Real-World Treatment Patterns and Characteristics Among Patients with Agitation and Dementia in the United States: Findings from a Large, Observational, Retrospective Chart Review.

BACKGROUND: Few studies have examined patient characteristics and treatment patterns among patients with dementia and agitation in the United States (US). OBJECTIVE: To examine real-world treatment patterns and characteristics of patients with agitation related to dementia who were treated with antipsychotics in US residential care and community-based settings. METHODS: This retrospective chart review collected US physician-level data from patients 55 to 90 years old initiated on an antipsychotic medication for the treatment of agitation related to dementia from January 2018 to May 2018. Clinical characteristics and treatment patterns were assessed overall and stratified by residential care and community-based settings. RESULTS: A total of 313 participating physicians, 59.5% of whom were primary care physicians, abstracted 801 patient charts (residential care: n = 312; community-based: n = 489). Of patients with agitation who were initiated on an antipsychotic, most patients (74.5%) were initiated within 3 months of the onset of their studied agitation episode, and 62.8% experienced multiple agitation episodes before initiation. While non-pharmacological therapies are recommended first-line approach for agitation in dementia, use of non-pharmacological therapy before initiation of antipsychotics was reported for only 37.8% of patients in residential care and 21.3% in community-based settings. CONCLUSION: Most patients were initiated on an antipsychotic treatment after multiple episodes of agitation and largely without initial non-pharmacological therapy, suggesting that current treatment guideline recommendations for first-line non-pharmacological intervention may not be adequately followed in clinical practice. Understanding the clinical burden and treatment patterns among dementia patients with agitation is imperative for effective disease management.

First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers.

BACKGROUND: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.3, 1, 3, 10, or 30 mg/kg; n = 6/cohort) or placebo (n = 2/cohort). RESULTS: PRX002 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity. No serious adverse events, discontinuations as a result of adverse events, or dose-limiting toxicities were reported. Serum PRX002 exposure was dose proportional; the average terminal half-life across all doses was 18.2 days. A significant dose-dependent reduction in free serum α-synuclein (unbound to PRX002) was apparent within 1 hour after PRX002 administration, whereas total α-synuclein (free plus bound) increased dose-dependently, presumably because of the expected change in kinetics following antibody binding. CONCLUSIONS: This study demonstrates that serum α-synuclein can be safely modulated in a dose-dependent manner after single intravenous infusions of an anti-α-synuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson's disease. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Improving Alzheimer's disease phase II clinical trials.

Over the past 30 years, many drugs have been studied as possible treatments for Alzheimer's disease, but only four have demonstrated sufficient efficacy to be approved as treatments, of which three are in the same class. This lack of success has raised questions both in the pharmaceutical industry and academia about the future of Alzheimer's disease therapy. The high cost and low success rate of drug development across many disease areas can be attributed, in large part, to late-stage clinical failures (Schachter and Ramoni, Nat Rev Drug Discov 2007;6:107-8). Thus, identifying in phase II, or preferably phase I, drugs that are likely to fail would have a dramatic impact on the costs associated with developing new drugs. With this in mind, the Alzheimer's Association convened a Research Roundtable on June 23 and 24, 2011, in Washington, DC, bringing together scientists from academia, industry, and government regulatory agencies to discuss strategies for improving the probability of phase II trial results predicting success when considering the go/no-go decision-making process leading to the initiation of phase III.

11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study.

BACKGROUND: Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease. METHODS: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. FINDINGS: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. INTERPRETATION: Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo. FUNDING: Elan Pharmaceuticals and Wyeth Research.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.