of 5-HT2A receptors than Clozaril. Studies found better results with lower doses, but lack of superior effectiveness over placebo has been consistent.

Zyprexa (olanzapine), which has higher affinity for 5-HT2A receptors than for dopaminergic D2 receptors, showed effective reduction of psychosis, but several studies showed worsened motor function, while others failed to observe differences compared to placebo. As a result, the American Academy of Neurology concluded that olanzapine should not be routinely used for PDP.

More recently, Acadia Pharmaceuticals developed Nuplazid (pimavanserin), a selective 5-HT2A/C receptor inverse agonist with no activity on dopamine receptors, which is an important feature given Parkinson’s patients’ loss of dopaminergic neurons. Inverse agonists induce pharmacological responses opposite to agonists though binding to the same receptors. Doses between 25 and 60 mg/day showed good safety and tolerability results without worsening motor symptoms.

In a larger Phase 3 clinical trial with 199 patients taking either Nuplazid 40 mg/day or placebo over six weeks, the therapy improved both sensory hallucinations and delusions, improved sleep and cognition, and did not lead to declined motor function. Nuplazid became the first medication approved by the U.S. Food and Drug Administration to treat PDP.

Several other atypical antipsychotics and non-antipsychotic medications have been assessed for PDP, but their variable effectiveness and potential motor-worsening falls short of a recommendation for standard use. These include risperidone, ziprasidone, aripiprazole, and melperone.

“While new therapeutics and targets continue to be investigated, a more complete understanding of PDP pathology is needed to further refine drug targets,” the researchers wrote.

“Ultimately, investigation into novel agents will require exploration of not only selective receptor targets, but also a unified approach to the clinical evaluation of PDP itself,” they added.

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Source: Parkinson's News Today