Donanemab for Alzheimer Disease—Who Benefits and Who Is Harmed?

Availability of safe and effective treatments for Alzheimer disease is an urgent challenge given the global shift toward an older population and increased risk of mild cognitive impairment and dementia as people age. Dementia-related burdens are disproportionately felt within historically marginalized communities because structural inequalities rooted in racism, xenophobia, and sexism increase risk factors for cognitive impairment, increase barriers to diagnosis, and reduce access to care.

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Agosto 2023

Novel Alzheimer Disease Treatments and Reconsideration of US Pharmaceutical Reimbursement Policy

Alzheimer disease (AD), the most common form of dementia, affects more than 5 million US residents and progressively leads to a loss of memory and cognitive function. The advent of new therapeutic agents for AD has the potential to lessen the enormous patient, family, and societal burden of illness. In this issue of JAMA, phase 3 trial results suggest that donanemab (an infused monoclonal antibody) is efficacious in slowing disease progression based on the Integrated Alzheimer’s Disease Rating Scale in patients with mild to moderate AD with amyloid and tau pathology. Another monoclonal antibody that produced similar improvements, lecanemab, was recently awarded traditional approval by the Food and Drug Administration (FDA). While these new therapies have been welcomed by many stakeholders, they also will challenge the US system of pharmaceutical regulation and reimbursement. In particular—assuming FDA approval is granted—payers and policy makers must design rules that optimize value, affordability, and equity of AD care.

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Agosto 2023

Ushering in a New Era of Alzheimer Disease Therapy

In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval of aducanumab, a monoclonal antibody against β-amyloid for treatment of early Alzheimer disease. The approval generated significant backlash due to unclear evidence of the drug’s clinical efficacy, risk of severe adverse effects, absence of diversity in trial populations, high costs, and an opaque approval process that, per one congressional inquiry, was “rife with irregularities.”

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Agosto 2023

Amyloid-Targeting Monoclonal Antibodies for Alzheimer Disease

In Alzheimer disease (AD) research and care, novel biomarkers that measure amyloid-β (Aβ) and phosphorylated tau (P-tau)–the principal components of amyloid plaques and neurofibrillary tangles–have facilitated early detection and biomarker-supported diagnosis. Therapeutics that modify the biology of AD are being tested in clinical trials, leveraging biomarkers so that investigators select the right patients, evaluate target engagement, and gauge the effects of therapy on AD pathophysiology. The first class of therapies to reach the clinic in this modern era of AD drug development are Aβ-targeting monoclonal antibodies, which bind different species in the Aβ aggregation cascade. This treatment approach is grounded in the “amyloid hypothesis,” which postulates that Aβ aggregation triggers a cascade of pathophysiologic events, including synaptic and network dysfunction, neuroinflammation, and aggregation and spread of P-tau tangles. The spread of tangles is associated with synaptic loss and neurodegeneration, culminating in cognitive decline and dementia. By binding Aβ aggregates, monoclonal antibodies facilitate Aβ clearance from the brain, potentially mitigating both direct and downstream deleterious effects of Aβ and hence slowing cognitive decline.

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Agosto 2023