The U.S. Food and Drug Administration (FDA) has rejected Acadia Pharmaceuticals’ request that Nuplazid (pimavanserin) be the first approved treatment of hallucinations and delusions associated with dementia-related psychosis.
The decision comes less than nine months since the agency agreed to review the company’s supplemental new drug application, and a month after it announced “deficiencies” that had to be resolved before further discussions on “labeling and post-marketing requirements/commitments” could take place.
While the FDA’s complete response letter (CRL) did not mention any safety issues, it raised concerns regarding effectiveness data from the Phase 3 HARMONY trial (NCT03325556), which mainly supported the application.
These included the lack of significant benefits in some dementia forms and the small number of patients with less common subtypes, which led the agency to conclude evidence was insufficient to support Nuplazid’s approval for this indication at this point.
HARMONY enrolled patients with the most common forms of dementia-related psychosis, including Alzheimer’s disease-related dementia (which accounted for 76% of all trial participants), Parkinson’s disease dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia.
“Acadia stands behind the robustly positive results from the pivotal Phase 3 HARMONY study and the prospectively agreed trial design and criteria for establishing efficacy in DRP [dementia-related psychosis],” Steve Davis, Acadia’s CEO, said in a press release.
“Over the entire course of the review, [FDA’s division of psychiatry] did not raise any concerns regarding the agreed upon study design, including the issues raised in the CRL,” Davis added.
Acadia will request a meeting immediately with the FDA to address the cited concerns, and determine the next steps for Nuplazid’s potential approval in dementia-related psychosis.
The advocacy group UsAgainstAlzheimers also strongly disagreed with the regulatory agency. “We are extremely frustrated and disappointed that the FDA has failed to approve pimavanserin,” it said in a release. “This drug was found to be safe and effective in a Phase 3 clinical trial whose study design was approved by the FDA.”
And, it added, “there are no other good options for treatment of dementia-related psychosis,” which it noted as “one of the most frequent causes for families’ decisions to place their loved ones in institutional care settings.”
In its letter, the FDA also stated that it considers the Phase 2 ACP-103-019 trial (NCT02035553) in people with Alzheimer’s-related psychosis — used as a supportive study in Nuplazid’s application — was not adequate or well controlled.
Issues with this trial included the use of patients from a single center, and the lack of appropriate error controls in secondary goals, in which certain protocol deviations occurred. Acadia countered that these observations affect neither the trial’s positive results in its main goal nor its overall effectiveness findings.
Classified as a selective serotonin inverse agonist, Nuplazid works by specifically blocking the activity of serotonin 5-HT2A receptors, which are involved in psychosis — commonly consisting of delusions and hallucinations, depression, and other neuropsychiatric disorders.
The oral therapy was approved by the FDA to treat Parkinson’s disease-related psychosis in 2016. This decision was supported by Phase 3 trial results showing that it safely and effectively eased psychosis symptoms in this patient population.
The latest application drew mainly on positive data from the pivotal Phase 3 HARMONY trial, which evaluated the safety and effectiveness of Nuplazid in 392 people with the five most common forms of dementia-related psychosis.
Participants, with a mean age of 74.5, underwent an initial 12-week period in which all were treated daily with Nuplazid, as a 34 mg tablet, until dementia symptoms stabilized. Daily dose reduction to 20 mg tablets was allowed for patients with tolerability issues.
A total of 217 (61.8%) patients responded favorably, and were eligible to enter the study’s second part, in which they were randomly assigned to continue Nuplazid treatment (either 34 or 20 mg daily tablets) or switch to a placebo for up to 26 weeks (six months) or until a psychosis relapse.
Top-line results showed that Nuplazid-treated patients were significantly less likely (by 2.8 times) to experience a psychosis relapse compared with those on a placebo.
Besides meeting its main goal, the trial also achieved a key secondary goal, with the therapy significantly reducing by 2.2 times the risk of patients leaving the study for any reason.
Nuplazid was generally well-tolerated, and not associated with common side effects of conventional antipsychotics, including cognitive decline or daytime sedation.
These findings show the trial met its main and secondary goals, an FDA prerequisite for the dementia-related psychosis indication, Acadia stated.
Based on these positive findings, HARMONY was stopped early in September 2019 on a recommendation from its data monitoring committee.
The FDA rejection, in its letter, drew “on analyses by dementia subgroup that the agreed upon pivotal program was not intended, designed, or powered to demonstrate,” Davis stated in a post-decision investor update. “We strongly disagree with the Division of Psychiatry’s decision.”
In the Phase 2 ACP-103-019 study, the therapy was tested against a placebo in 181 people (mean age, 86) with Alzheimer’s-related psychosis.
Results showed that, compared with a placebo, Nuplazid significantly reduced psychosis scores after six weeks of treatment (about 1.5 months), particularly in patients with more severe symptoms. However, these benefits were not sustained at six months of treatment.
The therapy was also reported to lessen irritability. No significant treatment versus placebo group differences regarding patients’ agitation or occupational distress, ability to perform daily life activities, or use of rescue medications were seen.
Nuplazid’s application was also supported by effectiveness data from a Phase 3 trial (NCT01174004) in people with Parkinson’s-related psychosis — which also supported Nuplazid’s prior approval for that indication, as well as safety findings from more 1,500 people with a neurodegenerative disease who enrolled in completed and ongoing clinical studies.
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