Neuropharmacology & Neurotherapeutics
Dec. 27, 2022
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Aducanumab, a monoclonal antibody, is the first approved treatment for the underlying biology of Alzheimer disease. It was approved by the U.S. Food and Drug Administration on June 7, 2021. Clinical trials showed that the drug, administered intravenously, crossed the blood-brain barrier and cleared amyloid deposits in the brain, which was used as the endpoint rather than clinical improvement. In a subset of Alzheimer disease patients who received the highest dose, clinical improvement occurred after long-term use. Approval was based on the assessment that the benefits outweigh the risks. Continued approval for this indication may be contingent on verification of the clinical benefit in a confirmatory trial.
Drugs currently used for the management of Alzheimer disease provide symptomatic relief and do not address the pathomechanism of the disease. Since 2003, there have been no new drug approvals for this disease, but there is considerable research activity for the discovery of new drugs.
Aducanumab, a human monoclonal antibody, was discovered at Neurimmune (a Swiss biotechnology company) in collaboration with the University of Zurich using reverse translational medicine technology. It was then licensed to Biogen in the United States in 2007, which developed it for the removal of amyloid from brains of patients with Alzheimer disease. A phase 1b study with brain scans to measure amyloid plaques was done from 1915 to 2016, based on 1 year of monthly intravenous infusions of aducanumab. Phase 2 trials were not required by the U.S. Food and Drug Administration (FDA) and were not conducted. A phase 3 trial followed the conclusion of phase 1 studies and was discontinued in March 2019.
The FDA approval process was restarted in October 2019 on the basis that analysis of a larger dataset of patients showed that the drug reduced clinical decline in a subset of patients with early Alzheimer disease when given at higher doses. On November 6, 2020, the Peripheral and Central Nervous System Drugs Advisory Committee of the FDA recommended against the approval of aducanumab because it was based on a single positive study (01). In a rare decision overriding the recommendation of its advisory committee, the FDA approved aducanumab to treat patients with Alzheimer disease on June 7, 2021, using the accelerated approval pathway. Under the accelerated approval pathway, the FDA approves a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drugs clinical benefit. Drug companies are required to conduct post-approval studies to verify the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial does not verify the drugs anticipated clinical benefit, the FDA has regulatory procedures in place that could lead to the removal of the drug from the market.
Despite the controversy over the FDAs approval of aducanumab, there are opinions supporting FDA approval. According to some experts on Alzheimer disease, the perspective of the panel (FDA Advisory) was too narrow, ignoring important scientific and clinically meaningful considerations. Based on the review of the totality of the data, and our extensive experience with Alzheimer disease trials, research, and clinical care of patients and families, we conclude that aducanumab achieves the standard of meaningful efficacy with adequate safety in early Alzheimer disease (04).
Aducanumab is an expensive drug. The wholesale cost of treatment with aducanumab is about $4312 per infusion, making the annual cost around $56,000 for a high dose. For commercially insured patients, the out-of-pocket costs could be reduced to nothing under certain assistance programs. Patients covered by Medicare through a Medicare Advantage plan have a maximum annual out-of-pocket cap.
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