The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(4), P. 306 - 318

Published: Feb. 17, 2022

Language: Английский

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Aducanumab: First Approval

Drugs, Journal Year: 2021, Volume and Issue: 81(12), P. 1437 - 1443

Published: July 29, 2021

Language: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

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Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics

Drugs, Journal Year: 2023, Volume and Issue: 83(7), P. 569 - 576

Published: April 15, 2023

Two anti-amyloid monoclonal antibodies (MABs)—lecanemab (Leqembi®) and aducanumab (Aduhelm®)—have been approved in the USA for treatment of Alzheimer's disease (AD). Anti-amyloid are first disease-modifying therapies AD that achieve slowing clinical decline by intervening basic biological processes disease. These breakthrough agents can slow inevitable progression into more severe cognitive impairment. The results trials MABs support amyloid hypothesis as a target drug development. success reflects relentless application neuroscience knowledge to solving major challenges facing humankind. these transformative will foster development MABs, other types therapies, treatments targets biology, new approaches an array neurodegenerative disorders. Monoclonal have side effects and, during period initiation, patients must be closely monitored occurrence amyloid-related imaging abnormalities (ARIA) infusion reactions. A successful step therapy defines desirable features next phase therapeutic including less frequent ARIA, convenient administration, greater efficacy. Unprecedented make demands on care partners, clinicians, payers, health systems. Collaboration among stakeholders is essential take advantage benefits offered them widely available. usher era define landscape what possible

Language: Английский

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Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease

BioDrugs, Journal Year: 2023, Volume and Issue: 38(1), P. 5 - 22

Published: Nov. 13, 2023

Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who proven β-amyloid pathology (Aβ). One these, has subsequently full other are poised positive review approval. Anti-amyloid mAbs share feature producing a marked reduction total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing cognitive decline achieved measurable plaque range 15–25 centiloids; trials agents that did not reach this threshold were benefit. differences terms titration schedules, MRI monitoring schedules amyloid-related imaging abnormalities (ARIA), continuing versus interrupted therapy. The approximate 30% observed is clinically meaningful extended integrity delay onset more severe dementia phases disease. Approval these initiates new era therapeutics disease-modifying properties. Further advances needed, i.e. greater efficacy, improved safety, enhanced convenience, better understanding ill-understood observations such as volume loss.

Language: Английский

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Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Clinical Interventions in Aging, Journal Year: 2022, Volume and Issue: Volume 17, P. 797 - 810

Published: May 1, 2022

Abstract: Aducanumab is a monoclonal antibody selective for amyloid β (Aβ) aggregates. In June 2021, aducanumab became the first drug underlying pathophysiology of Alzheimer's disease (AD) approved by US Food and Drug Administration (FDA), under accelerated approval pathway. The decision was based on ability to remove Aβ plaques, without any evidence that clearance correlated with less cognitive or functional decline. This has generated considerable debate in scientific community, especially because results from two Phase 3 trials, EMERGE ENGAGE, were divergent and, even after post hoc analysis, data insufficient prove efficacy. Moreover, some researchers think this will be an obstacle progress also demonstrated concerns about cost its safety profile. European Medicines Agency's rejection December 2021 just brought more controversy over FDA's decision. Now, Biogen designing required confirmatory study, named ENVISION, which should complete 2026. Despite controversy, showed affect downstream tau pathology, could open doors combination therapy approach AD (anti-tau anti-amyloid drug). review summarizes clinical development until regulatory agencies' decisions, available trials AD. Keywords: anti-Aβ antibody, ARIA, Agency, Administration, protein

Language: Английский

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Quantification of amyloid PET for future clinical use: a state-of-the-art review

European Journal of Nuclear Medicine and Molecular Imaging, Journal Year: 2022, Volume and Issue: 49(10), P. 3508 - 3528

Published: April 7, 2022

Abstract Amyloid-β (Aβ) pathology is one of the earliest detectable brain changes in Alzheimer’s disease (AD) pathogenesis. The overall load and spatial distribution Aβ can be determined vivo using positron emission tomography (PET), for which three fluorine-18 labelled radiotracers have been approved clinical use. In practice, trained readers will categorise scans as either positive or negative, based on visual inspection. Diagnostic decisions are often these reads patient selection trials increasingly guided by amyloid status. However, tracer deposition grey matter a function an inherently continuous process, not sufficiently appreciated through binary cut-offs alone. State-of-the-art methods PET quantification generate tracer-independent measures burden. Recent research has shown ability quantitative to highlight pathological at stages AD continuum more sensitive thresholds, well improving diagnostic confidence around established cut-offs. With recent FDA approval aducanumab candidate drugs horizon, early identification burden critical enrolling appropriate subjects help establish optimal window therapeutic intervention secondary prevention. addition, measurements used treatment response monitoring trials. settings, large multi-centre studies that results change both diagnosis management accurately predict rates cognitive decline. Whether reflect improvement outcomes yet further validation work required utility supporting endpoint decisions. this state-of-the-art review, several tools available summarised discussed. Use growing clinically domain. Concurrently, there duty care wider dementia community increase visibility understanding methods.

Language: Английский

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Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease

Frontiers in Neurology, Journal Year: 2022, Volume and Issue: 13

Published: March 23, 2022

Second-generation anti-amyloid monoclonal antibodies are emerging as a viable therapeutic option for individuals with prodromal and mild dementia due to Alzheimer's disease (AD). Passive immunotherapy aducanumab (Aduhelm), lecanemab, donanemab, gantenerumab all lower CNS amyloid (Aβ) burden but come significant risk of amyloid-related imaging abnormality (ARIA)—the most common side effect this class drugs. While usually asymptomatic detected only on brain MRI, ARIA may lead new signs symptoms including headache, worsening confusion, dizziness, visual disturbances, nausea, seizures. In addition, one fatality related ARIA-E (edema) ARIA-H (hemorrhage) donanemab reported date. be associated excessive neuroinflammation saturation perivascular clearance pathways, while vascular weakening rupture small blood vessels. The is higher at treatment initiation, in ApoE4 carriers, dosage, >4 microhemorrhages baseline MRI. increases age cerebrovascular disease. Dose titration mitigates the ARIA, contraindications include those prescribed anti-platelet or anti-coagulant A MRI required before initiated, each scheduled dose escalation, any neurologic sign symptom. Management ranges from continued antibody monthly monitoring temporary permanent suspension symptomatic moderate severe Controlled studies regarding prevention lacking, anecdotal evidence suggests that pulse intravenous corticosteroids benefit, well course anticonvulsant

Language: Английский

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Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review

International Journal of Alzheimer s Disease, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 10

Published: March 9, 2022

Background. Aducanumab, a new monoclonal antibody that targets β-amyloid aggregates, has been granted conditional approval by the U.S. FDA for treatment of mild Alzheimer’s disease (AD). The this drug without confirmed significant clinical impact resulted in several debates. Objective. In narrative review, aducanumab approval-related controversy, drug’s pharmacokinetics and pharmacodynamic characteristics, evidence from efficacy safety trials aducanumab, implications approval, future directions management patients with AD are summarized. Methods. Using relevant keywords, Google Scholar, Web Science, MEDLINE databases manufacturer’s website were searched. Results. Infusion at higher dose modest slowing cognitive decline among impairment or early-onset dementia. however can cause amyloid-related imaging abnormalities. Due to on cognition, use will most likely be limited. manufacturer is required run an extended phase IIIb trial verify benefit drug. Access therapy requires careful selection periodic monitoring ensure optimal Conclusion. Despite limitations, first disease-modifying approved AD. Aducanumab addresses part pathogenesis AD; therefore, drugs act multiple needed. addition, search preventive strategies, validated plasma-based assays, newer AD, which effective, safe, convenient, affordable, vital.

Language: Английский

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Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease in the US

JAMA Neurology, Journal Year: 2022, Volume and Issue: 79(5), P. 478 - 478

Published: March 28, 2022

Several anti-amyloid monoclonal antibodies have been developed for slowing the progression of Alzheimer disease (AD). Among furthest are aducanumab, which received accelerated approval from US Food and Drug Administration in 2021, donanemab, is currently undergoing phase 3 trials. The cost-effectiveness these treatments has not established.

Language: Английский

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