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Alzheimer’s disease psychosis (ADP) is a common and serious condition with substantial unmet need for safe and effective treatments. Pimavanserin is approved in the US to treat Parkinson’s disease hallucinations and delusions. This post-hoc analysis of randomized, double-blind, placebo-controlled, phase 2 trial of nursing-home-residents with ADP evaluated the efficacy of pimavanserin by improvements (least squares mean change) in the Neuropsychiatric Inventory–Nursing Home Version Psychosis Score (NPI-NH PS). The clinical significance of the primary endpoint was assessed using responder analyses (≥ 30% and ≥ 50%); numbers needed to treat (NNT); cumulative response (0-100% improvement); All Patients and Severe Psychosis (NPI-NH PS ≥ 12) subgroups were evaluated; improvements in hallucinations and delusions by NPI-NH-PS frequency (3 or 4 points) and severity (2 or 3 points); and ≥ 50% responder analysis at earlier timepoints (weeks 2 and 4). Among 345 patients screened, 181 patients were randomized to pimavanserin (n = 90) and placebo (n = 91). Patients were elderly (mean age: 86 years) and frail (baseline mean NPI-NH PS scores of 9.5 and 10 for pimavanserin and placebo, respectively). Pimavanserin significantly improved NPI-NH PS relative to placebo (−3.76 versus −1.93, respectively; p = 0.0451). In responder analyses, pimavanserin demonstrated a significantly greater reduction in NPI-NH PS versus placebo at both the ≥ 30% (p = 0.0159) and ≥ 50% (p = 0.0240) thresholds with NNTs of 6 and 7, respectively. Furthermore, pimavanserin demonstrated significantly earlier reductions in NPI-NH PS compared with placebo for the ≥ 30% (p = 0.0336) and ≥ 50% (p = 0.0044) thresholds. The cumulative response analysis demonstrated significantly greater efficacy of pimavanserin for All Patients (p = 0.052) and Severe Psychosis (p = 0.004), and Severe Patients versus All Patients demonstrated a greater reduction in NPI-NH PS (p = 0.011; effect size = 0.73). Pimavanserin also demonstrated numerically greater improvements for the frequency and severity of delusions and hallucinations. Responder analyses at earlier timepoints demonstrated significantly greater response rates with pimavanserin versus placebo at week 2 (p = 0.016) but not 4 (p = 0.051). These findings support pimavanserin as safe and effective in a population of nursing-home-resident patients with ADP.

Background: Parkinson’s disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP. Objective: Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study. Methods: Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales. Results: Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was – 3.4 (6.3); p

OBJECTIVES Patients with Alzheimer's disease psychosis (ADP) commonly experience concomitant agitation and aggression. We investigated whether a reduction in ADP following pimavanserin treatment conferred a reduction in associated agitation and aggression. METHODS ACP-103-019 was a 12-week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of pimavanserin (34 mg) in reducing psychotic symptoms in patients with ADP. The primary endpoint was change from baseline in Neuropsychiatric Inventory-Nursing Home Version-Psychosis Score (NPI-NH-PS) at week six. A post hoc analysis examined whether there was a greater reduction in agitation and aggression (NPI-NH domain C [agitation/aggression] and Cohen-Mansfield Agitation Inventory-Short Form [CMAI-SF]) in pimavanserin-treated patients who experienced a reduction of hallucinations and delusions (psychosis responders defined as ≥50% reduction from baseline in NPI-NH-PS, week six) when compared with those who did not (nonresponders). RESULTS Pimavanserin-treated patients with ≥50% response in psychotic symptoms (n = 44) showed a greater improvement in agitation and aggression symptoms on the NPI-NH domain C (week six, least squares mean [LSM] difference = -3.64, t = -4.69, P

Background: PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective: To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods: Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results: Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 (P = 0.012) and –5.66 versus –3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions: The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Background: Many patients with Parkinson’s disease (PD) experience depression. Objective: Evaluate pimavanserin treatment for depression in patients with PD. Methods: Pimavanserin was administered as monotherapy or adjunctive therapy to a selective serotonin reuptake inhibitor or serotonin/noradrenaline reuptake inhibitor in this 8-week, single-arm, open-label phase 2 study (NCT03482882). The primary endpoint was change from baseline to week 8 in Hamilton Depression Scale–17-item version (HAMD-17) score. Safety, including collection of adverse events and the Mini-Mental State Examination (MMSE) and Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS III) scores, was assessed in patients who received ≥1 pimavanserin dose. Results: Efficacy was evaluated in 45 patients (21 monotherapy, 24 adjunctive therapy). Mean (SE) baseline HAMD-17 was 19.2 (3.1). Change from baseline to week 8 (least squares [LS] mean [SE]) in the HAMD-17 was –10.8 (0.63) (95% CI, –12.0 to –9.5; p

© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license., 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.

Pimavanserin is a selective 5-HTWe did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (6 or ≥6) and Neuropsychiatric Inventory-Nursing Home version (NPI-NH) psychosis score (12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI-NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553.Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI-NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI-NH psychosis score at week 6 was -3·76 points (SE 0·65) for pimavanserin and -1·93 points (0·63) for placebo (mean difference -1·84 [95% CI -3·64 to -0·04], Cohen's d=-0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference -0·51 [95% CI -2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group.Pimavanserin showed efficacy in patients with Alzheimer's disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo.ACADIA Pharmaceuticals.

Study Objectives:The INSYTE study provides an understanding of the management of Parkinson disease psychosis (PDP) in actual practice settings, including use of antipsychotic (APs) and their impact on clinical, economic, and humanistic outcomes. Treatment paradigms or the benefits/consequences of various “real world” PDP treatment strategies have not been evaluated. Thus, providers may be using a wide range of AP treatment strategies that contrast with consensus recommendations.Method:The INSYTE study is enrolling up to 750 patients from up to 100 sites in the US. Data are compiled at the baseline (BL) visit and from standard-of-care follow up visits over 3 years. PDP treatment pathways are defined from 3 BL cohorts reflecting (1) no AP medication, (2) use of pimavanserin (PIM), or (3) other AP treatment. Information about APs used is collected at each follow-up visit: history, duration, dose, adjustment, and rationale for adjustment of treatment. Outcomes assessments (clinical, quality of life, disease burden) by the physician, patient, and caregiver are also collected. AP medication and outcomes data are analyzed for patients completing a BL and 1 follow up visit (FU1).Results:For 404 patients with BL and FU1 visits (mean 120.7 days from BL), 56.8% used no AP medications, 26.0% used PIM, and 13.6% used other APs at BL. The No Medication group was noted to be less severe in key BL disease parameters. Considering primary PDP treatments at BL and FU1 (including no treatment), 26 distinct pathways were being employed. 12.6% of patients had AP medication adjustments between BL and FU1 visits, most frequently from the non-PIM group. Adjustments of APs occurred in many forms: introduction of a single AP (64.7%%), introduction of multiple APs (5.9%), switching to another AP (3.9%), decreasing the number of APs (5.9%), and discontinuation (19.6%).Conclusions:Multiple, divergent AP treatment strategies for PDP exist in actual practice. No identifiable BL characteristics correlated with the broad range of AP treatment pathways. The numerous distinct AP treatment pathways utilized (n=26) reflect discordance with the updated 2019 MDS evidence-based recommendations, which recognize only 2 APs as “efficacious” and “clinically useful”: pimavanserin and clozapine. Education of healthcare professionals remains a priority for PDP management.Funding Acknowledgements:ACADIA Pharmaceuticals Inc.

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

Background: The phase 4, METABOLIK trial demonstrated that changes in metabolic parameters with darunavir with low-dose ritonavir (DRV/r) were comparable to those observed with atazanavir with low-dose ritonavir (ATV/r). A comprehensive assessment of the effects of these agents on insulin sensitivity will provide additional, relevant clinical information. Methods: In this substudy of METABOLIK, HIV-1–infected, antiretroviral agent–naïve male subjects aged ≥18 years with a viral load of >1,000 copies/mL were randomized to receive DRV/r 800/100 mg once daily (qd) or ATV/r 300/100 mg qd, both with a fixed dose of tenofovir disoproxil fumarate/emtricitabine 300/200 mg qd. The effects of DRV/r versus ATV/r on insulin sensitivity over 48 weeks were compared using the euglycemic hyperinsulinemic clamp, the preferred method to assess insulin sensitivity; primary end point was the effect on insulin sensitivity during the first 12 weeks. Results: Twenty-seven subjects completed the study. In the DRV/r arm (n = 14), median glucose disposal from baseline through weeks 12 and 48 was 9.3, 11.4, and 9.9 mg/kg*min, respectively; in the ATV/r arm (n = 13), these values were 8.9, 8.6, and 9.1 mg/kg*min, respectively. Median insulin sensitivity in the DRV/r arm at baseline, week 12, and week 48 was 24.0, 25.0, and 21.5 mg/kg*min per μIU/mL × 100, respectively; these values in the ATV/r arm were 20.7, 22.0, and 22.0 mg/kg*min per μIU/mL × 100, respectively. Most subjects had ≥1 adverse event, including three serious adverse events (n = 2 [DRV/r], n = 1 [ATV/r]). Conclusions: DRV/r and ATV/r displayed similar modest effects on insulin sensitivity using a euglycemic hyperinsulinemic clamp.

Study Objectives:Depression occurs in ~50% of Parkinson’s disease (PD) patients, increases in severity and duration as the disease progresses, and is associated with increased morbidity. Improvement of depression in PD patients is correlated with reduced physical disability and improved quality of life. We are assessing use of pimavanserin (PIM) for treatment of depression in adults with PD.Method:A Phase-2, 8-week, open-label, single-arm study is being conducted to evaluate the safety and efficacy of PIM as an adjunct to SSRI/SNRI or as monotherapy in adults with both PD and symptoms of depression (baseline Hamilton Depression Scale [17-items] total score [HAMD-17] ≥15). The primary endpoint of the study is change from Baseline to Week 8 in the HAMD-17. Secondary measures included the Clinical Global Impression (CGI) scales (improvement and severity) and Scales of Outcomes in PD-Sleep (SCOPA).Results:Interim results based on the first 34 of 40 planned patients have been evaluated: 55.9% of patients were male, and average age was 68.1 years, with 19 patients on adjunctive therapy and 15 on monotherapy. At baseline, patients had a mean (SE) HAMD-17 of 19.8(0.6). Change from Baseline to Week 8 (least squares mean [LSM] [SE]) in the HAMD-17 was –10.7(1.0) (95% CI; –12.7,–8.7; PConclusions:These interim data suggest that PIM as adjunctive treatment or monotherapy is associated with early improvement of depressive symptoms in patients with PD and is well tolerated. This is consistent with recently reported data of PIM in major depressive disorder. Final data will be shared at the time of this presentation. However, additional placebo-controlled data will be needed to determine fully the efficacy of PIM in patients with comorbid PD and depression.Funding Acknowledgements:ACADIA Pharmaceuticals Inc.

Introduction Impaired nocturnal sleep and excessive daytime sleepiness are common problems for patients with Parkinson's disease, and patients with Parkinson's disease with sleep dysfunction are 5 times more likely to experience psychotic symptoms. Pimavanserin, a 5-HT2A inverse agonist approved to treat Parkinson's disease psychosis, may improve sleep quality in patients with Parkinson's disease experiencing sleep disturbances. Methods Scales for Outcomes in Parkinson's Disease nighttime sleep (SCOPA-NS) and SCOPA-daytime sleepiness (DS) data obtained during 2 double-blind placebo-controlled studies of pimavanserin in persons with Parkinson's disease psychosis were evaluated. Data from the placebo and pimavanserin 34 mg groups in the 2 studies were pooled to provide further information on the effect of pimavanserin 34 mg on sleep. Additional analyses on the pooled study data were performed on participants with significantly impaired nighttime sleep and daytime sleepiness, defined as SCOPA-NS ≥7 and SCOPA-DS ≥5, respectively. Results In the pooled analysis, treatment effects, expressed as least squares mean reductions in SCOPA-NS at week 6, were -1.4 for pimavanserin 34 mg and -0.5 for placebo. At week 6, the decrease from baseline in SCOPA-DS for the pimavanserin 34 mg group was -1.7 and -1.2 for the placebo group (P = 0.108). When evaluating participants with impaired nighttime sleep and daytime sleepiness at baseline, the SCOPA-NS score change was -4.4 for the pimavanserin 34 mg group and -2.3 for the placebo group (P = 0.002), whereas the SCOPA-DS change was -2.9 and -1.9 for the pimavanserin 34 mg and placebo groups (P = 0.120), respectively. Conclusion The data from the trials suggest that nighttime sleep improved with administration of pimavanserin, a novel 5-HT2A receptor inverse agonist/antagonist.

Background: PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective: To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods: Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results: Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 (P = 0.012) and –5.66 versus –3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions: The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Objectives Following antiretroviral therapy failure, patients are often treated with a three-drug regimen that includes two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. An alternative two-drug nucleoside-sparing regimen may decrease the pill burden and drug toxicities associated with the use of N(t)RTIs. The Intelence aNd pRezista Once A Day Study (INROADS; NCT01199939) evaluated the nucleoside-sparing regimen of etravirine 400 mg with darunavir/ritonavir 800/100 mg once-daily in HIV-1-infected treatment-experienced subjects or treatment-naive subjects with transmitted resistance. Methods In this exploratory phase 2b, single-arm, open-label, multicentre, 48-week study, the primary endpoint was the proportion of subjects who achieved HIV-1 RNA

Anemia is a common adverse event associated with telaprevir-based triple therapy of chronic, genotype 1 hepatitis C. Identification of patients at risk of developing anemia could allow evaluation of suitability for therapy, and aid in determining frequency of anemia monitoring and treatment management.This post-hoc analysis utilized data from the no lead-in telaprevir, peginterferon and ribavirin arm of the REALIZE study. Anemia was defined as a single occurrence of hemoglobin10 g/dl at any point during treatment. Pre-treatment factors with potential to act as prognostic indicators of anemia including age, sex, BMI, and baseline hemoglobin were analysed by univariate and multivariate logistic regression analyses. Nomograms (graphical representations of risk factors) were developed to predict the likelihood of developing anemia.Among the 265 patients, 102 (38%) had anemia, with 78/102 (77%) developing anemia on or before week 12. Most patients developed anemia after week 2 and an inverse correlation was found between week 2 hemoglobin and the likelihood of developing anemia. Overall, 60% of patients (60/100) with week 2 hemoglobin13 g/dl subsequently developed anemia. The multivariate analysis revealed older age (45 years), lower BMI (≤25 mg/m(2)) and baseline hemoglobin (continuous variable) were significantly associated with the probability of developing anemia during telaprevir treatment.These analyses indicate the potential of using predictive risk factors such as low baseline and on-treatment hemoglobin to identify patients at risk of developing anemia on telaprevir-based triple therapy, which may increase the potential for treatment success by careful patient monitoring.

Introduction The objective of this post hoc analysis was to evaluate whether Alzheimer's disease (AD) patients with psychosis who experience an improvement in their hallucinations and delusions with pimavanserin treatment also experience an improvement in agitation and aggression. Methods ACP-103-019 was a 12 week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of pimavanserin (PIM) 34mg once-daily in reducing the frequency and/or severity of hallucinations and delusions in patients with AD psychosis. The primary endpoint was change from baseline in the Neuropsychiatric Inventory Nursing Home Version Psychosis Score (NPI-NH PS) [domain A (delusions) + domain B (hallucinations)] at Week 6. A post hoc analysis was conducted to determine if there was a greater reduction in agitation and aggression, as measured by NPI-NH Domain C (agitation/aggression) and Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF), in patients who experienced a reduction in the frequency and/or severity of their hallucinations and delusions when compared with those who did not experience a reduction in hallucinations and delusions. Results Overall in ACP-103-019, there were only minor differences between the placebo (n=91) and PIM (n=87) treatment arms when evaluating changes from baseline to Week 6 in Agitation/Aggression based on CMAI SF total score or NPI-NH Domain C score (0.30 [p=0.8031] and -0.66 [p=0.254], respectively). However, when subjects treated with PIM who responded to the treatment (n=48), defined as a 30% reduction in NPI-NH PS at Week 6, were compared with those who did not respond to PIM treatment (n=28), there was a greater reduction in both CMAI-SF and NPI-NH Domain C scores: -3.74 (p=0.0550) and -2.75 (p=0.0021), respectively. When response was defined as a 50% reduction in NPI-NH PS at Week 6, the greater improvement of agitation/aggression in responders (n=44) vs non-responders (n=32) was also observed for both CMAI-SF and NPI-NH Domain C: -3.714 (p=0.0483) and -3.64 (p Conclusions In this post-hoc analysis, some AD patients whose hallucinations and delusions responded to pimavanserin also experienced improvement in their symptoms of agitation and aggression. These results suggest a correlation between a reduction in hallucinations and delusions and a reduction in agitation/aggression in AD patients with psychosis. This research was funded by Sponsored by ACADIA Pharmaceuticals Inc. (San Diego, CA, USA).

Objectives: Increasing life expectancy of HIV-1–infected patients raises interest in how trial results apply to older patients. This post-hoc analysis evaluated potential differences in efficacy and safety in older (≥50 years) versus younger (

Objectives Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women. Methods HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using 14C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis. Results Data were available for 14 women. The area under the plasma concentration–time curve from 0 to 12 h (AUC12h) for total darunavir was 17–24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43–86% and 10–14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (

Background: The disease profile of treatment-experienced HIV-1 patients (TEPs) looks different today compared with that of 5 years ago. Because less highly treated DUET patients may more closely resemble today’s TEPs, we conducted a post hoc efficacy and safety analysis of the pooled 96-week DUET data stratified by level of treatment experience. Methods: TEPs with HIV-1 were randomised to etravirine (ETR) 200mg twice daily (bid) or placebo bid with a background regimen for 48 weeks (plus optional 48-week extension). TEPs were categorized using 10 demographic and disease characteristics that in prior studies of treatment-experienced subjects had been associated with virologic response; patients meeting ≥5 criteria were categorized as less TEP. Results: 183 patients (men, 87.4%) who received ETR were less TEP and 413 patients (men, 91.0%) were more TEP. At baseline, more TEPs had more advanced disease, more previous antiretroviral (ARV) exposures and fewer options for active ARVs. At Week 96, for patients receiving ETR, response rates for the less TEP group and more TEP group were 68.3% and 52.8%, respectively. Incidence of adverse events (AEs) was similar between groups. A greater proportion of nonresponders in the more TEP group discontinued due to AEs (9.0% vs 5.5%) and virologic failure (18.9% vs 5.5%) compared with the less TEP group. Conclusion: Less TEPs had higher virologic response rates with ETR compared with more TEPs. Because the less TEP population from DUET more closely resembles TEPs with HIV-1 today, data from this subgroup may provide valuable information for real-life treatment decisions.

ObjectiveA planned subgroup analysis of a phase 3 study was performed to evaluate the efficacy and safety of pimavanserin (PIM) in Parkinson’s disease psychosis (PDP) patients withglobal cognitive impairment.BackgroundPDP is frequent, distressing, a leading cause of institutionalization, complicates PD management and is linked to increased morbidity, incident dementia and mortality. PIM, a selective serotonin receptor (5-HT2A) inverse agonist/antagonist, is newly FDA-approved for the treatment of hallucinations and delusions associated with PDP.MethodsIn Study 020, a 6-week FDA registration study, 199 patients with baseline Mini-Mental State Examination (MMSE) score ≥21, moderate-severe psychosis, and on stable PD meds, were randomized to PIM (34 mg/day) or placebo (PBO) for 6 weeks. This subgroup analysis evaluates efficacy and safety between two groups: those with MMSE total score ≥21 but ResultsOverall, patients in the PIM group experienced a statistically significant improvement in SAPS-PD scores from baseline to Day 43 compared with PBO (-5.79 vs. -2.73; p=0.001). In the subgroup analysis stratifying by baseline MMSE score, the change from baseline to Day 43 compared with PBO in the cognitively-impaired group (N=50) was numerically larger (-7.11 vs. -0.47; p=0.002). In the full safety dataset examining cognitively impaired patients, there were no between-group (PIM vs. PBO) differences in any treatment-emergent adverse event (TEAE) (57.6% vs. 56.1%) or serious TEAE (6.8% vs. 5.3%). The most common TEAEs occurring at ≥5% in either group were fall (7.4% vs.10.5%), confusional state (6.5% vs.1.8%), and orthostatic hypotension (0.0% vs. 8.8%).ConclusionsIn this subgroup analysis of PDP patients, the treatment effect of PIM on SAPS-PD was larger in the cognitively-impaired group, with similar TEAE and serious TEAE rates. These results hold promise for cognitively-impaired patients that will be further elucidated in future studies.Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.

Objectives To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort. Design Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics. Setting Primary and secondary care medical centers in the United States, Canada, Europe, and India. Participants A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis. Interventions Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications (“concurrent APD”) and those who did not take antipsychotic medications at any time during the study (“no APD”). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications. Main Outcome Measures Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). Results There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13–7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02–4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18–2.29), cognition-related events (IRR 2.70, 95% CI 1.19–5.58), infections (IRR 1.97, 95% CI 1.17–3.16), and edema (IRR 2.61, 95% CI 1.09–5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant. Conclusions This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality.

Objectives: To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort. Design: Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics. Setting: Primary and secondary care medical centers in the United States, Canada, Europe, and India. Participants: A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis. Interventions: Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications (“concurrent APD”) and those who did not take antipsychotic medications at any time during the study (“no APD”). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications. Main Outcome Measures: Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson’s Disease Rating Scale Parts II and III (UPDRS-IIþIII, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). Results: There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13e7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02e4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18 e2.29), cognition-related events (IRR 2.70, 95% CI 1.19e5.58), infections (IRR 1.97, 95% CI 1.17e3.16), and edema (IRR 2.61, 95% CI 1.09e5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant. Conclusions: This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people

Antiretroviral (ARV) therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission (MTCT). Physiologic changes during pregnancy can affect PK. We present the PK of total and unbound (pharmacologically active) DRV in HIV-1-infected pregnant women receiving twice-daily (bid) DRV/ritonavir (rtv). This Phase IIIb study enrolled HIV-1-infected pregnant women ≥18 years old in the 2 nd trimester of pregnancy receiving DRV/rtv 600/100mg bid and other ARVs. DRV (total and unbound) and rtv (total) plasma concentrations were obtained predose and 1, 2, 3, 4, 6, 9 and 12 hours postdose during the 2 nd and 3 rd trimesters and postpartum. Total DRV and rtv plasma concentrations were determined using a previously validated HPLC-MS/MS assay (lower limit of quantification 5.00 ng/mL). Unbound DRV was determined by fortifying plasma samples with 14-C DRV and separating total and unbound DRV using ultrafiltration. Total and unbound 14-C DRV were measured using liquid scintillation counting. Total and unbound PK parameters were derived using a noncompartmental analysis. Safety and efficacy were investigated at each visit and summarized using descriptive statistics. Sixteen women (10 black, 4 Hispanic, 2 white) were enrolled; 11 had evaluable PK data. Total DRV AUC 12h was 24% and 17% lower during 2 nd and 3 rd trimesters, respectively, vs postpartum (Table). Unbound DRV AUC 12h was unchanged during 2 nd and 3 rd trimesters vs postpartum. Total and unbound DRV C min increased by 43% and 10%, respectively, during 2 nd trimester and by 86% and 14%, respectively, during 3 rd trimester vs postpartum. Unbound DRV was above the EC 50 (27.5 ng/mL) for PI-resistant HIV in all patients. Albumin and α 1 -acid glycoprotein (AAG) concentrations were 22%-29% lower during pregnancy vs postpartum. Viral load decreased and CD4+ count increased over time. One serious adverse event was reported (increased transaminase). Three of 12 infants were born prior to 37 weeks (30, 36 and 36 weeks), and all 12 infants were HIV-1-negative by standard PCR testing. Total DRV and rtv PK decreased during pregnancy likely due to pregnancy-related dilution of albumin and/or AAG. No clinically relevant change in unbound DRV AUC 12h and C min occurred during pregnancy, and there was no MTCT; therefore no dose adjustment is required for DRV/rtv 600/100mg bid in pregnant women. This ongoing trial will further evaluate the effects of pregnancy on DRV/rtv once daily, etravirine and rilpivirine PK. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Zorrilla C et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18340 http://www.jiasociety.org/index.php/jias/article/view/18340 | http://dx.doi.org/10.7448/IAS.15.6.18340