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BACKGROUND Parkinson's disease-related psychosis increases patients' risk of falls. Pimavanserin is an atypical antipsychotic approved in the USA in 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease-related psychosis. OBJECTIVE We aimed to compare the risk of falls/fractures among patients with Parkinson's disease-related psychosis treated with pimavanserin vs other atypical antipsychotics. PATIENTS AND METHODS We identified a cohort of patients with Parkinson's disease-related psychosis aged ≥ 40 years initiating either pimavanserin or a comparator antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) in US commercial insurance and supplementary Medicare claims (2015-2019). Comparators were propensity score matched 2:1 with pimavanserin initiators; incidence rates of falls/fractures were compared using incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS We identified 112 eligible pimavanserin initiators and 982 comparators. Pimavanserin initiators were younger and had fewer severe comorbidities, indicators of impairment, and healthcare encounters, though they had higher Parkinson's disease medication use. The crude incidence rates [cases/100 person-years] (95% CI) for composite falls/fractures were 17.8 (7.7-35.0) for pimavanserin and 40.8 (35.0-47.4) for comparators. Matching retained 108 pimavanserin initiators and 216 comparators-all characteristics were well balanced after matching-with a matched IRR (pimavanserin vs comparator) of 0.71 (95% CI 0.27-1.67). Sensitivity analysis IRR estimates were consistently below 1.00, with a sensitivity analysis not requiring a diagnosis of psychosis resulting in an IRR estimate of 0.55 (95% CI 0.34-0.86). CONCLUSIONS The results of this study do not suggest an increase in the risk of falls or fractures associated with pimavanserin compared with other antipsychotics in patients with Parkinson's disease-related psychosis. Sensitivity analyses suggest a decreased risk.

Introduction Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin. Methods This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS). Results Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years). Conclusions Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

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.

ObjectiveOur aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH).MethodsCategorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event.ResultsNNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson’s disease) versus discontinuation due to an adverse event.ConclusionsUsing the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

Objective Evaluate whether the risk of falls and fractures differs between patients with Parkinson disease with psychosis (PDP) and patients with Parkinson disease (PD) without psychosis at similar disease stages. Methods Patients with PD without psychosis were identified in the Medicare claims databases (2008–2018) and followed from the first PD diagnosis date during the study period. Patients with a subsequent diagnosis of psychosis were included in the PDP group. Patients with PDP and PD without psychosis were propensity score-matched based on characteristics within blocks of time since cohort entry. The incidence rates (IRs), expressed per 100 person-years, and 95% confidence intervals (CIs) of falls and fractures were evaluated as composite and separate outcomes. Incidence rate ratios (IRRs) were used to compare patients with PDP and PD without psychosis in the matched cohort. Results 154,306 patients had PD without psychosis and no falls or fractures before cohort entry; the IR for falls and fractures was 11.41 events (95% CI, 11.29–11.53). 12,127 patients (7.8%) had a subsequent PDP diagnosis. PDP patients had a higher prevalence of most comorbidities and risk factors for falls and fractures than those without psychosis. The crude IR for falls and fractures among PDP patients was 29.03 events (95% CI, 28.27–29.81). PD without psychosis and PDP groups had more falls than fractures. After matching, 24,144 PD patients without psychosis (15.6%) and 12,077 PDP patients (99.6%) were retained. Matched PDP patients had a higher incidence of falls and fractures than PD patients without psychosis (IRR = 1.44; 95% CI, 1.39–1.49). The higher increased rate was noted separately for falls (IRR = 1.48; 95% CI, 1.43–1.54) and any fractures (IRR = 1.17; 95% CI, 1.08–1.27) as well as within specific types of fracture, including pelvis and hip fractures. Conclusions Our findings suggest a modest but consistently higher increased risk of falls and fractures in PDP patients compared with PD patients without psychosis.

Study ObjectivePsychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.MethodsNNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.ResultsNNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.ConclusionsUsing the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.

This meta-analysis evaluated the frequency of neutralizing antibody (nAb) conversion with onabotulinumtoxinA (BOTOX®; Allergan) across five studied indications. The analysis was based on large, controlled or prospective, open-label trials (durations 4 months to ≥2 years). Serum samples were analyzed for nAbs using the Mouse Protection Assay. Subjects who were antibody negative at baseline and had at least one analyzable postbaseline antibody assay result were included. The 16 clinical studies included 3,006 subjects; of these, 2,240 met the inclusion criteria for this analysis. Subjects received 1-15 treatments (mean 3.8 treatments) with onabotulinumtoxinA. Total doses per treatment cycle ranged from 10 or 20 units in glabellar lines to 20-500 units in cervical dystonia. The numbers of subjects who converted from an antibody-negative status at baseline to antibody-positive status at any post-treatment time point were: cervical dystonia 4/312 (1.28%), glabellar lines 2/718 (0.28%), overactive bladder 0/22 (0%), post-stroke spasticity 1/317 (0.32%), and primary axillary hyperhidrosis 4/871 (0.46%). Across all indications, 11/2,240 subjects (0.49%) converted from antibody negative at baseline to positive at one or more post-treatment time points, but only three subjects became clinically unresponsive to onabotulinumtoxinA at some point following a positive assay. Based on these large trials, the frequency of antibody conversion after onabotulinumtoxinA treatment is very low, and infrequently leads to loss of efficacy. © 2010 Movement Disorder Society.

Objective: Describe the safety profile of bimatoprost 0.03% ophthalmic solution as once-daily topical treatment for idiopathic or chemotherapy-induced eyelash hypotrichosis. Design: Pooled data from six randomized, multicenter, double-masked, parallel-group clinical studies of at least three-months’ duration with at least one bimatoprost treatment group. Setting: Study sites in the United States, Canada, United Kingdom, and Japan from 2007 to 2012. Participants: Adults with eyelash hypotrichosis, defined as baseline Global Eyelash Assessment of minimal or moderate, who received bimatoprost 0.03% (n=680) or vehicle, with no prior exposure to bimatoprost (n=379). Measurements: Safety assessments included adverse events, vital sign measurements, and physical examinations. Common (≥2%) and treatment-related adverse events were analyzed at time points up to four months and through end of treatment, up to 12 months. Results: Similar overall adverse events incidence was reported in bimatoprost and vehicle groups for subjects with idiopathic hypotrichosis; a higher incidence in both groups was reported for postchemotherapy subjects. Common adverse events included conjunctival hyperemia, eyelid pruritus, blepharal pigmentation, nasopharyngitis, eyelid erythema, and punctate keratitis. Most adverse events occurred early in treatment, were mild in intensity, localized to treatment site, and reversible with treatment cessation. Discontinuations due to adverse events were low (3.2% for bimatoprost and 2.4% for vehicle). Conclusion: Adverse events were consistent with the known pharmacologic mechanism of bimatoprost. The safety profile was similar across the studies and no new safety signals were observed. Once-daily bimatoprost 0.03% for treatment of eyelid hypotrichosis has a favorable safety and tolerability profile when applied topically to the upper eyelid margin.

Background and purpose OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed. Methods The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. Results OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA. Conclusions Multiple treatments with onabotulinumtoxinA at doses of 75–260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM.

Background OnabotulinumtoxinA for the treatment of facial lines is a widely used cosmetic medical procedure and, as such, the safety and tolerability profile is of interest to health care providers and patients. Based on data from individual studies that were conducted according to regulatory guidelines to provide adequate safety and efficacy data to support product licensure (registration studies), the overall benefit:risk profile of onabotulinumtoxinA for facial lines has been favorable. Objective Our objective was to increase statistical power through meta-analysis to detect treatment group differences in adverse event (AE) incidence that may not have been evident in individual registration studies. Methods Individual participant data (n = 1678) were from 6 randomized, double-blind, placebo-controlled and 3 open-label studies. Two double-blind, placebo-controlled studies were for lateral canthal lines (3-18 U/side) and all others were for glabellar lines (10 or 20 U). Doses used reflect global product labeling in countries where licensed. Results Participant population was non-Hispanic white (43%) or Asian (52%) and predominantly female (88%). In double-blind, placebo-controlled studies, overall AE incidence did not significantly differ by treatment group (onabotulinumtoxinA vs placebo). The only individual AEs with significantly greater incidence in the onabotulinumtoxinA group were eyelid sensory disorder (2.5% vs 0.3%, P = .004; verbatim phrases "tight," "pressured," "heavy," "drooping feeling," "feeling of droopiness") and eyelid ptosis (1.8% vs 0%, P = .02), both present only in glabellar studies. Overall treatment-related (per investigator) AE incidence was greater in the onabotulinumtoxinA group versus placebo (24% vs 16%, P = .005), and treatment-related eyelid edema was an additional AE with significantly higher incidence in the onabotulinumtoxinA group versus placebo ( P = .04). Incidence of all 3 of these AEs significantly decreased as number of treatment cycles increased. Eyelid sensory disorder and eyelid edema were more common in Asian participants. Acne, injection site pruritus, oral herpes, rash, lower respiratory tract infection, dental caries, and eye pain were significantly more common in placebo-treated compared with onabotulinumtoxinA-treated participants. Serious AE incidence did not significantly differ by treatment (onabotulinumtoxinA vs placebo) and no serious AEs were treatment related. There were no symptoms of weakness remote to the injection site or related to the central nervous system. Limitations Limitations included: (1) highly visible efficacy of onabotulinumtoxinA may have resulted in reporting bias; (2) reliance on participant intervisit recall; (3) a relatively short follow-up period (1 year); (4) conclusions are based solely on the doses analyzed (ie, those used in the respective trials); and (5) exclusion of patients with severe medical disease in registration studies. Conclusion This meta-analysis confirms the safety and tolerability of onabotulinumtoxinA for glabellar and lateral canthal lines, at the doses studied, based on the most comprehensive controlled safety analysis of onabotulinumtoxinA performed to date. The AEs observed were generally mild to moderate; most treatment-related AEs were related either to physical injection of product or local pharmacologic effects. Even with the increased statistical power of a large sample size, no new onabotulinumtoxinA-associated AEs emerged.