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

Abstract

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

Progress in Pharmacologic Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders

“…Disease-modifying therapies have been introduced for treatment of AD and have been shown to slow disease progression by approximately 30% . With reduced AD pathology, decreased emergence or improvement of NPSs may be observed as demonstrated in studies of aducanumab .…”

Donanemab outperformed Aducanumab and Lecanemab on cognitive, but not on biomarker and safety outcomes: systematic review, frequentist and Bayesian network meta-analyses

“…Afterwards, the FDA granted breakthrough status to Lecanemab and Donanemab, in order to speed up their approval [50], which finally resulted in full FDA approval of Lecanemab in the U.S. and more recently in Japan. Furthermore, Lecanemab is currently undergoing regulatory review in the European Union (EU), United Kingdom, South Korea, and Canada, while Donanemab is reviewed in the EU and the U.S [7]. Recent exploratory post hoc modeling based on phase III RCT of Donanemab suggested that Aβ levels in immunized patients would remain below the positivity threshold for almost 4 years without the treatment.…”

“…Instead of binding the N-terminus of fulllength Aβ, Donanemab targets the N-truncated pyroglutamate Aβ (at position 3), present only in Aβ plaques. It is reported to rapidly induce plaque removal and reduce cognitive decline in patients with early symptomatic AD [7,8].…”

Ethical considerations for the use of anti‐amyloid immunotherapy in patients with early Alzheimer's disease

“…Dear Editor, Recently, the US Food and Drug Administration (FDA) approved two anti-amyloid antibodies for the treatment of patients with early Alzheimer's disease (AD), with a third expected to be approved soon. 1 These drugs are designed to remove amyloid-β peptides from the brains of patients in the early stages of AD to slow down cognitive decline. The use of anti-amyloid immunotherapy has raised several ethical issues, mostly centered around the dimensions of beneficence, nonmaleficence, and informed consent.…”