The approval of aducanumab for Alzheimer’s disease by the U.S. Food and Drug Administration (FDA) marked a significant moment. It was the first new Alzheimer’s drug approved since 2003 and the first to target the disease’s underlying biological processes rather than just managing symptoms. Marketed as Aduhelm, its approval signaled a potential shift in how the disease could be approached.
Alzheimer’s Disease and Aducanumab’s Mechanism
Alzheimer’s disease is a progressive neurological disorder characterized by the gradual decline of memory and cognitive abilities. A defining feature is the accumulation of abnormal protein deposits in the brain, specifically amyloid beta plaques. These plaques are believed to disrupt communication between brain cells and contribute to neuronal damage. The “amyloid cascade hypothesis” suggests that this buildup of amyloid-beta is a key driver of the disease’s progression.
Aducanumab is a monoclonal antibody designed to address this underlying pathology. It selectively binds to aggregated forms of amyloid-beta, including both soluble oligomers and insoluble fibrils, which are the components of the plaques. By attaching to these aggregates, aducanumab facilitates their removal from the brain. Clinical trials showed that aducanumab significantly reduced amyloid beta plaques in the brains of patients with mild cognitive impairment or mild Alzheimer’s disease.
The FDA Accelerated Approval Pathway
The FDA approved aducanumab through its Accelerated Approval pathway, designed for drugs that treat serious conditions with unmet medical needs. This pathway allows for earlier approval based on a “surrogate endpoint”—a measure reasonably likely to predict a clinical benefit, even if direct clinical benefit has not yet been fully confirmed. For aducanumab, the reduction of amyloid beta plaques in the brain served as this surrogate endpoint.
The Accelerated Approval pathway mandates that a drug approved under this provision must undergo post-approval confirmatory studies to verify its clinical benefit. If these studies fail to confirm the anticipated benefit, the FDA can initiate proceedings to withdraw the drug from the market. This pathway aims to provide patients with earlier access to potentially beneficial therapies while requiring ongoing research to solidify their effectiveness.
Debate Surrounding the Approval
The FDA’s approval of aducanumab was met with considerable debate and dissent from medical experts and its own advisory committee. A significant concern revolved around the sufficiency and consistency of the clinical trial data. While aducanumab consistently reduced amyloid beta plaques, the evidence for its ability to slow cognitive decline was less clear.
The manufacturer, Biogen, conducted two identical Phase 3 clinical trials, EMERGE and ENGAGE. Although both studies were terminated early, only one, EMERGE, showed a significant benefit in slowing cognitive decline at a high dose, while ENGAGE did not. In November 2020, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee overwhelmingly voted against recommending aducanumab’s approval, with 10 out of 11 members finding insufficient evidence of clinical effectiveness. Despite this advisory committee’s recommendation, the FDA proceeded with the accelerated approval. This divergence led to the resignation of some advisory committee members, who expressed concerns about the process and the strength of the evidence.
Impact on Alzheimer’s Treatment
Aducanumab’s approval represented a landmark moment for the Alzheimer’s field, being the first new treatment for the disease in nearly two decades and the first to target its underlying pathology. This approval initiated a new era of amyloid-targeting therapies. It underscored the importance of amyloid beta plaques as a therapeutic target in Alzheimer’s research.
The approval also brought attention to the eligibility criteria for such treatments, as aducanumab was indicated for patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease. While Biogen later discontinued aducanumab, its initial approval paved the way for further research and development in disease-modifying Alzheimer’s therapies. The ongoing need for confirmatory studies following accelerated approval continues to shape the landscape of Alzheimer’s treatment development.