Acadia’s Nuplazid: US FDA Panel Will Focus On Efficacy For Alzheimer’s Disease Psychosis
Executive Summary
Agency questions clinical significance of change in primary efficacy endpoint measured in one study and raises doubts about numerous exploratory analyses for a second study aimed at explaining why Alzheimer’s patient subgroup appeared to derive less benefit than other types of dementia patients.
The US Food and Drug Administration is raising a host of questions about adequacy of the efficacy evidence for Acadia Pharmaceuticals Inc.’s Nuplazid (pimavanserin) in treating hallucinations and delusions associated with Alzheimer’s disease psychosis (ADP).
In a briefing document released ahead of a 17 June advisory committee meeting, the FDA questioned the clinical significance of the primary efficacy endpoint change measured in one study, as well as validity of the clinical outcomes assessment used to assess that endpoint and how the instrument was administered.
In a second study of pimavanserin’s effect on patients with different types of dementia, the agency raises doubts about Acadia’s numerous exploratory analyses aimed at explaining why the Alzheimer’s disease patient subgroup appeared to derive less benefit than other types of dementia patients.
The agency is asking its Psychopharmacologic Drugs Advisory Committee to discuss the extent to which the two studies, and pimavanserin’s prior approval for Parkinson’s disease psychosis patients, contribute to the overall assessment of effectiveness in Alzheimer’s disease patients, and to vote on whether the available evidence supports a conclusion of efficacy.
Narrowing Of Indication
Pimavanserin, a serotonin inverse agonist, was approved in 2016 for hallucinations and delusions associated with Parkinson’s disease psychosis (PDP).
In June 2020, Acadia submitted a supplemental new drug application for treatment of hallucinations and delusions associated with dementia-related psychosis. The sNDA was supported by data from Study 045, a Phase III, randomized withdrawal study in subjects with psychosis related to several types of dementia, with supportive evidence from Study 019, a Phase II proof-of-concept study.
In April 2021 the agency issued a complete response letter, concluding that the sNDA did not provide substantial evidence of effectiveness.
The FDA noted that although Study 045 was not powered to demonstrate an effect in subgroups of dementia, results for the relatively small Parkinson’s disease dementia (PDD) group appeared to drive the overall study results, while results for the Alzheimer’s disease subgroup, the largest in the study, were not nominally statistically significant. (Also see "Nuplazid Complete Response Letter For Dementia Psychosis Driven By Effectiveness Concerns In Subgroups" - Pink Sheet, 6 Apr, 2021.)
These findings from Study 045 suggested a differential response to pimavanserin across dementia subtypes, calling into question the overarching indication for dementia-related psychosis, the FDA said.
In addition, the agency said it did not consider Study 019 to be an adequate and well-controlled study due to study design and conduct issues.
At a June 2021 end-of-review meeting, the agency advised Acadia to conduct a new study assessing pimavanserin’s effect on specific subpopulations of patients with dementia, such as Alzheimer’s disease.
At a December meeting, Acadia said it planned to resubmit for a narrower indication – hallucinations and delusions associated with ADP – based on new analyses of Study 045 data and additional information regarding the adequacy of Study 019.
“The agency noted that it would be prepared to consider the applicant’s arguments in a resubmission but continued to advise the applicant that an additional adequate and well-controlled study in subjects with ADP would likely provide the strongest data in support of a resubmission,” the FDA’s briefing document states.
The application was resubmitted in February; the user fee goal date is 4 August. (Also see "Keeping Track: Opdivo Extends Label Into Neoadjuvant Lung Cancer; Acadia, Revance Resubmit" - Pink Sheet, 11 Mar, 2022.)
Is Magnitude Of Improvement Clinically Meaningful?
In the resubmission, Acadia positioned Study 019 as the primary source of evidence, with supportive evidence coming from Study 045.
Study 019 was a Phase II, randomized, placebo-controlled, 12-week study in 181 nursing home residents in the UK who met criteria for ADP. Subjects were randomized to either oral pimavanserin tartrate 40 mg (equivalent of 34 mg free base pimavanserin) or placebo. The primary endpoint was the mean change from baseline to day 43 on the Neuropsychiatric Inventory-Nursing Home Version Psychosis Score (NPI-NH-PS).
The NPI was developed to evaluate 12 neuropsychiatric disturbances, or domains, common in dementia. The score of each item, if present, represents the product of symptom frequency (range 1-4) and severity (range 1-3), for a maximum score of 12 on each domain, with higher scores representing more serious symptoms. The primary endpoint in Study 019 measured only two domains, delusions and hallucinations, meaning that the maximum possible score was 24.
The agency said that although it considers the NPI-NH an adequate endpoint for exploratory purposes, this instrument is supported by limited evidence of content validity because Acadia has not provided a comprehensive review of the literature with a summary focused on how the items measure the targeted concept of interest – hallucinations and delusions – in the AD population. Acadia also has not undertaken research within its own development program to provide evidence of content validity, the agency said.
“Nonetheless, the items of the NPI-NH PS are consistent with the classifications of hallucinations and delusions that may be experienced by patients with ADP and our primary concerns lie with the scoring and the interpretation of group and individual differences,” the agency said. “In particular the scoring algorithm, which totals the product of severity and frequency item scores, yields a metric that is difficult to interpret.”
The agency also questioned whether administration of the instrument by caregivers was standardized.
On the primary endpoint, pimavanserin demonstrated a statistically significant treatment effect versus placebo, with a treatment difference of -1.84 (95% CI: -3.64, -0.04, p=0.451). Various sensitivity analyses to explore the impact of missing outcomes yielded similar results, the agency said.
“Although pimavanserin achieved statistical significance at the primary endpoint, the clinical significance of a -1.84 placebo-subtracted difference on the NPI-NH PS is unclear.” – FDA
“Although pimavanserin achieved statistical significance at the primary endpoint, the clinical significance of a -1.84 placebo-subtracted difference on the NPI-NH PS is unclear,” the agency said.
None of the secondary or relevant exploratory endpoints met nominal significance. In addition, pimavanserin did not separate from placebo on the NPI-NH PS at days 64 or 85. Consequently, the results raise questions both as to whether the treatment difference at day 43 is a chance finding and as to durability of effect, the agency said.
With the resubmitted sNDA, the agency determined that Study 019 was designed with features that could allow it to be considered an adequate and well-controlled trial suitable for regulatory decision-making. However, questions remain as to whether the methods of assessment of subjects’ response are well-defined and reliable, the agency said.
The FDA reviewers also questioned the generalizability of the trial’s results for the US because the study population was not representative in terms of racial or ethnic characteristics.
More than 95% (171) of the 181 subjects were White, with only four Black subjects and none identifying as Hispanic or Latino. “Multiple analyses have found a higher risk of dementia in Black and Hispanic/Latino populations than in White populations,” the agency said.
In addition, more than 80% of the study participants were female, which may reflect the predominance of AD in women given longer life expectancy, the agency said.
Differential Effects By Dementia Subgroup
Study 045 was a randomized withdrawal study in subjects ≥50 to ≤90 years who met criteria for all-cause dementia with psychosis and clinical criteria for dementia subtype. Subjects received pimavanserin 34 mg once daily for a 12-week, open-label period, although the dose could be decreased to 20 mg for tolerability.
Subjects who met certain response criteria at weeks eight and 12 of the open-label period were permitted to enter the double-blind period, where they were randomized to either continue their current pimavanserin dose or switch to placebo for up to 26 weeks. The primary endpoint was time from randomization to relapse in the double-blind period.
The study was stopped early for efficacy, and the primary efficacy analysis was based on the interim analysis dataset. Among the 351 subjects who had completed or discontinued from the open-label period at the time the study was stopped, 217 met sustained response criteria at weeks eight and 12 and were randomized to the double-blind period. Among those randomized, 137 subjects had AD and 42 had PDD.
More subjects in the placebo group experienced a relapse event compared to the pimavanserin arm (28.3% vs. 12.6%), for a hazard ratio of 0.353, a statistically significant result.
“Based on these results, Study 045 did meet its primary endpoint. However, exploratory subgroup analyses were also conducted to assess consistency across subgroups with respect to the primary analysis results,” the FDA said. “Only the treatment effect in the combined ‘PDD or dementia with Lewy body’ subgroup or the PDD subgroup appears to separate from placebo – the confidence intervals excluded a hazard ratio of 1.”
A key secondary endpoint was time from randomization to discontinuation in the double-blind period for any reason. Pimavanserin statistically significantly reduced the risk of all-cause discontinuation compared to placebo. However, similar to the primary endpoint results, the overall significance appears to have been driven primarily by results in the PDD group.
“The apparent differential effects of pimavanserin in the PDD subgroup relative to the other dementia subgroups was the primary reason for the complete response action in the first review cycle and the reason that a broad ‘dementia-related’ psychosis indication is no longer being considered,” the agency said.
Exploratory Analyses
In its resubmission, Acadia asserted there was consistency of response across dementia subtypes and that the PDD subgroup’s smaller hazard ratio is an outlier resulting from use of dopaminergic therapy to manage PD motor symptoms, and which can cause or worsen psychotic symptoms.
“The applicant has explored the interaction of treatment by dementia subgroup, examined the potential confounding effect of dopaminergic therapy in the PDD subgroup, conducted re-analyses of primary and exploratory efficacy endpoints in the AD subgroup, and performed simulations to evaluate the potential impact on the final analysis if the effect in the PDD subgroup were attenuated,” the agency said.
“The applicant also believes that higher pimavanserin exposures are associated with greater efficacy and has compared efficacy results in subjects treated with pimavanserin 34 mg compared to those treated with 20 mg and has conducted an analysis of the relationship between plasma pimavanserin concentration and the primary efficacy endpoint.”
The FDA said that the dopaminergic drug hypothesis is reasonable given that such drugs may worsen psychiatric symptoms. However, most subjects taking these drugs were in the PDD subgroup, making it “not possible to statistically adjust for the dopaminergic medication effect for PDD subjects receiving placebo. Furthermore, it is unclear whether the effect of dopaminergic medication on the risk of relapse is the only explanation for possible difference in treatment effect between the AD and the PDD subgroups.”
Acadia reanalyzed primary endpoint data in the AD subgroup by including a set of covariates selected post hoc, which led to a smaller hazard ratio estimate for this group. However, the choice of covariates was not prespecified and results of “post hoc, potentially data-driven analyses such as this are very challenging to interpret,” FDA reviewers said.
The agency also raised questions about other post hoc analyses performed by Acadia, including one on post-baseline dose. Although results numerically favored placebo against pimavanserin in patients in the AD subgroup who received the 20 mg dose, “focusing on 34 mg only after knowing the unfavorable results of the 20 mg would result in biased estimates,” the agency said.
“In summary, AD was the largest subgroup with only 22 relapse events observed at the interim analysis. The efficacy results of the AD subgroup showed a HR of 0.618 (nominal p=0.28) with a wide confidence interval (0.257, 1.487). The agency would like the [advisory committee ] to consider whether these exploratory analyses inform our understanding of the treatment effect in the AD population.”
No Issue With Safety
The agency said it is not bringing any safety issues to the advisory committee because findings from the sNDA development program generally were consistent with pimavanserin’s known safety profile.
The most common adverse reactions include peripheral edema and confusional state. Current labeling includes a warning about the risk of QT interval prolongation; use with drugs that also increase the QT interval, and in patients with risk factors for prolonged QT interval, should be avoided.
Labeling also includes a boxed warning on the increased risk of death for elderly patients with dementia-related psychosis treated with antipsychotic drugs.