Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial

Lannfelt, Lars; Blennow, Kaj; Zetterberg, Henrik; Båtsman, Stellan; Ames, David; Harrison, John; Masters, Colin L.; Targum, Steve; Bush, Ashley I.; Murdoch, Ross; Wilson, Janet; Ritchie, Craig W.

doi:10.1016/s1474-4422(08)70167-4

Cited by 662 publications

(490 citation statements)

References 25 publications

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“…In a phase 2a clinical trial of 78 patients, 12 weeks of PBT2 treatment caused a dosedependent lowering of cerebrospinal fluid Aβ and improved 2 measures of executive function at the highest dose in the study (250 mg) [216,217]. In a recent phase 2b clinical trial of 1 year's duration, PBT2 did not show favorable clinical outcomes.…”

Section: Clioquinol and Pbt2mentioning

confidence: 95%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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Section: Clioquinol and Pbt2mentioning

confidence: 95%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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“…PBT2 [112,113,193] AD = Alzheimer's disease; NA, not available; Aβ = β-amyloid; EPA = eicospentaenoic acid; DHA = docosahexaenoic acid; EEG = electroencephalography reportedly decreased Aβ levels and improved performance on 2 cognitive function tests [191,192]. In addition to metal chelation, PBT2 has a second mechanistic action to increase Aβ clearance, increasing activity of matrix metalloproteases including neprilysin, insulin degrading enzyme, and tissue plasminogen activator [191,192]. Souvenaid was originally developed to improve nutrient deficiencies common in patients with AD and contains high doses of the omega-3 fatty acids eicospentaenoic acid and docosahexaenoic acid [112].…”

Section: Systems Approaches For Ad Prevention and Treatmentmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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“…Evidence regarding changes in the brain mineral distribution of AD patients is apparently conflicting (Schrag et al 2011b), and our understanding of the mechanisms regulating zinc distribution in the brain during normal development, aging, and disease remains incomplete. Nevertheless, preclinical studies and early clinical trials have provided encouragement for mineral targeted therapies in the treatment and prevention of AD (Constantinidis 1992;Ritchie et al 2003;Lannfelt et al 2008;Faux et al 2010). These include zinc supplementation as well as pharmaceutical approaches designed to alter zinc and copper distribution.…”

Section: Introductionmentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial

Cited by 662 publications

References 25 publications

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Zinc and the aging brain

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