Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup

Sperling, Reisa A.; Jack, Clifford R.; Black, Sandra E.; Frosch, Matthew P.; Greenberg, Steven M.; Hyman, Bradley T.; Scheltens, Philip; Carrillo, María C.; Thies, William; Bednar, Martin M.; Black, Ronald S.; Brashear, H. Robert; Grundman, Michael; Siemers, Eric; Feldman, Howard; Schindler, Rachel

doi:10.1016/j.jalz.2011.05.2351

Cited by 580 publications

(647 citation statements)

References 102 publications

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“…An increase in cardiac diseases was nonetheless seen in patients treated with solanezumab compared to those who received the placebo (3.1 vs. 1.6 %). As opposed to previous findings [60], there was no significant increase in amyloid-related imaging abnormalities with edema or hemorrhage associated with solanezumab in phase III trials [22].…”

Section: Safety Concernscontrasting

confidence: 99%

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

2015

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Alzheimer's disease (AD) is the most common form of dementia and is a major cause of disability and dependency amongst older people. AD drugs approved so far are symptomatic treatments and are not thought to affect the underlying disease process. Trials conducted with agents aiming to slow or stop disease progression in patients with AD have all failed, perhaps because they were tested too late in the disease process. Therefore, there has been a move towards prevention of AD. This paper presents an overview of trials testing pharmacological interventions for sporadic AD prevention. Those tested to date were initially developed for the treatment of AD or for the treatment of other conditions, rather than being specifically developed for AD prevention. Associated issues, such as evidence of 'proof-of-concept,' doses and safety, are discussed. A major shift has taken place in the methodology of AD prevention trials since the results of the first trials were published in the 1990s. New directions that are currently being considered in ongoing or future prevention trials are discussed, in terms of endpoints, target populations, and study design. The use of AD-specific drugs to prevent AD in high-risk individuals is currently limited by a lack of validated predictive and surrogate markers. Population approaches, such as lifestyle changes, are an alternative strategy that could be of public health interest, but may provide only limited benefits for individuals. The best chance of preventing AD may come from a combination of individual and population prevention approaches. Key PointsFollowing the failure of treatment trials in symptomatic Alzheimer's disease (AD), there has been a move towards prevention of AD.To date, no specific pharmacological intervention has been developed for sporadic AD prevention and trial results have been disappointing.A major shift has taken place in the methodology of AD prevention trials and new directions are being considered in terms of endpoints, target populations, and study design.

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Section: Safety Concernscontrasting

confidence: 99%

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

2015

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“…The latter may explain the peripheral rise in Aβ observed after dosing [28,63]. Consistent with this hypothesis, antibodies that fully engage microglia while binding plaque may cause reduction of amyloid plaque, but also disrupt the BBB causing vasogenic edema [62], a phenomenon renamed amyloid-related imaging abnormalities-edema [64]. These adverse effects have been dose-limiting for bapineuzumab [62].…”

Section: Using Anti-bace1 To Reduce Aβ Productionmentioning

confidence: 84%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

176

171

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The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

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“…Vasogenic edema sometimes occurs as part of the natural history of AD, 25 so the relatedness of the single observed event to IVIg is uncertain.…”

Section: Resultsmentioning

confidence: 99%

A phase 3 trial of IV immunoglobulin for Alzheimer disease

et al. 2017

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Objective: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. Results:No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Ab42 (but not Ab40) levels were observed in IVIgtreated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.Conclusions: Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.Clinicaltrials.gov identifier: NCT00818662.

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Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup

Cited by 580 publications

References 102 publications

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

Developing Therapeutic Antibodies for Neurodegenerative Disease

A phase 3 trial of IV immunoglobulin for Alzheimer disease

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