番茄社区

Update: FDA's Psychopharmacologic Drugs Advisory Committee has weighed in. Check out 番茄社区's coverage here.

An FDA advisory committee will seek to determine whether the atypical antipsychotic pimavanserin (Nuplazid) is also an effective treatment for hallucinations and delusions in patients with Alzheimer's disease psychosis, where there are currently no approved therapies.

On Friday, the Psychopharmacologic Drugs Advisory Committee will consider the potential label expansion for pimavanserin, a serotonin selective inverse agonist that preferentially targets the 5-HT2A receptor subtype, which was first approved in 2016 for hallucinations and delusions associated with Parkinson's disease psychosis.

Last year, the FDA turned away developer Acadia Pharmaceuticals' bid for an indication in dementia-related psychosis due to insufficient "evidence of effectiveness," according to agency released ahead of Friday's meeting.

Support for the current approval request is derived from three studies.

The first, ACP-103-019, was a randomized phase II trial in patients with Alzheimer's disease psychosis that met its primary efficacy endpoint, demonstrating a clinically meaningful improvement in psychosis symptoms versus placebo.

The second study showed confirmatory evidence of effectiveness from a positive study in patients with Parkinson's disease psychosis.

Acadia describes Parkinson's disease and Alzheimer's disease psychosis as "closely-related conditions," according to the FDA, and asserts that the prior approval should be considered an additional source of evidence for the current application. But the Division of Psychiatry/Office of Neuroscience reviewing the application "does not agree," according to the briefing documents.

The third study, the phase III HARMONY trial (ACP-103-045), tested relapse prevention in patients with dementia-related psychosis and showed a statistically significant reduction in the risk of psychosis relapse. In the initial open-label phase, 61.8% of patients had a sustained response to once-daily 34 mg pimavanserin. And during a randomized withdrawal phase, 13% of patients who continued on pimavanserin had a relapse of symptoms versus 28% of those who switched to placebo (HR 0.35, 95% CI 0.17-0.73, P=0.005).

HARMONY included several dementia subgroups, and while Alzheimer's disease made up the largest (66%), the positive results with pimavanserin appeared to be driven by the smaller subgroup of patients with Parkinson's disease dementia. In the subgroup analysis, relapses were seen in 13.1% of the Alzheimer's disease patients on pimavanserin versus 23% of those on placebo (HR 0.68, 95% CI 0.26-1.49). By contrast, relapse rates among the Parkinson's group were 6.7% and 50%, respectively (HR 0.05, 95% CI 0.02-0.18).

"The findings from Study 045 [HARMONY] suggest a differential response to pimavanserin across dementia subtypes, and the Division noted this in the complete response to the prior submission," said FDA staff. "In the resubmission, the applicant explored the subgroup results of Study 045 to support their hypothesis that the study demonstrated a consistent response to pimavanserin treatment in all subgroups, including a clinically meaningful effect in the [Alzheimer's disease] subgroup."

At the Friday meeting, the FDA's advisers are slated to discuss the supporting evidence from all the pimavanserin studies (plus the prior approval in Parkinson's disease psychosis) and vote on whether the available evidence supports a conclusion that pimavanserin is effective for the treatment of hallucinations and delusions in the Alzheimer's disease psychosis population.

Pimavanserin's safety will not be a focus of the discussion, as the trial findings were "largely consistent" with what is known about the safety of the drug to date, FDA noted.

While the agency is not required to follow the recommendations of its advisory committees, it typically does.

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