Safety Profile of Pimavanserin Therapy in Elderly Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study.

Background: Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, is the only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Further expanding knowledge of the safety profile of pimavanserin in PDP and neurodegenerative diseases (NDD) such as Alzheimer's disease is of great interest for informing its use in patients with PDP (with or without dementia), given this population is highly sensitive to adverse effects following antipsychotic use. Objective: This trial evaluated the effects of pimavanserin compared to placebo in frail older adults and elderly patients with neuropsychiatric symptoms related to NDD, such as hallucinations and delusions, to better understand the safety of pimavanserin in this population. Methods: This was a phase 3b, 8-week treatment (study duration of up to 16 weeks), multicenter, randomized, double-blind, placebo-controlled, two-arm parallel-group trial (NCT03575052). The primary endpoint was safety and tolerability, measured by treatment-emergent adverse events (TEAEs). Secondary safety endpoints were change from baseline in motor and cognitive function; exploratory endpoints included suicidality, sleep quality, and neuropsychiatric symptoms. Results: Incidences of TEAEs were similar between treatment groups; 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%), and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%). Pimavanserin did not impact motor- or cognitive-related function. Conclusions: Pimavanserin was well tolerated and not associated with motor or cognitive impairment. Together, these findings highlight the manageable and generally favorable safety profile of pimavanserin in patients with NDD, contributing to our knowledge on the safety of pimavanserin as it generalizes to patients with PDP.

The effects of treatment with pimavanserin on activities of daily living in patients with Parkinson's disease psychosis: a 16-week, single-arm, open-label study.

Background: More than half of patients with Parkinson's disease will experience psychosis symptoms in the form of hallucinations or delusions at some point over the course of their disease. These symptoms can significantly impact patients' health-related quality of life, cognitive abilities, and activities of daily living (ADLs) and function. Clinical assessment of how psychosis impacts these measures is crucial; however, few studies have assessed this sufficiently, in part due to a lack of appropriate scales for comprehensively assessing function. Objective: The objective was to assess how symptoms of Parkinson's disease psychosis (PDP) impact ADLs and function, cognitive function, and health-related quality of life. Design: To address this unmet need, we utilized a modified version of the Functional Status Questionnaire (mFSQ) to measure the impact of psychosis on ADLs and function in patients with PDP treated with pimavanserin, a US Food and Drug Administration-approved medication to treat hallucinations and delusions associated with PDP. Methods: Eligible patients entered a 16-week, single-arm, open-label study of oral pimavanserin (34 mg) taken once daily. The primary endpoint was change from baseline to Week 16 on the mFSQ. Secondary endpoints included the Movement Disorders Society-modified Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I and II; Schwab and England ADL; Clinical Global Impression-Severity of Illness (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I), and were also measured as change from baseline to Week 16 using mixed-effects model for repeated measures (MMRM) and least-squares mean (LSM). Results: Our results in a proof-of-concept, 16-week, open-label clinical study in 29 patients demonstrated that an improvement in psychosis symptoms following treatment with pimavanserin was associated with improvements in multiple measures of ADLs and function. Notably, a significant improvement was found on the primary endpoint, change from baseline to Week 16 in mFSQ score [LSM [SE] 14.0 [2.50], n = 17; 95% CI (8.8, 19.3); p < 0.0001]. Conclusion: These findings highlight the potential for improvement in function with improvement of psychosis symptoms in patients with PDP and suggest that the mFSQ may be a measurement tool to evaluate the level of improvement in function. Trial registration: ClinicalTrials.gov Identifier: NCT04292223.

Gastrointestinal manifestations in pediatric and adult patients with Rett syndrome: an analysis of US claims and physician survey data.

Aim: Patients with Rett syndrome (RTT) experience gastrointestinal (GI) manifestations. This study aimed to describe the prevalence of GI manifestations and the associated medical costs in patients with RTT in the USA. Patients & Methods: The study combined an insurance claims database analysis with a survey of 100 physicians experienced in RTT management. Results: GI manifestations affected 43.0% of 5940 patients, with increased prevalence in pediatric patients (45.6%) relative to adult patients (40.2%). Annualized mean medical cost of managing GI manifestations was $4473. Only 5.9-8.2% of neurologists and pediatricians ranked GI symptom management among the five most important treatment goals. Conclusion: Patients with RTT experience a high burden of GI manifestations, which translate to considerable medical costs. Importantly, the prevalence of GI manifestations was likely underestimated in this study, as only those symptoms which resulted in a healthcare encounter were captured.

Pimavanserin for psychosis in Parkinson's disease dementia: Subgroup analysis of the HARMONY Trial.

INTRODUCTION: Pimavanserin is FDA-approved to treat Parkinson's disease (PD) psychosis. We analyzed the effect of pimavanserin on psychosis in the PD dementia (PDD) subgroup from the phase 3 HARMONY trial. METHODS: This subgroup analysis included PDD patients enrolled in an international, multicenter, randomized discontinuation study of pimavanserin for dementia-related psychosis. PDD patients with moderate-to-severe psychosis, age 50-90 years, received pimavanserin 34 mg/day for 12 weeks (open-label period). Those with a sustained psychosis response to pimavanserin at weeks 8 and 12 were randomized during the double-blind period to continue pimavanserin or receive placebo. Primary efficacy endpoint was time to psychosis relapse as measured by the SAPS-H + D and CGI-I. Safety was assessed, as were effects on motor symptoms and cognitive abilities using the ESRS-A and MMSE. RESULTS: 392 patients were enrolled in HARMONY (mean age: 72.6 years; 38.8 % female): 59 had PDD; 49/59 remained on pimavanserin during the open-label period (safety analysis set), and 36/49 were randomized to pimavanserin (n = 16) or placebo (n = 20) in the double-blind phase (intent-to-treat analysis set). Risk of psychosis relapse was lower with pimavanserin 34 mg compared with placebo in the double-blind phase (HR = 0.052; 95 % CI 0.016-0.166; 1-sided nominal p < 0.001). During the open-label period, 46.9 % experienced a treatment-emergent adverse event; event incidence was similar across arms in the double-blind period. Pimavanserin did not adversely affect motor or cognitive function in either treatment phase. CONCLUSIONS: Pimavanserin significantly reduced risk of psychosis relapse in patients with PDD, was well tolerated, and did not worsen motor or cognitive function.

Meaningful Improvements in Rett Syndrome: A Qualitative Study of Caregivers.

BACKGROUND: Rett syndrome is a rare neurodevelopmental disorder primarily affecting females. This syndrome is associated with many comorbidities and impairments related to motor function, breathing, sleep, expressive language, and repetitive hand movements. The Rett Syndrome Behaviour Questionnaire (RSBQ) is one measure used to assess changes in Rett syndrome-related manifestations or core symptoms. Little is known about how caregivers think about meaningful changes in the items that make up the RSBQ scale. METHODS: This qualitative study explored how caregivers of individuals with Rett syndrome viewed changes in the symptoms covered in the RSBQ. We conducted semistructured interviews with 40 caregivers and employed thematic analysis, identifying themes using an iterative process. RESULTS: Two factors characterized caregivers' thoughts about meaningful changes in Rett syndrome manifestations. First, general features of these symptoms rendered them bothersome: the extent of bother compared to other symptoms, if or how they prevented desirable behaviors and their temporal qualities. Second, caregivers evaluated the meaning of improvements by considering the decrease in bother and the potential benefits of change. Improvements had social and psychological consequences for individuals with Rett syndrome and caregivers. In addition, implications for health, fine and gross motor skills, and communication were also substantial.

Burden of Illness Among Patients with Psychosis due to Dementia with Lewy Bodies and Other Dementias.

Limited research is available on the real-world experiences of patients with dementia with Lewy bodies (DLB). This study evaluated clinical events, healthcare utilization, and healthcare costs of patients with DLB vs other dementia types with psychosis (ODP). Study patients included commercial and Medicare Advantage with Part D enrollees aged ≥40 years with evidence of DLB and ODP from 6/01/2015‒5/31/2019. Compared with patients with ODP, more patients with DLB had clinical events including anticholinergic effects, neurologic effects, and cognitive decline. Patients with DLB used more healthcare resources with greater dementia-related office and outpatient visits and psychosis-related inpatient stays and office, outpatient, and emergency visits compared with their ODP patient counterparts. Patients with DLB also incurred higher healthcare costs for all-cause and dementia-related office visits and pharmacy fills, and psychosis-related total costs. Understanding the clinical and economic impact of DLB and ODP is important to improve care for patients with dementia.

Motor- and cognition-related safety of pimavanserin in patients with Parkinson's disease psychosis.

Background: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is the only treatment approved by the US Food and Drug Administration for hallucinations and delusions associated with Parkinson's disease (PD) psychosis. Aim: We aimed to evaluate motor- and cognition-related safety in pimavanserin-treated patients with PD psychosis. Methods: This analysis included patients with PD psychosis treated with pimavanserin 34 mg from a pooled analysis of 3 randomized, double-blind, placebo-controlled, 6-week studies [NCT00477672 (study ACP-103-012), NCT00658567 (study ACP-103-014), and NCT01174004 (study ACP-103-020)] and a subgroup of patients with PD dementia with psychosis from HARMONY (NCT03325556), a randomized discontinuation study that included a 12-week open-label period followed by a randomized double-blind period of up to 26 weeks. Motor- and cognition-related safety were examined. Results: The pooled analysis included 433 randomized patients (pimavanserin, 202; placebo, 231). Least squares mean (standard error [SE]) change from baseline to week 6 Unified Parkinson's Disease Rating Scale (UPDRS) II + III score was similar for pimavanserin [-2.4 (0.69)] and placebo [-2.3 (0.60)] (95% Confidence Interval [CI]:-1.9, 1.6). The change from baseline to week 6 for UPDRS II and UPDRS III scores was similar between groups. In the HARMONY open-label period, 49 patients with PD dementia with psychosis were treated with pimavanserin 34 mg, 36 of whom were randomized in the double-blind period (pimavanserin, 16; placebo, 20). In the open-label period, the mean (SE) change from baseline to week 12 (n = 39) Extra-Pyramidal Symptom Rating Scale (ESRS-A) score was -1.7 (0.74); in the double-blind period, the results were generally comparable between the pimavanserin and placebo arms. The change from baseline in Mini-Mental State Examination (MMSE) score was also comparable between pimavanserin- and placebo-treated patients in HARMONY [open-label (n = 37): mean (SE) change from baseline to week 12, 0.3 (0.66)]. Rates of motor- and cognition-related adverse events were similar between pimavanserin and placebo in both analyses. Conclusions: Pimavanserin 34 mg was well tolerated and did not yield a negative impact on motor- or cognition-related function in patients with PD psychosis.

Economic Evaluation of Healthcare Resource Utilization and Costs for Newly Diagnosed Dementia-Related Psychosis.

This retrospective cohort study described changes in all-cause healthcare resource utilization (HCRU) and associated costs in dementia patients newly diagnosed with psychosis. Dementia and incident psychosis were identified using diagnostic and pharmacy claims using a Medicare 20% random sample dataset. All-cause HCRU and unweighted and weighted (by person-years of follow-up) HCRU-associated costs were evaluated in the year prior to and the 4 years following diagnosis of psychosis. In 49,509 dementia patients with psychosis, physician visits per patient per year increased from a mean of 26.7 (standard deviation (SD) 20.0) prior to psychosis to 38.4 (SD 41.9) post-psychosis diagnosis. The number of inpatient stay claims increased from 1.0 (SD 1.4) to 1.7 (SD 5.8). Mean unweighted costs for inpatient stays and home healthcare/hospice during 2008-2016 were USD 9989 and USD 3279 prior to a diagnosis of psychosis but increased to USD 25,982 and USD 9901 (weighted: USD 11,779 and USD 6709), respectively, in the year after a psychosis diagnosis. This pattern of a sharp increase in mean costs was also observed in costs adjusted to 2015 USD, and in both unweighted and weighted total and psychosis-related costs. These results indicate the importance of identifying newly diagnosed psychosis in dementia patients as well as the pressing need for management strategies and treatments that can reduce HCRU and costs.

Medicare claims analysis of agents used to manage dementia-related psychosis: a treatment pattern study.

Currently, no agents are approved in the USA to treat dementia-related psychosis. After failure of a nonpharmacologic approach to treatment, antipsychotics or divalproex is often prescribed. We characterized existing treatment patterns in patients with dementia-related psychosis. Medicare claims data from 2008 to 2016 were used to identify patients with dementia-related psychosis. The agents and associated dosages prescribed, time to first use, and patterns of use were evaluated for agents prescribed to treat dementia-related psychosis. In total, 49 509 patients were identified as having dementia-related psychosis. Over three-quarters (76.8%) received an antipsychotic or divalproex. The most prescribed first-line agents were quetiapine (30.5%), risperidone (19.5%), and divalproex (11.2%). More than 80% of patients received a low dose of an agent, and 65.5% switched or discontinued their first-line treatment during a mean follow-up period of 1.8 years. In the absence of US FDA-approved therapies to treat dementia-related psychosis, treatment after behavioral intervention involves frequent use of low-dose antipsychotics or divalproex. The high rate of treatment switching or discontinuation is consistent with current treatment guidelines and suggests a need for an improved, standardized pharmacological approach to treat dementia-related psychosis.

Adverse Outcomes Associated With Off-Label Agents Used to Treat Dementia Patients With Psychosis: A Case-Control Medicare Database Study.

INTRODUCTION: Currently, there are no Food and Drug Administration-approved therapies to treat dementia-related psychosis (DRP). This study investigated the association between using antipsychotics and the anticonvulsant divalproex (sodium valproate) to manage DRP and adverse outcomes. METHODS: A retrospective case/control matching study evaluated the risk of mortality, extrapyramidal symptoms (EPS), ischemic stroke, and cardiac arrest/ventricular arrhythmia (CA/VA) with ever-use of antipsychotics/divalproex in patients with DRP vs never-use. RESULTS: 49 509 patients were included; 76.8% used an antipsychotic/divalproex. Treatment ever-use was associated with an increased risk of all-cause mortality (odds ratio, 1.14; 95% CI, 1.10-1.18) and a smaller increase in the risk of EPS (1.10; 1.00-1.19) relative to never-use (adjusted for matching demographic variables, comorbid conditions, and disability). CONCLUSIONS: Current agents used for DRP were associated with increased risk of death and adverse outcomes. An increased risk of death was evident within 3 months of antipsychotic/divalproex initiation and persisted with long-term use.

Comparative Outcomes of Commonly Used Off-Label Atypical Antipsychotics in the Treatment of Dementia-Related Psychosis: A Network Meta-analysis.

INTRODUCTION: Dementia-related psychosis (DRP) is characterized by hallucinations and delusions, which may increase the debilitating effects of underlying dementia. This network meta-analysis (NMA) evaluated the comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) commonly used off label to treat DRP. METHODS: We included 22 eligible studies from a systematic literature review of AAPs (quetiapine, risperidone, olanzapine, aripiprazole, and brexpiprazole) used off label to treat DRP. Study outcomes were: (1) efficacy-neuropsychiatric inventory-nursing home (NPI-NH psychosis subscale), (2) safety-mortality, cerebrovascular events (CVAEs), and others (somnolence, falls, fractures, injuries, etc.), and (3) acceptability-discontinuations due to all causes, lack of efficacy, and adverse events (AEs). We used random-effects modeling to estimate pooled standardized mean differences (SMDs) for NPI-NH psychosis subscale scores and odds ratios (OR) for other dichotomous outcomes, with their respective 95% confidence intervals (CIs). RESULTS: Compared with placebo, aripiprazole (SMD - 0.12; 95% CI - 0.31, 0.06), and olanzapine (SMD - 0.17; 95% CI - 0.04; 0.02) demonstrated small, non-significant numerical improvements in NPI-NH psychosis scores (5 studies; n = 1891), while quetiapine (SMD 0.04; 95% CI - 0.23, 0.32) did not improve symptoms. The odds of mortality (15 studies, n = 4989) were higher for aripiprazole (OR 1.58; 95% CI 0.62, 4.04), brexpiprazole (OR 2.22; 95% CI 0.30, 16.56), olanzapine (OR 2.21; 95% CI 0.84, 5.85), quetiapine (OR 1.68; 95% CI 0.70, 4.03), and risperidone (OR 1.63; 95% CI 0.93, 2.85) than for placebo. Risperidone (OR 3.68; 95% CI 1.68, 8.95) and olanzapine (OR 4.47; 95% CI 1.36, 14.69) demonstrated significantly greater odds of CVAEs compared to placebo. Compared with placebo, odds of all-cause discontinuation were significantly lower for aripiprazole (OR 0.71; 95% CI 0.51, 0.98; 20 studies; 5744 patients) and higher for other AAPs. Aripiprazole (OR 0.5; 95% CI 0.31, 0.82) and olanzapine (OR 0.48; 95% CI 0.31, 0.74) had significantly lower odds of discontinuation due to lack of efficacy (OR 12 studies; n = 4382) compared to placebo, while results for quetiapine and risperidone were not significant. Compared with placebo, the odds of discontinuation due to AEs (19 studies, n = 5445) were higher for olanzapine (OR 2.62; 95% CI 1.75, 3.92), brexpiprazole (OR 1.80; 95% CI 0.80, 4.07), quetiapine (OR 1.25; 95% CI 0.82, 1.91), aripiprazole (OR 1.38; 95% CI 0.90, 2.13), and risperidone (OR 1.41; 95% CI 1.02, 1.94). CONCLUSIONS: Overall results demonstrate that, compared with placebo, quetiapine is not associated with improvement in psychosis in patients with dementia, while olanzapine and aripiprazole have non-significant small numerical improvements. These off-label AAPs (quetiapine, risperidone, olanzapine, aripiprazole, and brexpiprazole) are associated with greater odds of mortality, CVAEs, and discontinuations due to AEs than placebo. These results underscore the ongoing unmet need for newer pharmacological options with a more favorable benefit-risk profile for the treatment of DRP.

Incidence, Prevalence, and Mortality of Psychosis Associated with Parkinson's Disease (1991-2010).

BACKGROUND: Parkinson's disease (PD)-associated psychosis is a well-known non-motor complication, occurring years after diagnosis of PD. Incidence data vary across different studies highlighting a need for long-term observation and clinical definition. OBJECTIVE: To determine the incidence of psychosis in patients with PD and to investigate their survival in an incident cohort study from 1991-2010 in Olmsted County, MN. METHODS: We used the Rochester Epidemiology Project to define an incident-cohort study of parkinsonism (1991-2010) in Olmsted County, MN. A movement-disorder specialist reviewed the electronic medical records and applied diagnosis criteria to PD. Psychosis was diagnosed using of NINDS/NIMH unified criteria. RESULTS: We identified 669 cases of parkinsonism; 297 patients were clinically diagnosed with PD. 114/297 (38.4%) patients had evidence of psychosis (60% male); the median onset age of psychosis was 79.4 years. The incidence of Parkinson's disease psychosis (PDP) was 4.28/100 person-years. PDP patients had a 71% increased risk of death compared to PD patients. In PD patients without psychosis, men had 73.4% increased risk of death compared to women, whereas no significant sex difference was observed among PDP men vs. women. Of 114 patients diagnosed with psychosis, 59 were treated with antipsychotics. There was no significant difference in survival between treated and untreated patients. CONCLUSION: PDP increased the odds of death compared to PD patients. Men with PD without psychosis had greater odds of death compared to women; however, in PD with psychosis the odds of death were comparable among sexes. Lastly, treatment with anti-psychotics did not significantly affect survival.

Symptoms and Treatment Needs of People with Dementia-Related Psychosis: A Mixed-Methods Study of the Patient Experience.

OBJECTIVES: This study describes the person-centered experience and impact of symptoms and the treatment needs of dementia-related psychosis (DRP) from a patient and care partner perspective. METHODS: Qualitative interviews and a quantitative survey were used to collect patient experience data from persons with DRP or their care partners. RESULTS: Sixteen participants (1 person with DRP, 15 care partners) completed the qualitative interview; 212 participants (26 persons with DRP, 186 care partners) completed the quantitative survey. The most commonly reported symptoms were visual hallucinations, auditory hallucinations, persecutory delusions, and distortion of senses. The most common impacts were difficulty differentiating what is real from what is not real, increased anxiety, and effects on personal relationships. Current treatments were less than moderately helpful, and the ability to distinguish what is real from what is not real and overall symptom improvement were described as the most important benefits of an ideal treatment. CONCLUSIONS: Patient experience data provide insights into urgent therapeutic needs of patients by describing the nature, frequency, and severity of symptoms and the impacts they have on individuals' lives. CLINICAL IMPLICATIONS: Patient experience data demonstrate an unmet need for treatments to reduce the symptoms and impacts of DRP.

Treatment Patterns With Antipsychotics in Long-Term Care Patients With Parkinson's Disease Psychosis.

This study assessed treatment change patterns in Parkinson's disease psychosis (PDP) residents receiving antipsychotic (AP) therapies in U.S. long-term care (LTC) facilities. Residents with PDP in LTC between 01/01/13 and 06/30/16 were identified with ≥1 claim of psychosis, hallucinations, or delusions after PD diagnosis. Treatment patterns were evaluated during the 12 months post index. We identified 864 PDP residents: 408 (47.2%) on AP therapy and 456 (52.8%) on no AP therapy. A total of 335 residents (82.1%) continued, 13 (3.2%) discontinued, 11 (2.7%) switched, and 49 (12.0%) augmented (used ≥2 APs) their index AP therapy. Based on the multivariate regression analysis, younger age, male gender, anemia, anxiolytic use or anxiety, sedatives/hypnotic use, bladder disorders including urinary tract infections, coronary conditions, diabetes, hypertension, and dementia were associated with a higher likelihood of treatment change. Understanding the factors associated with treatment change may inform ways to improve management of PDP in the U.S. LTC setting.

Lewy Body Dementia Association's Industry Advisory Council: proceedings of the second annual meeting.

In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council's goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.

Real-World Medication Treatment Patterns for Long-Term Care Residents with Dementia-Related Psychosis.

Objectives: This study evaluated treatment patterns and factors associated with medication treatment changes in residents with dementia-related psychosis in a long-term care (LTC) setting. Methods: A retrospective database cohort study was conducted using the national PharMerica® database and included dementia residents with or without incident psychosis. Treatment patterns were assessed and a multivariate logistic regression model was used to identify factors associated with any treatment change (discontinuation, switch, or sporadic use) in dementia-related psychosis therapy. Results: Among 11,921 residents with incident dementia-related psychosis, 11,246 (94.3%) were prescribed ≥1 index medication to treat psychosis, including 77.3% who received ≥1 typical or atypical antipsychotic. Treatment change was evaluated during the post-index period: 38.7% of residents with dementia-related psychosis discontinued treatment, 13.9% switched treatments, and 7.9% had sporadic use. Factors associated with treatment change were age ≥65 years, Medicare insurance, and comorbid conditions (anemia, coronary heart disease, diabetes, falls, depression, hypertension, or hyperlipidemia) during the pre-index period. Discussion: Approximately 60% of dementia-related psychosis LTC residents experienced a medication treatment change. This treatment change was associated with higher age and higher comorbidities. Medications that treat symptoms of dementia-related psychosis without adding to safety concerns are needed to facilitate long-term, consistent treatment.

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients.

INTRODUCTION: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. METHODS: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. RESULTS: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Burden of illness among patients with dementia-related psychosis.

BACKGROUND: More than 5.6 million Americans suffer from dementia, and that number is expected to double by 2060. This comes at a considerable burden to the health care system with costs estimated at $157-$215 billion in 2010. Depending on dementia type and disease progression, approximately 20%-70% of patients experience dementia-related psychosis (DRP), characterized by hallucinations and/or delusions resulting in worse clinical outcomes and greater caregiver burden compared with patients without DRP. OBJECTIVE: To compare real-world clinical events, health care resource utilization (HCRU), and health care costs among matched cohorts of DRP versus dementia-only patients. METHODS: This retrospective database analysis examined commercial and Medicare Advantage with Part D enrollees aged ≥ 40 years with evidence of DRP and dementia from January 1, 2010, through March 31, 2017. The first observed indicator of psychosis (≥ 2 diagnoses and/or antipsychotic pharmacy fills) co-occurring with or following evidence of dementia (≥ 2 diagnoses and/or dementia medication pharmacy fills) was the index date among patients with DRP. DRP patients were propensity score matched 1:1 to patients with dementia only based on demographics, comorbidities, dementia type, dementia severity, and pre-index all-cause HCRU. Continuous health plan enrollment ≥ 12 months before evidence of dementia through the index date and ≥ 12 months following the index date was required. Outcomes included clinical events, HCRU, and health care costs. RESULTS: A significantly higher percentage of DRP patients had ≥1 diagnosis for behavioral health conditions in the pre-index period compared with dementia-only patients (depression: 32.4% vs. 22.8%; anxiety: 19.1% vs. 11.5%; and insomnia: 9.0% vs. 6.3%; P < 0.001 for all comparisons). Diagnoses of post-index clinical events were significantly more likely among DRP patients compared with dementia-only patients including falls/fractures (28.3% vs. 14.1%), neurologic effects (17.7% vs. 12.9%), sedation (15.0% vs. 2.4%), cardiovascular effects (7.0% vs. 4.1%), and extrapyramidal reactions (3.2% vs. 1.7%; P < 0.001 for all comparisons). Higher percentages of DRP patients had an all-cause outpatient visit (80.2% vs. 68.9%), emergency visit (65.0% vs. 36.6%), or inpatient stay (47.2% vs. 20.0%) during the post-index period (P < 0.001 for all comparisons). The proportions of DRP patients with a post-index dementia-related office visit, outpatient visit, emergency visit, or inpatient stay was 48%, 147%, 339%, and 286% higher, respectively, compared with patients with dementia only. Compared with patients with dementia only, patients with DRP had significantly higher mean total post-index all-cause costs ($21,657 vs. $12,026; P < 0.001) and dementia-related costs ($11,852 vs. $3,013; P < 0.001). CONCLUSIONS: Patients with DRP were more likely to have diagnoses for behavioral health conditions, experience clinical events, and have higher mean all-cause and dementia-related HCRU and costs compared with patients with dementia only. These results reflect the unmet need of patients with DRP and an urgency for new treatment options to reduce substantial clinical and economic burden in this population. DISCLOSURES: This study was funded by Acadia Pharmaceuticals, which participated in the study design, interpretation of study results, and critical review of the manuscript. Abler, Skoog, and Rashid were employees of Acadia Pharmaceuticals at the time this study was conducted. Frazer and Halpern were employees of Optum at the time this study was conducted and were funded by Acadia Pharmaceuticals to conduct the study.