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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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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

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