FDA Rejects Nuplazid as Treatment for Alzheimer’s-related Psychosis

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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The U.S. Food and Drug Administration (FDA) has kept to its initial decision to reject a request by Acadia Pharmaceuticals to expand Nuplazid (pimavanserin) to treat hallucinations and delusions associated with Alzheimer’s disease-related psychosis.

In a complete response letter (CRL) indicating it had finished its review of the company’s resubmitted supplemental new drug application (sNDA), the FDA said it wouldn’t approve the current application and recommended Acadia conduct an additional clinical trial for psychosis due to Alzheimer’s disease.

The sNDA was reviewed by FDA’s Psychopharmacologic Drugs Advisory committee meeting. While the committee recognized the positive results with Nuplazid in the Phase 3 HARMONY trial (NCT03325556), which supported the sNDA, the FDA said these were mainly seen in people with dementia due to Parkinson’s disease. Nuplazid was approved by the FDA to treat this patient population in 2016.

The FDA also raised concerns over the “limitations in the interpretability” of the results of the Phase 2 ACP-103-019 trial (NCT02035553) in people with Alzheimer’s-related psychosis, whihc was also used as a supportive study in Nuplazid’s application.

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“We are disappointed with this outcome. The treatment of Alzheimer’s disease psychosis continues to be an area of high unmet need, for which there is no approved therapy,” Steve Davis, CEO of Acadia, said in a press release. “We want to express our gratitude to all of the patients, their families and investigators who have participated in our clinical trials.”

Nuplazid works by blocking serotonin signaling in the brain, a pathway believed to contribute to developing psychotic symptoms.

Acadia resubmitted its sNDA in February to treat hallucinations and delusions in dementia-related psychosis of Alzheimer’s disease after the FDA rejected its first request to expand Nuplazid’s use to a broader category of dementia-related psychosis.

HARMONY enrolled 392 people with common types of dementia-related psychosis, but the majority (76%) had Alzheimer’s-related psychosis. Other causes of psychosis were linked with Parkinson’s disease dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia.

A total of 217 patients (61.8%) responded to an initial 12-week Nuplazid treatment period, given at a dose of 34 or 20 milligrams (mg) daily. These patients entered the study’s second part wherein they were randomly assigned to continue with Nuplazid (either 34 or 20 mg daily) or a placebo for 26 weeks (about six months), or until a psychosis relapse.

Results showed Nuplazid reduced the risk of a psychosis relapse by nearly three times. The oral therapy was also generally well tolerated.

Acadia’s application also included data from the ACP-103-019 trial that tested Nuplazid against a placebo for 12 weeks in 181 people with Alzheimer’s-related psychosis. Results showed it decreased symptoms after six weeks of treatment, but the results were not sustained at 12 weeks.