Pimavanserin is an oral therapy targeting serotonin (a neurotransmitter carrying chemical signals between nerve cells). It is being developed by San Diego-based Acadia Pharmaceuticals for managing psychosis, aggression, and agitation in Alzheimer’s disease patients. Psychotic symptoms occur in up to a 50 percent of Alzheimer’s patients.

In 2016, pimavanserin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hallucinations, delusions, and psychosis in patients with Parkinson’s disease. It is sold under the brand name Nuplazid for these indications.

How pimavanserin works

Alzheimer’s disease alters serotonin signaling in the brain, resulting in patients experiencing behavioral and psychotic symptoms such as hallucinations, delusions, aggression, and agitation.

Pimavanserin is a selective serotonin (5-HT) 2A receptor inverse agonist, meaning that it binds not only to the 5-HT2A receptor (like an agonist), but has the additional ability to block serotonin signaling. Blocking this receptor has been shown to reduce psychotic symptoms.

Pimavanserin in clinical trials

Data from a Phase 2 trial (NCT02035553) completed in 2016 with 181 patients (mean age 86 years) revealed that a daily dose of 34 mg of pimavanserin was able to significantly reduce symptoms of psychosis (as determined by the neuropsychiatric inventory-nursing home (NPI-NH) psychosis score) after one-and-a-half months of treatment, compared to placebo. Patients with more severe baseline psychotic symptoms and those who were on antipsychotics previously experienced larger improvements in their symptoms.

However, there was no difference between pimavanserin and placebo in the NPI-NH score at three months after treatment. Furthermore, no differences between the two groups were found in terms of agitation and ability to perform activities of daily living.

There are two other ongoing Phase 2 clinical trials testing pimavanserin. The first one, the SERENE trial (NCT02992132), is looking into the safety and effectiveness of pimavanserin to treat agitation and aggression in people with Alzheimer’s disease. Patients are given either 34 mg or 20 mg of daily pimavanserin, or a placebo for three months.

Patients who successfully complete the SERENE trial are eligible to take part in an open-label extension study (NCT03118947). This follow-up study assesses the safety and tolerability of 34 mg and 20 mg of pimavanserin taken for a year. It was initiated in February 2017 and is estimated to be completed in May 2020.

A Phase 3 clinical trial (NCT03325556) called HARMONY was launched in September 2017 to study the ability of pimavanserin to prevent the relapse of psychotic symptoms in dementia-related psychosis and will include patients with Alzheimer’s, dementia with Lewy bodies, Parkinson’s disease dementia, frontotemporal dementia, and vascular dementia.

It will consist of an initial three-month period where all patients receive 34 mg of pimavanserin once daily. After this period, patients either will continue receiving 34 mg of pimavanserin once a day, switch to a 20 mg dose, or be given a placebo. Patients then will be followed up for six months or until a relapse of psychotic symptoms. HARMONY is actively recruiting participants at 42 locations across the U.S. and in Slovakia and Ukraine. It is expected to be completed in March 2020.

More details

Pimavanserin was granted two breakthrough therapy designations by the FDA — one for the treatment for Parkinson’s disease psychosis in 2014 and the second for the treatment of dementia-related psychosis in 2017. This designation is reserved for therapies for serious medical conditions. The FDA expedites the review and development of drugs granted this designation.

Pimavanserin also is being investigated for its potential use in schizophrenia (NCT02970305, NCT02970292, NCT03121586) and depression (NCT03018340).

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