The US Food and Drug Administration Approves Use of Aducanumab for Alzheimer’s Disease Treatment

Post by Shireen Parimoo

Treatments for Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative illness characterized by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain that lead to widespread neurodegeneration, resulting in dementia and eventual death. AD affects more than 20 million people in the world, and with a growing global aging population, it has become increasingly crucial to develop treatments that can stop or delay the progression of AD symptoms.

Over the decades, several drugs have been developed and tested in randomized clinical trials. The drugs that have previously been approved for treating symptoms of AD help regulate the level of neurotransmitters in the brain. For example, the drug Donepezil helps temporarily mitigate memory-related symptoms by preventing the breakdown of acetylcholine. So far, however, none of these drugs have been effective in preventing the progression of AD or treating the underlying neuropathology. In fact, no new drug has been approved by the United States Food and Drugs Administration (FDA) for AD treatment since 2003.

In The Lancet Neurology, Lon Schneider provides an overview of a novel AD drug – aducanumab – created by the company Biogen. Schneider outlines the mechanism by which the drug targets AD pathology along with the history of its development. Aducanumab is a monoclonal antibody that is markedly different from other AD drug candidates because it directly binds to and clears out Aβ deposits in the brain, thereby targeting the hypothesized neuropathological mechanism underlying AD progression.

Is aducanumab effective?

Early randomized clinical trials showed that aducanumab injections over a year reduced Aβ levels in patients with prodromal or mild AD, though the clinical effects were less conclusive. Following up on these promising results, 1650 patients were enrolled in two separate multi-year phase 3 trials in 2015 to determine the efficacy of aducanumab in reducing the clinical symptoms of AD.

Despite initially promising results, several factors halted further testing of the drug. Firstly, there were issues with uneven participant dropout, missed doses, and poor compliance with the treatment protocol between the placebo and drug groups. Secondly, futility analyses conducted to monitor the interim efficacy of the drug showed mixed results and undesirable side effects like brain swelling. Specifically, differences in clinical symptoms between patients taking aducanumab and placebo only emerged in one of the trials. Moreover, it is unclear whether the differences were due to the drug’s efficacy in improving symptoms or because of worsening symptoms in the placebo group.

Finally, some of the positive results were observed in patients who received high doses of aducanumab, were genetically less at risk for experiencing side effects, and were highly compliant with the treatment protocol. In contrast, the placebo group consisted of more patients who were genetically predisposed to developing side effects and experienced greater clinical decline. Together, these factors posed a challenge to the validity of the findings from the clinical trials.

What’s happening now?

In June 2021, the FDA approved aducanumab under its accelerated approval pathway. This decision came after the FDA advisory committee had initially voted against approving the drug in November 2020. The accelerated approval approach is typically taken when the benefits provided by a drug under consideration outweigh those of existing treatments and are likely to have desirable long-term effects as well.

According to the FDA, their primary reason for approving aducanumab was the reliable dose- and time-dependent reduction in Aβ plaques. It is hoped that in turn, a lower Aβ burden will reduce further clinical decline, even though the evidence for this effect is currently uncertain. The next steps include conducting phase 4 clinical trials to confirm the clinical benefits of aducanumab in AD patients.

Schneider, L. A resurrection of aducanumab for Alzheimer’s disease. Neurology (2020). Access the original scientific publication here.

https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease