FDA Approval Again Wanted for Nuplazid in Easing Psychosis

Yedida Y Bogachkov PhD avatar

by Yedida Y Bogachkov PhD |

Share this article:

Share article via email
Tau NexGen | Alzheimer's News Today | Illustration of oral treatments

Acadia Pharmaceuticals intends to again request that oral Nuplazid (pimavanserin) be approved to treat hallucinations and delusions, but this time only when associated with the dementia-related psychosis of Alzheimer’s disease.

Its planned request to the U.S. Food and Drug Administration (FDA), in the form of a resubmitted supplemental new drug application (sNDA), follows the FDA’s rejection last year of Nuplazid in treating hallucinations and delusions in a much broader category of dementia-related psychosis.

The FDA, in its response letter, raised concerns regarding efficacy data from the Phase 3 HARMONY trial that supported the initial request, including a lack of evidence of significant benefits in some dementia forms. Alzheimer’s patients accounted for 76% of all trial participants, while those with four other types of dementia-related psychosis made up the remaining 15%.

“Following our recent meetings with the FDA, we plan to resubmit our sNDA for pimavanserin, narrowing the proposed indication from dementia-related psychosis to Alzheimer’s disease psychosis,” Steve Davis, CEO of Acadia, said in a press release.

Recommended Reading

#AANAM – Nuplazid Not Linked to Side Effects Common to Antipsychotics

“Our resubmission will include new analyses of existing clinical study data supporting the treatment of hallucinations and delusions associated with Alzheimer’s disease,” Davis added.

Nuplazid is a selective serotonin inverse agonist, which means that it can bind and block the activity of serotonin 5-HT2A receptors. These receptors are involved in psychosis, commonly consisting of delusions and hallucinations, depression, and other neuropsychiatric disorders.

Nuplazid is approved to treat hallucinations and delusions associated with Parkinson’s psychosis.

The resubmitted sNDA will include data from two placebo-controlled studies, the Phase 3 HARMONY study (NCT03325556) and the Phase 2 ACP-103-019 trial (NCT02035553).

HARMONY evaluated the safety and effectiveness of Nuplazid in 392 people with the five most common forms of dementia-related psychosis: those associated with Alzheimer’s, Parkinson’s and Lewy bodies, and vascular and frontotemporal dementia.

All enrolled were initially treated daily for 12 weeks with Nuplazid as a 34 mg tablet (20 mg was given patients with tolerability issues), until dementia symptoms stabilized. Those who responded (217 people or 61.8%) were eligible to enter the study’s 26-week second part, and randomly assigned to continued Nuplazid treatment (either 34 or 20 mg daily) or to a placebo until study end or a psychosis relapse.

HARMONY met its main goal, significantly lowering the risk of a psychosis relapse by 2.8 times compared with placebo. It also met a key secondary endpoint, significantly reducing by 2.2 times the risk of patients leaving the study for any reason, including treatment tolerability.

Among the FDA’s concerns was the lack of significant benefits in some forms of dementia, and too few patients with less common dementia types being included in the HARMONY study.

In the ACP-103-019 trial, 181 people with Alzheimer’s-related psychosis were treated with either Nuplazid or placebo for 12 weeks. Nuplazid was shown to significantly reduce patients’ psychosis scores, particularly in those with more severe symptoms, at six weeks of treatment relative to placebo, meeting the trial’s main goal. However, these benefits were not sustained at 12 weeks.

The FDA also noted that this Phase 2 trial, whose data also supported the initial request, was not a well-controlled or adequate study.

Additional trial analyses will be included in its resubmission to further validate study findings and address the FDA’s concerns, Acadia stated. It is re-analyzing Nuplazid’s benefit as specifically seen in patients with Alzheimer’s psychosis, rather than the entire randomized HARMONY trial population.

“The resubmission is intended to demonstrate pimavanserin’s clinically meaningful benefit in ADP [Alzheimer’s disease psychosis] patients, without worsening of cognition or motor function in this elderly population,” the company stated.

“We are aware there are challenges to overcoming our complete response letter, but are pleased with the high level of engagement from the FDA over the last three meetings and their willingness to review our resubmission, allowing us to make our case that pimavanserin should be the first drug approved to treat Alzheimer’s disease psychosis,” Davis said.