Nuplazid (pimavanserin also known as ACP-103) is an oral therapy targeting serotonin (a neurotransmitter carrying chemical signals between nerve cells). It is being developed by San Diego, California-based Acadia Pharmaceuticals for managing psychotic symptoms such as psychosis, aggression, and agitation in Alzheimer’s disease patients. Psychotic symptoms occur in up to 50% of Alzheimer’s patients.
How Nuplazid 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.
Nuplazid is a selective serotonin receptor inverse agonist, meaning that it binds not only to the serotonin receptor (like an agonist), but also has the ability to block serotonin signaling. Research has shown that blocking this receptor can reduce psychotic symptoms in Parkinson’s disease patients.
Nuplazid in clinical trials
Data from a Phase 2 clinical trial (NCT02035553) that was completed in 2016 revealed that a daily dose of 34 mg of Nuplazid was able to significantly reduce symptoms of psychosis (as determined by the neuropsychiatric inventory-nursing home (NPI-NH) psychosis score) after 1.5 months of treatment, compared to placebo. Patients with more severe baseline psychotic symptoms and those who were on antipsychotics previously experienced greater improvements in their symptoms. The results of this study were published in the Journal of Prevention of Alzheimer’s Disease.
Two other Phase 2 clinical trials testing Nuplazid were initiated in 2017. The first one was called the SERENE trial (NCT02992132) and was looking into the safety and effectiveness of Nuplazid to treat agitation and aggression in people with Alzheimer’s disease. Patients were given either 34 mg or 20 mg of daily Nuplazid, or a placebo for three months.
Patients who successfully completed the SERENE trial were eligible to take part in the second trial, an open-label extension study (NCT03118947). This follow-up study aimed to assess the safety and tolerability of 34 mg and 20 mg of Nuplazid taken for a year.
The SERENE trial was halted in October of 2017 due to overlap in patient recruitment with another Phase 3 study. Patients already enrolled in the study and its open-label extension were allowed to complete the studies. Results of the SERENE trial were posted for the 111 patients who were enrolled. However, since the trial was discontinued early, it did not have enough patients to detect an effect of the treatment using the Cohen Mansfield Agitation Inventory (CMAI).
A Phase 3 clinical trial (NCT03325556) called HARMONY was launched in September 2017 to study the ability of Nuplazid to prevent the relapse of psychotic symptoms in dementia-related psychosis. The trial enrolled 392 patients with Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease dementia, frontotemporal dementia, and vascular dementia.
It consisted of an initial three-month period in which all patients received 34 mg of Nuplazid once daily. After this period, patients either continued receiving 34 mg of Nuplazid once a day, switched to a 20 mg dose, or received a placebo. Patients were then followed up for six months or until a relapse of psychotic symptoms.
HARMONY met its main goal, significantly lowering the risk of a psychosis relapse by 2.8 times compared to placebo, and also found most patients unlikely to discontinue Nuplazid’s use for any reason. The therapy was found to be well tolerated, and its use did not associate with the cognitive decline that accompanies the use of other antipsychotic medications throughout the trial’s nine months.
Nuplazid 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.
Acadia submitted a request to the FDA to expand the treatment’s use to cover dementia-related psychosis in July 2020, with a decision expected by April 3.
Last updated: March 12, 2021
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