Long-term safety and tolerability of bapineuzumab in patients with Alzheimer's disease in two phase 3 extension studies.

Background: Immunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer's disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols.

Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials.

Background: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD).

Methods: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.

Cognition in MCI and Alzheimer's disease: baseline data from a longitudinal study of the NTB.

Baseline data are summarized from a study examining the psychometric properties of the Neuropsychological Test Battery (NTB) and its subtests, and correlating the NTB with other cognitive and functional assessments. A multicenter, longitudinal, non-interventional study included mild to moderate Alzheimer's disease (AD, n = 196), mild cognitive impairment (MCI, n = 70), or normal cognition participants (NC, n = 75). The NTB, other cognitive assessment tools, functional/behavioral questionnaires, and health outcome assessments were administered.

Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.

Background: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.

Methods: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks.

Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease.

Background: Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms.

Objective: To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease.

Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis.

Background: Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors.

Targeting Beta amyloid: a clinical review of immunotherapeutic approaches in Alzheimer's disease.

As the societal and economic burdens of Alzheimer's disease (AD) continue to mount, so does the need for therapies that slow the progression of the illness. Beta amyloid has long been recognized as the pathologic hallmark of AD, and the past decade has seen significant progress in the development of various immunotherapeutic approaches targeting beta amyloid. This paper reviews active and passive approaches aimed at beta amyloid, with a focus on clinical trial data.

Global issues in drug development for Alzheimer's disease.

The number of clinical trials for Alzheimer's disease conducted outside the United States in a broad array of countries is increasing. As the number of compounds ready for clinical testing increases, and as trials become longer and more complex, this trend is expected to grow. The cultural and ethical context of global clinical trials, potential benefits for those involved, and practical approaches to obstacles generated by these global trials were discussed at a meeting of the Alzheimer's Association Research Roundtable.

A single ascending dose study of bapineuzumab in patients with Alzheimer disease.

The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB-001), a humanized monoclonal antibody to amyloid beta, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.

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.

Scales as outcome measures for Alzheimer's disease.

The assessment of patient outcomes in clinical trials of new therapeutics for Alzheimer's disease (AD) continues to evolve. In addition to assessing drugs for symptomatic relief, an increasing number of trials are focusing on potential disease-modifying agents. Moreover, participants with AD are being studied earlier in their course of disease.

Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis.

Background: In a phase 2a clinical trial of AN1792 (Study 201), a potential immunotherapeutic agent for use in Alzheimer's disease (AD), approximately 6% of the treated AD patients (18/300) developed meningoencephalitis (ME).

Objective: To elucidate potential immune mechanisms of treatment-induced ME.

Methods: Peripheral blood mononuclear cells obtained from patients who received AN1792 were stimulated in vitro either with beta-amyloid (Abeta) or various overlapping peptides of Abeta(1-42), followed by quantification of cytokine-secreting cells by enzyme-linked immunosorbent spot assay.

Volumetric MRI and cognitive measures in Alzheimer disease : comparison of markers of progression.

Background: Both cognitive tests and MRI-based measures have been suggested as outcomes in trials assessing disease-modifying therapies in Alzheimer's disease (AD).

Objective: To compare changes in longitudinal MRI measures with changes in performance on cognitive tests routinely used in AD clinical trials.

Method: Fifty-two subjects from the placebo-arm of a clinical trial in mild-to-moderate AD had volumetric T(1)-weighted scans and cognitive tests including the Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale, Disability Assessment for Dementia, AD Cooperative Study-Clinical Global Impression of Change and Clinical Dementia Rating at baseline and one-year later.

A neuropsychological test battery for use in Alzheimer disease clinical trials.

Objective: To report the psychometric properties of an alternative instrument to the cognitive subscale of the Alzheimer's Disease Assessment Scale, a neuropsychological test battery (NTB) for measuring drug efficacy in Alzheimer disease clinical trials.

Design: The NTB was evaluated in a randomized, double-blind, placebo-controlled trial of AN1792(QS-21) (synthetic beta-amyloid plus an adjuvant) (300 patients) and isotonic sodium chloride solution (72 patients). The test-retest reliability of the NTB was examined, and the NTB was correlated with other cognitive (cognitive subscale of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination) and functional (Disability Assessment Scale for Dementia and Clinical Dementia Rating Sum of Boxes) measures.

Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia.

Objective: To describe the neuropathological and biochemical findings of the brain examination of a patient enrolled in the AN-1792(QS-21) trial with an initial clinical diagnosis of Alzheimer disease (AD), in whom Lewy body variant was thereafter clinically diagnosed.

Design: A case report.

Setting: University memory clinic.

Risk factors associated with beta-amyloid(1-42) immunotherapy in preimmunization gene expression patterns of blood cells.

Background: A phase 2a, double-blind, placebo-controlled, multicenter study was conducted to evaluate safety, tolerability, and pilot efficacy of immunization with beta-amyloid((1-42)) in patients with Alzheimer disease. Six immunizations were planned but were halted when meningoencephalitis was recognized as an adverse event in 6% of immunized patients.

Objective: To identify biomarkers associated with both the risk of meningoencephalitis and antibody responsiveness.

Abeta42 immunization in Alzheimer's disease generates Abeta N-terminal antibodies.

Serum samples from Alzheimer's disease (AD) patients immunized with Abeta42 (AN1792) were analyzed to determine the induced antibody properties including precise amyloid-beta peptide (Abeta) epitopes and amyloid plaque-binding characteristics. The predominant response in these patients is independent of whether or not meningoencephalitis developed and is against the free amino terminus of Abeta. The immunostaining of amyloid plaques in brain tissue by patient sera is adsorbable by a linear Abeta1-8 peptide, demonstrating that the antibodies are directed predominantly to this epitope and not dependent on Abeta conformations or aggregates specific to plaques.

Over-the-counter medications in pregnancy.

Pregnant women commonly use over-the-counter medications. Although most over-the-counter drugs have an excellent safety profile, some have unproven safety or are known to adversely affect the fetus. The safety profile of some medications may change according to the gestational age of the fetus.