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PIMAVANSERIN IN ALZHEIMER’S DISEASE PSYCHOSIS: EFFICACY IN PATIENTS WITH MORE PRONOUNCED PSYCHOTIC SYMPTOMS

 

C. Ballard1, J.M. Youakim2, B. Coate2, S. Stankovic2

 

1. University of Exeter Medical School, Exeter, UK; 2. ACADIA Pharmaceuticals Inc., San Diego, CA, USA

Corresponding Author: Clive Ballard, MBChB, Institute of Health Research, University of Exeter Medical School, Exeter EX1 2LU, UK, C.Ballard@exeter.ac.uk

J Prev Alz Dis 2018 inpress
Published online August 16, 2018, http://dx.doi.org/10.14283/jpad.2018.30

 


Abstract

Background: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
Objective: Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer’s disease (AD).
Design: Randomized, double-blind, placebo-controlled trial
Setting: Nursing home residents
Participants: Patients with AD psychosis
Interventions: Pimavanserin 34 mg or placebo daily for 12 weeks
Measurements: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated.
Results: Of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen’s d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks.
Conclusions: Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with pimavanserin showed an acceptable tolerability profile.

Key words: Pimavanserin, Alzheimer’s disease, psychosis, severe.


 

Worldwide, over 40 million people have Alzheimer’s disease (AD) or related dementia (1). Neuropsychiatric symptoms such as psychosis including delusions and visual hallucinations occur in 25% to 50% of individuals with AD (2, 3). In addition to occurring in patients with AD, psychosis also occurs in patients with other dementias of a wide variety of etiologies (4). The occurrence of psychotic symptoms in people with AD places a substantial burden on patients with AD, family, and caregivers (1). Patients experiencing psychotic symptoms have more rapid cognitive and functional decline, increased co-morbidity with other neuropsychiatric symptoms including depression and agitation, have higher rates of nursing home admissions, and greater treatment-related mortality (5, 6). An increased severity of psychotic symptoms may be associated with increased disease severity and duration and may be a negative predictor of the overall disease outcomes (7).
Although antipsychotics are commonly used to treat psychosis in patients with dementia and Parkinson’s disease (8, 9), randomized, controlled trials of antipsychotics indicate modest efficacy for the treatment of psychosis (10, 11). Meta-analyses of antipsychotic use in patients with AD suggest a small effect size (<0.2) from clinical trials (12, 13), and their use is associated with cognitive decline as well as increased rates of stroke, bronchopneumonia, pulmonary embolism, and mortality (14, 25). However, until recently, no drug was approved for the treatment of the symptoms of psychosis associated with a neurodegenerative disease.
In 2016, based on the results from controlled clinical studies (16, 17) pimavanserin was approved in the United States for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Pimavanserin, is a selective 5-hydroxytryptamine (HT)2A receptor inverse agonist/antagonist with substantively lower affinity for the 5-HT2C receptor and negligible affinity for dopaminergic, muscarinic, histaminergic, or adrenergic receptors (18). Results from previous studies suggested that activity at the 5-HT2A receptor could also provide benefits for AD psychosis (19) and formed the basis for a randomized, double-blind, placebo-controlled Phase 2 study where pimavanserin demonstrated significant efficacy in AD patients with psychosis (20). Unlike atypical antipsychotics, pimavanserin did not have a negative impact on cognitive function (20, 21). In addition, no negative effects on motor function were observed with pimavanserin, and the incidence and types of adverse events were comparable with pimavanserin and placebo.

This report describes the efficacy and tolerability of pimavanserin and placebo in a prespecified subgroup of patients with severe psychosis associated with Alzheimer’s disease as classified by the cut-off score of ≥12 on the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) psychosis score (22, 23).

 

Methods

Primary results from this Phase 2 study were previously reported (20). In brief, the study was conducted at King’s College London in a network of nursing homes across the United Kingdom. An Independent Data Monitoring Ethics Committee provided study oversight. The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; Good Clinical Practices; and the United States Code of Federal Regulations. Ethics Committee approval was obtained for the study protocol and informed consent form, and patients or their legally authorized representative provided informed consent prior to any study procedures.

Study Design

This was a randomized, double-blind, placebo-controlled study, with the primary efficacy analysis at the 6-week time point. Study participants continued treatment to 12 weeks with the objective to evaluate overall safety, effects on cognition, and assess maintenance of effect. Patients were randomized equally to pimavanserin 34 mg or placebo once daily, and randomization was stratified by baseline Mini-Mental State Examination (MMSE) (24) in two levels (MMSE <6 and MMSE ≥6) and NPI-NH psychosis score in two levels (hallucinations and delusions <12 and ≥12).

Patient Selection

Adults ≥50 years of age were eligible if they had possible or probable AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) (25) and satisfying criteria for psychosis associated with Alzheimer’s disease (26). Patients were required to have psychotic symptoms including visual and/or auditory hallucinations and/or delusions that developed after the diagnosis of AD was established and must have been a nursing home resident for ≥4 weeks prior to randomization. Further, patients were required to be actively experiencing psychotic symptoms during the month prior to screening that required treatment for psychotic symptoms (26). Patients were required to have a score of ≥4 on either hallucinations (Frequency × Severity) or delusions (Frequency × Severity) of the NPI-NH psychosis subscale or a total combined score ≥6 (hallucinations + delusions) and have symptoms that required treatment with an antipsychotic medication. Treatment with other antipsychotics or other centrally acting medications was not allowed, and doses of antidepressant and anxiolytic drugs had to remain unchanged during the study. Doses of an acetylcholinesterase inhibitor (and/or memantine) must have been stable for 3 months prior to baseline and during the study. Patients were excluded for a history of significant psychotic disorders prior to or concomitant with the diagnosis of AD, as well as any medical condition that could interfere with the conduct of the study.

Study Assessments

The NPI-NH psychosis score (hallucinations + delusions) was used to assess psychosis and determine the primary outcome. Behavioral symptoms were assessed using the NPI-NH Total score, as well as the individual behavioral domain scores, and using the Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF) (27). Cognitive status was evaluated with the MMSE; overall condition was rated with the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (28); and activities of daily living (ADL) were evaluated using the Alzheimer’s Disease Cooperative Study-ADL instrument (ADCS-ADL) (29). Safety was assessed from adverse events (AEs), physical examinations, clinical laboratory tests, electrocardiograms, and vital signs.

Statistical Analysis

The primary efficacy outcome was change from baseline to Week 6 for the NPI-NH psychosis score (hallucinations + delusions) for pimavanserin vs. placebo. The focus of the prespecified subgroup analysis was efficacy assessment for baseline NPI-NH psychosis score ≥12 on the primary outcome (NPI-NH psychosis score) and the responder analysis.
For the responder analyses, the reported responder rates were the observed proportions with a response (improvement from baseline) at Week 6, after conservatively imputing any missing values as non-responders. The treatment groups were compared using a Cochran-Mantel-Haenszel test, stratified by baseline MMSE category (<6 or ≥6). For prespecified efficacy outcomes, the analysis model included fixed effects of baseline MMSE category (<6 or ≥6), treatment (pimavanserin 34 mg or placebo), visit (Days 15, 29, 43, 64, and 85), treatment-by-visit interaction, and a continuous, fixed covariate of baseline score (except for ADCS-CGIC where there is no baseline score). All efficacy analyses used the full analysis set (FAS), which included all randomized participants who received at least one dose of study drug and had both a baseline and at least one post-baseline NPI-NH psychosis score assessment. All efficacy analyses were conducted using 2-sided tests at the 5% significance level. Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 17.0.

 

Results

In the overall study population, 181 patients were randomized to pimavanserin (n=90) and placebo (n=91). In the FAS, the group with an NPI-NH psychosis score ≥12 (more severe group) comprised 27 patients randomized to pimavanserin and 30 randomized to placebo. At baseline, demographic and clinical characteristics were generally similar between the overall population and the more severe subgroup (Table 1). However, among patients in the more severe subgroup vs. the overall population, mean NPI-NH total, psychosis, and agitation/aggression scores were higher, and the mean MMSE score was lower, consistent with the overall greater severity of illness (Table 1).

Table 1. Baseline demographics and clinical characteristics for the subgroup with NPI-NH psychosis score ≥12 vs. overall population

Table 1. Baseline demographics and clinical characteristics for the subgroup with NPI-NH psychosis score ≥12 vs. overall population

 

In the overall population, the adjusted mean change (SE) from baseline to Week 6 (adjusted mean, MMRM analysis) for the NPI-NH psychosis score was -3.76 (0.65) for pimavanserin and -1.93 (0.63) for placebo (delta = -1.84, 95% confidence interval [CI] [-3.64, -0.04] Cohen’s d = -0.32, p=0.045).
Among patients with baseline NPI-NH psychosis score ≥12, mean baseline scores were 15.3 and 16.7 with pimavanserin and placebo, respectively. The mean change in NPI-NH psychosis score from baseline to Week 6 was -10.15 (95% CI: -12.50, -7.80) for pimavanserin and -5.72 (95% CI: -8.14, -3.30) for placebo (Figure 1A), resulting in a delta of -4.43 (95% CI: -7.81, -1.04) and Cohen’s d effect size of -0.73 (p=0.011).

Figure 1A. Least square mean change from baseline in NPI-NH psychosis score at each study assessment in participants with baseline NPI-NH psychosis score ≥12 (pimavanserin, n=27; placebo, n=30)

Figure 1A. Least square mean change from baseline in NPI-NH psychosis score at each study assessment in participants with baseline NPI-NH psychosis score ≥12 (pimavanserin, n=27; placebo, n=30)

* Cohen’s d effect size of -0.73 (p=0.011)

 

Overall, in the more severe subgroup, 81% of patients had both hallucinations and delusions at baseline. In this subgroup, pimavanserin was superior to placebo in treating both hallucinations and delusions with significant improvements observed at Week 6 for both the NPI-NH hallucinations (p=0.046) and delusions (p=0.034) domain scores (Table 2). Significant differences between pimavanserin and placebo were not observed for other secondary or exploratory outcomes. In the severe subgroup, the change for the NPI-NH psychosis score was significantly (Spearman Correlation=0.4571, p<0.001) correlated with the ADCS-CGIC score at Week 6.

Table 2. Secondary and exploratory outcomes for the subgroup with baseline NPI-NH psychosis score ≥12

Table 2. Secondary and exploratory outcomes for the subgroup with baseline NPI-NH psychosis score ≥12

 

Responder Analysis

A responder analysis was conducted of the proportion of patients achieving a decrease in the NPI-NH psychosis score of ≥20%, ≥30%, ≥50%, ≥75%, and 100% at Week 6. The proportion with a baseline NPI-NH psychosis score ≥12 achieving a response was significantly (p<0.05) greater with pimavanserin vs. placebo at all increments except for 100% (Figure 1B).

Figure 1B. Responder analysis at Week 6 for subgroup with NPI-NH psychosis score ≥12 (pimavanserin, n=27; placebo, n=30)

Figure 1B. Responder analysis at Week 6 for subgroup with NPI-NH psychosis score ≥12 (pimavanserin, n=27; placebo, n=30)

To enter the study, participants needed to have a score of ≥4 on the either hallucinations or delusions domains of the NPI-NH psychosis scale or an NPI-NH psychosis score ≥6. The baseline score for the severe group was 15.3 and 16.7 for pimavanserin and placebo, respectively (Table 1). At Week 6, 66.7% of pimavanserin patients improved to an NPI-NH psychosis score <6 vs. 32.0% of placebo patients with a treatment difference of 34.7% in favor of pimavanserin. At Week 12, 45.5% of both pimavanserin and placebo-treated patients had an NPI-NH psychosis score <6.

Tolerability

The incidence of adverse events (AEs) was comparable for the more severe (score ≥12) subgroup vs. the overall population (Table 3). In the pimavanserin group, the incidence of aggression was 14.3% in the severe subgroup vs. 10.0% in the overall population, and the incidence of agitation was 17.9% and 21.1% in the severe subgroup and overall population, respectively. The overall incidence of adverse events, serious adverse events, and adverse events causing discontinuation as well as the incidence of all other individual adverse events was similar or lower with pimavanserin in the severe subgroup (Table 3). Minimal change from baseline was observed for the mean MMSE score in either treatment group in the overall study population over 12 weeks of treatment (Figure 2).

Table 3. Incidence of adverse events for subgroup with baseline NPI-NH psychosis score ≥12 vs. overall population (Safety Population)

Table 3. Incidence of adverse events for subgroup with baseline NPI-NH psychosis score ≥12 vs. overall population (Safety Population)

Figure 2. Least square mean change from baseline for MMSE for Safety Population (pimavanserin, n=90; placebo, n=91)

Figure 2. Least square mean change from baseline for MMSE for Safety Population (pimavanserin, n=90; placebo, n=91)

 

Discussion

In the overall population of patients with AD psychosis, pimavanserin exhibited efficacy for the primary endpoint, NPI-NH psychosis score, at Week 6 without negative cognitive effects (20). This prespecified analysis was conducted in participants with more severe psychosis at baseline based on an NPI-NH psychosis score ≥12, which represented approximately 30% of the overall study population, a population that is at critical risk for untoward outcomes. While many baseline characteristics were similar between the overall and severe populations, the higher baseline scores for the NPI-NH total, NPI-NH psychosis score, and agitation/aggression domain scores along with lower mean MMSE score supports the hypothesis that the more severe population defined by an NPI-NH psychosis score ≥12 represents a more impaired group of patients with AD psychosis than was represented by the overall population and thus in a greater need for suitable pharmacologic treatment.
For the primary endpoint of mean change in the NPI-NH psychosis score from baseline to Week 6, a notably large Cohen’s d effect size of -0.73 was observed compared with the effect sizes in the overall population (-0.32). In this vulnerable group of patients, the effect size was more than two-fold greater than reported in the overall study population and more than three-fold greater than the effect size of atypical antipsychotics reported from meta-analyses in populations of patients with dementia-related psychosis (11). Thus, the effect of pimavanserin was markedly greater in the prespecified subgroup with more severe psychotic symptoms. Even more impressive were the results of responder analyses. With 88.9% of patients responding to pimavanserin treatment with at least a 30% reduction in psychotic symptoms and 77.8% responding with at least a 50% reduction, the placebo-adjusted responder rates in this group were in the range of 35%-45%. In addition, a clinically and statistically meaningful reduction in severity was observed with pimavanserin for both hallucination and delusion domains of the NPI-NH. Importantly, these statistically significant findings were observed despite a small sample size in the severe subgroup.
The mean NPI-NH psychosis score in the pimavanserin group maintained the effect through Week 12 in the more severe subgroup but the difference from placebo was not significant due to observed improvement in the placebo group from Weeks 6 and 12. No statistically significant differences were observed for other secondary endpoints although a statistically significant correlation was observed between the NPI-NH psychosis score and the ADCS-CGIC score.
Among patients with AD psychosis, it is reported that an increased occurrence of severe psychosis is associated with an increased presence of delusions and hallucinations as well as symptoms of agitation/aggression (30). Despite an urgent need for effective treatment of these patients, no pharmacological treatment is approved for patients with AD psychosis, in particular, in patients experiencing severe psychotic symptoms. Others have reported an association between the NPI score and the duration and severity of psychosis, which also was associated with the occurrence of delusions and hallucinations (7). In this planned analysis of the severe subgroup from the overall study (20), our results are consistent with these reports, where we found not only a markedly increased NPI-NH total and psychosis score among the severe subgroup at baseline, but also a greater presence of delusions and hallucinations. In addition, baseline factors may have an impact on the magnitude of effect with pimavanserin in the AD population. In the overall study population, prior antipsychotic drug use and increased NPI-NH agitation/aggression scores at baseline were associated with greater effect sizes with pimavanserin that were significant for prior antipsychotic use (p=0.037 and p=0.001, respectively).
Limitations of this analysis are the small number of patients included in the severe subgroup and the secondary nature of this subgroup analysis. However, patients included in this prespecified analysis were from a prospective, randomized, placebo-controlled study, and a significant difference was observed for the primary outcome, the NPI-NH psychosis score in the overall population. The findings of an association between dementia-related psychosis and neuropsychiatric complaints are consistent with previous reports in patients with dementia and suggest that this severe population is at greater risk for adverse outcomes that require effective treatments (3, 6, 8).
The robust efficacy of pimavanserin in patients with more severe psychotic symptoms is relevant to the therapeutic benefits of pimavanserin in patient populations with AD and psychosis. These results extend and confirm the results from the primary analysis in the overall population (20) and the results from the subgroup analysis of patients with mild dementia in the PDP study with pimavanserin (16). These findings coupled with the results from other studies of pimavanserin suggest a potential role for pimavanserin in treating psychosis in patients across a range of neuropsychiatric conditions.

 

Acknowmedgement: The authors acknowledge the editorial assistance of Richard S. Perry, PharmD in the preparation of this manuscript, which was supported by ACADIA Pharmaceuticals Inc., San Diego, California.
Funding:  This study was funded by ACADIA Pharmaceuticals Inc., San Diego, California. All authors as well as the sponsor were involved in the design and conduct of the study; the collection, analysis, and interpretation of data; in the preparation of the manuscript; and in the review or approval of the manuscript.

Disclosures:  Dr. Ballard has received grants and personal fees from ACADIA and Lundbeck, personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline, and Pfizer. JY, BC, and SS, are employees and may be stockholders in ACADIA Pharmaceuticals Inc.

Ethical standard: The study adheres to the Declaration of Helsinki human protection guidelines and was reviewed by ethical standards boards for all participating sites.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

 

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PIMAVANSERIN: POTENTIAL TREATMENT FOR DEMENTIA-RELATED PSYCHOSIS

 

J. Cummings1, C. Ballard2, P. Tariot3, R. Owen4, E. Foff4, J. Youakim4, J. Norton4, S.Stankovic4

 

1. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; 2. University of Exeter Medical School, Exeter, UK; 3. Banner Alzheimer’s Institute and University of Arizona College of Medicine, Phoenix, AZ, USA; 4. ACADIA Pharmaceuticals Inc., San Diego, CA, USA

Corresponding Author: Jeffrey Cummings MD, ScD, Cleveland Clinic Lou Ruvo Center for Brain Health, 888 W. Bonneville Ave, Las Vegas, NV, USA, cumminj@ccf.org

J Prev Alz Dis 2018 inpress
Published online August 16, 2018, http://dx.doi.org/10.14283/jpad.2018.29

 


Abstract

Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms – Parkinson’s disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer’s disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS

Key words: Dementia, psychosis, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia;, dementia with Lewy bodies.


 

Psychosis is a common feature of dementia and becomes more frequent with disease progression (1-3). Psychosis is common in neurodegenerative disorders such as Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) and often occurs concurrently with cognitive decline and other non-motor symptoms and sleep disturbances (4-9). Among patients with PD, psychosis occurs in up to 60% of patients over the course of their disease (10, 11), Similarly, psychosis occurs with varying prevalence across other neurodegenerative diseases including Alzheimer’s disease (AD), Vascular dementia (VaD), and frontotemporal dementia (FTD) (Table 1). In most neurodegenerative dementias, neurobehavioral symptoms such as psychosis are more common among those with cognitive impairment (1-3). The presence of neuropsychiatric signs and symptoms in neurodegenerative diseases is predictive of increased caregiver burden, decreased quality of life, and earlier progression to nursing home care, severe dementia, and death (3, 12). Thus, there is a close relationship between the clinical manifestations of dementia-related psychosis (DRP) and morbidity/mortality in many neurodegenerative diseases (1, 5).

 

Table 1. Prevalence of delusions and hallucinations in patients with dementia, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies

Table 1. Prevalence of delusions and hallucinations in patients with dementia, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies

 

No pharmacological agents are approved for treating patients with DRP, and antipsychotic (AP) drugs are often prescribed off-label for treating psychosis despite safety concerns with use of these medications in this population (13). Meta-analyses of randomized, controlled trials of APs demonstrate limited efficacy for treating DRP (14, 15). The effect size for treatment is modest (effect size=0.2) for psychosis in patients with AD (16-18). Results from the Clinical Antipsychotic Trials on Intervention Effectiveness-Alzheimer’s disease (CATIE-AD) study showed a significant decline in cognitive function with AP use (19), and a meta-analysis of AP in dementia patients found a similar negative effect on cognitive function (20). Further, use of APs for treating patients with dementia and PD is associated with a higher risk of mortality compared with placebo (14, 20-23) as well as an increased risk of morbidity (24). Hence, there is a major unmet need for pharmacological treatment of DRP that effectively manages symptoms of psychosis without compromising cognition and with an acceptable safety and tolerability profile.
Pimavanserin, a selective 5-hydroxytryptamine (HT)2A receptor inverse agonist/antagonist, has minimal affinity for dopaminergic, muscarinic, histaminergic or adrenergic receptors (25). Pimavanserin was developed on the basis of the observation that antagonism of the 5-HT2A receptor is the common feature of most approved and efficacious APs (26).
Pimavanserin is the only drug approved in the United States for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP) (27). Early supportive evidence of the efficacy of pimavanserin was provided from the results of two placebo-controlled clinical trials in PDP (NCT00477672; NCT00658567; data on file, ACADIA Pharmaceuticals) (28). These studies together with a pivotal Phase 3 study (29) formed the basis of approval of pimavanserin by the US Food and Drug Administration (FDA) in 2016 for the treatment of hallucinations and delusions associated with PDP.
Recently, pimavanserin was shown to improve hallucinations and delusions in patients with AD psychosis (ADP) (30). Analyses from this study also demonstrated that pimavanserin did not negatively impact cognitive function in these patients (Table 2).

Table 2. Completed or ongoing analyses from randomized, placebo-controlled studies with pimavanserin for neuropsychiatric disorders

Table 2. Completed or ongoing analyses from randomized, placebo-controlled studies with pimavanserin for neuropsychiatric disorders

 

The findings of efficacy for pimavanserin in the PDP and ADP populations indicate that pimavanserin may have a favorable treatment effect on psychotic features across many neurodegenerative dementing illnesses. Here we review the pimavanserin clinical development program leading to the approval for PDP along with the data from the study in ADP leading to a proposed trial in DRP across a spectrum of neurodegenerative diseases. The rationale and methodology for DRP development is discussed.

 

A phase 3 study of Pimavanserin for Pakinson’s disease psychosis

The efficacy of pimavanserin in the treatment of hallucinations and delusions associated with PDP was demonstrated in a Phase 3, double-blind, randomized, placebo-controlled study (29).
Patients satisfying diagnostic criteria for PDP were randomized to pimavanserin 34 mg or placebo for a 6-week treatment period. The study included a 2-week screening, baseline (Day 1), 6 weeks of treatment, and a follow up visit 4 weeks after study drug discontinuation. During the 2-week screening period, patients received brief psychosocial therapy (45). The primary efficacy endpoint was mean change from baseline to Week 6 in the SAPS-PD score.
This study demonstrated clinically and statistically significant superiority of pimavanserin 34 mg over placebo in treatment of hallucinations and delusions in patients with PDP. A 5.79 point improvement (least square (LS) mean change) at Week 6 was observed with pimavanserin compared to a 2.73 point improvement for placebo in the SAPS-PD score. This represents a clinically meaningful change with a treatment difference of 3.06 points (p=0.001; effect size 0.50). The effect size of 0.50 indicates a robust effect compared with the 0.2 effect size typically reported with APs (16-18). In addition, pimavanserin was generally well tolerated with no effects on motor function as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II+III.

 

Subgroup analysis of outcome by baseline MMSE

Patients with dementia (Mini-Mental State Examination (MMSE) score <20) were excluded in the pivotal clinical trial (30); but some patients exhibited a limited degree of cognitive impairment. A post hoc subgroup analysis conducted from the Phase 3 study, evaluated randomized patients according to the presence or absence of cognitive impairment, defined as a MMSE score of 21 to 24 for cognitive impairment versus ≥25 for non-impaired (46). The cognitively impaired subgroup constituted about 25% of the overall study population (pimavanserin, n=29; placebo, n=21). The primary endpoint of this analysis was mean change from baseline to Week 6 for the SAPS-PD score.
Patients with cognitive impairment (MMSE score 21-24) demonstrated a 6.62 point improvement (LS mean change) in the SAPS-PD score with pimavanserin at Week 6 compared to a 0.91 point improvement with placebo, representing a treatment difference of 5.71 points (p=0.002) (Figure 1). The observed effect size (Cohen’s d) in the subgroup of patients with PDP and dementia was 0.99. This compares to a treatment difference of 3.06 in the overall study population. In the non-cognitively impaired group (MMSE score ≥25) the LS mean change from baseline to Week 6 for the SAPS-PD was -5.50 with pimavanserin vs. -3.23 with placebo with a treatment difference of 2.27 (p=0.046). At Week 6, among the cognitively impaired subgroup for Clinical Global Impressions-Improvement (CGI-I) score, the mean difference from baseline for pimavanserin vs. placebo was 1.0 (p=0.012), and for the non-impaired, the mean difference for pimavanserin vs. placebo was -0.6 (p=0.022).
The results from this subgroup analysis suggest that pimavanserin is efficacious in PDP patients with cognitive impairment and may exhibit a more robust effect in this subgroup of patients. No notable differences were observed for the incidence of adverse events between impaired and non-impaired groups.

Figure 1. LS mean change in the SAPS-PD score to Week 6 for pimavanserin and placebo in the overall population and by baseline MMSE score (46)

Figure 1. LS mean change in the SAPS-PD score to Week 6 for pimavanserin and placebo in the overall population and by baseline MMSE score (46)

 

A Phase 2 study of Pimavanserin for ALzheimer’s disease psychosis

A completed study suggests that pimavanserin is effective in reducing hallucinations and delusions in patients with ADP (30).
This was a Phase 2, 12-week, randomized, double-blind, placebo-controlled, single-center study to assess the safety and efficacy of pimavanserin 34 mg once daily in nursing home residents with ADP (30). The pre-specified primary and secondary endpoints were evaluated at Week 6 of treatment. Eligible patients were required to have a score ≥4 on either the hallucinations or delusions component or a combined hallucinations and delusions score of ≥6 on the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). During the screening period, patients received brief psychosocial therapy. The primary efficacy endpoint was change from baseline to Week 6 for the NPI-NH psychosis score (delusions + hallucinations domains).
A total of 181 patients were randomized (n=90 pimavanserin and n=91 placebo) with 178 patients were included in the full analysis set (n=87 pimavanserin and n=91 placebo). The mean age of patients was 85.9 years. The mean baseline NPI-NH psychosis score for all patients was 9.8 with comparable mean scores in the pimavanserin (9.5) and placebo (10.0) groups. The mean baseline MMSE score for all patients was 10.1.
For the primary endpoint – drug-placebo difference on change from baseline in NPI-NH psychosis score at Week 6 – pimavanserin demonstrated a significant (p=0.045) treatment effect vs. placebo with a treatment difference of -1.84 and a Cohen’s d effect size of 0.32. Response on the NPI-NH (defined as ≥30% improvement from baseline to Week 6) was observed in 55.2% of subjects in the pimavanserin group and 37.4% of subjects in the placebo group (p=0.016); ≥50% improvement occurred in 50.6% of subjects in the pimavanserin group and 34.1% of subjects in the placebo group (p=0.024). Mean changes from baseline for the MMSE score and UPDRS Part III (motor function) scores were minimal and comparable for pimavanserin and placebo. Patients were followed until week 12. Both pimavanserin and placebo-treated patients continued to improve. The drug-placebo difference at Week 12 – a secondary endpoint – did not reach statistical significance.
This study suggests that pimavanserin may be effective in treating hallucinations and delusions in patients with ADP. Pimavanserin had no adverse effects on motor function (UPDRS) or cognition (MMSE).

 

Subgroup analysis of patients with more severe psychosis at baseline

In the analytic plan of the ADP Phase 2 study data, a pre-specified subgroup analysis was conducted in patients who had more severe psychotic symptoms (hallucinations and delusions) at baseline as measured by NPI-NH psychosis score (30, 47). This pre-specified analysis corroborated the primary endpoint results and showed that patients with more severe psychotic symptoms at baseline (NPI-NH psychosis score ≥12) experienced greater improvement compared to patients with less severe symptoms at baseline (NPI-NH psychosis score <12) (Figure 2). In patients with baseline NPI-NH psychosis score ≥12, LS mean change to Week 6 was -10.15 with pimavanserin vs. -5.72 with placebo (delta= 4.43, Cohen’s d = 0.734, p=0.011), which was a substantively larger treatment effect compared to patients with NPI-NH psychosis score Prespecified responder analyses in residents with more severe baseline symptoms also demonstrated the significant effect of pimavanserin compared with placebo in patients with ADP (Figure 3). A significantly greater proportion of the pimavanserin patients showed ≥30% improvement from baseline and ≥50% improvement from baseline on their NPI-NH psychosis score. Among patients with a NPI-NH psychosis score ≥12, response for pimavanserin and placebo (defined by ≥30% improvement from baseline to Week 6) was observed in 88.9% vs. 43.3% (p<0.001) and, when defined by ≥50% improvement was 77.8% vs. 43.3% (p=0.008), respectively.
Thus, in the subgroup of patients with more severe psychotic symptoms at baseline, significant improvements in mean NPI-NH psychosis score and in NPI-NH responder rates were observed with pimavanserin vs. placebo. These findings were consistent with the observations in the overall population and demonstrate the robust significant treatment effect of pimavanserin vs. placebo in patients with severe symptoms of psychosis at baseline.

Figure 2. LS mean change from baseline to Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

Figure 2. LS mean change from baseline to Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

Figure 3. Response rate at Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

Figure 3. Response rate at Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

 

Pimavanserin for the treatment of DRP

The efficacy and safety of pimavanserin for treatment of psychotic symptoms in dementia are being evaluated in an ongoing study: a Double-blind, Placebo-controlled, Relapse Prevention Study of Pimavanserin for the Treatment of Hallucinations and Delusions Associated With Dementia Related Psychosis (Clinicaltrials.gov. NCT03325556). The study is designed to evaluate the efficacy of pimavanserin in preventing relapse of psychotic symptoms in patients with DRP following 12 weeks of open-label treatment with pimavanserin followed by blinded randomized withdrawal of treatment or continued pimavanserin therapy.
Eligible patients will include those who meet criteria for all-cause Dementia according to National Institute on Aging-Alzheimer’s Association (NIA-AA) guidelines (48) as well as satisfying clinical criteria for one of the following disorders (with or without cerebrovascular disease): PDD (49), DLB (50), possible or probable AD, frontotemporal degeneration spectrum disorders (51-53) or vascular dementia (54). In addition, patients will have an MMSE score ≥6 and ≤24, have psychotic symptoms for at least 2 months, SAPS H+D ≥10; CGI-S ≥4 (moderately ill), and have at least one SAPS H+D global item ≥4 (corresponding to moderate or severe psychosis). For those patients taking a cholinesterase inhibitor and/or memantine, the dose of this medication must remain stable for at least 12 weeks prior to baseline. Patients on AP medications at screening will need to be tapered off their medication prior to baseline, if medically appropriate, or they will be excluded. Brief psychosocial therapy will be administered during screening to identify patients who respond to non-pharmacological therapy, and thus who are no longer appropriate for enrollment.
After a 4-week screening period, approximately 360 patients will enter an open-label period with flexible dosing of pimavanserin. At 12 weeks, patients who met specific criteria for sustained response to open-label treatment at both 8 and 12 weeks will be randomized to a daily dose of pimavanserin 20 or 34 mg (based on their open-label dose) or placebo for 26 weeks. The primary outcome is time from randomization to relapse of psychosis in the double-blind period. Relapse is defined as a ≥30% increase from Week 12 on the SAPS-H+D Total Score and a CGI-I score of 6 or 7; treatment with an additional antipsychotic for DRP; patient withdrawing from the study for lack of efficacy; or hospitalization for worsening DRP. A key secondary outcome is time from randomization to “all-cause” discontinuation from the double-blind period.
There are several advantages of the relapse prevention design of this study. First, it maximizes the duration of exposure to a potentially effective treatment (pimavanserin) and minimizes the duration of exposure to placebo (55, 56). A second advantage is the enrichment of the study population with an open-label, run-in phase, which helps to minimize inclusion of non-responders. Also, Brief Psychosocial Therapy will be used at screening to eliminate patients who respond to non-pharmacological therapies, ensuring that most patients in need, receive pharmacological treatment. In addition, the withdrawal design affords the advantage of offering potentially therapeutic medication to all participants at enrollment, making it more feasible to enroll persons with active psychosis who might otherwise be unwilling or unable to consider trial participation. This addresses a major barrier to enrollment in trials when treatment is perceived as most necessary. Similar designs have been used successfully with a number of antipsychotics and antidepressants to demonstrate long-term efficacy and safety in a range of psychiatric indications (57). This design is aligned with 2017 American Psychiatric Association guidelines for use of antipsychotic drugs in dementia patients: if a drug demonstrates no efficacy after 4-6 weeks, therapy should be discontinued. If a drug demonstrates efficacy within 16 weeks, an attempt should be made to taper off medication to determine if ongoing therapy is necessary.
The conceptual basis for using pimavanserin in DRP is based on the observation that a common feature of antipsychotics is antagonism of the 5-HT2A receptor (26) and that this effect is applicable regardless of the associated neuropathology (plaques, tangle, Lewy bodies, TDP-43, vascular lesions). The emergence of psychotic symptoms in many types of dementia suggests that diverse pathologies may give rise to a common symptom complex; this final pathway may be subject to modification from 5-HT2A receptor antagonism.

 

Summary

Clinical evidence is now available that supports potential efficacy of pimavanserin in DRP. This includes results from a Phase 3 study in patients with PDP (29), a secondary analysis of 25% of patients enrolled in this study who also had cognitive impairment (MMSE of 21 to 24) where the observed effect size (Cohen’s d) in the subgroup of patients with PDP and cognitive impairment was 0.99, and a Phase 2 study in patients with ADP (30) indicating a robust effect in patients with more severe psychosis (47).
Across two different models of DRP (PD and AD) pimavanserin has demonstrated meaningful efficacy larger than that reported with current off-label treatments. These clinical data, coupled with a substantial body of research, suggest that psychotic symptoms can manifest independent of the underlying dementia subtype.
In summary, based on the overlap in clinical presentation and pathology, as well as in management of psychotic symptoms in patients with dementia, and importantly, the positive clinical trial results in two neurodegenerative patient populations (PD and ADP), pimavanserin’s effect in patients experiencing hallucinations and delusions associated with DRP across a number of neurodegenerative disorders is being investigated.

 

Acknowmedgement: The authors acknowledge the editorial assistance of Richard S. Perry, PharmD in the preparation of this manuscript, which was supported by ACADIA Pharmaceuticals Inc., San Diego, CA.

Funding: This study was funded by ACADIA Pharmaceuticals Inc., San Diego, California. All authors as well as the sponsor were involved in the design and conduct of the study; the collection, analysis, and interpretation of data; in the preparation of the manuscript; and in the review or approval of the manuscript.

Conflicts of interest: JLC has provided consultation to ACADIA, Accera, Actinogen, ADAMAS, Alkahest, Allergan, Alzheon, Avanir, Axovant, Axsome, BiOasis Technologies, Biogen, Boehinger-Ingelheim, Eisai, Genentech, Grifols, Kyowa, Lilly, Lundbeck, Merck, Nutricia, Otsuka, QR Pharma, Resverlogix, Roche, Samus, Servier, Suven, Takeda, Toyoma, and United Neuroscience companies. Dr. Cummings is supported by Keep Memory Alive (KMA), COBRE grant # P20GM109025; TRC-PAD # R01AG053798; DIAGNOSE CTE # U01NS093334. PT reports the following (pertinent for the last two years): consulting fees from Abbott Laboratories, AbbVie, AC Immune, Acadia Pharmaceuticals, Auspex, Boehringer-Ingelheim, Chase Pharmaceuticals, Eisai, Glia Cure, Insys Therapeutics, and Pfizer; Consulting fees and research support from AstraZeneca, Avanir, Eli Lilly, Lundbeck, and Roche; Research support only from Amgen, Avid, Biogen, Elan, Functional Neuromodulation (f(nm)), GE Healthcare, Genentech, Novartis, Targacept, NIA, and Arizona Department of Health Services; he is a contributor to a patent owned by the University of Rochester, “Biomarkers of Alzheimer’s disease” and owns stock options in Adamas, and he has received research support, consulting fees, and serves on an advisory board for Merck and Co. Dr. Ballard has received grants and personal fees from ACADIA and Lundbeck, personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline, and Pfizer. JY, EF, SS, RO, and JN are employees of and stockholders in ACADIA Pharmaceuticals Inc.

Ethical standard: The study adheres to the Declaration of Helsinki human protection guidelines and was reviewed by ethical standards boards for all participating sites.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

 

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