Statement on the FDA Approval of Aducanumab
On June 7th, 2021, the U.S. Food and Drug Administration (FDA) gave accelerated approval to a drug intended to slow cognitive decline in Alzheimer’s disease.
Aducanumab (Aduhelm) is the first drug approved in its class and the first for this disease since 2003. While the approval has generated both excitement and controversy, it is clear that much more work is needed before we declare that a cure has arrived.
A hallmark of Alzheimer’s disease is the accumulation of a protein known as beta-amyloid, which clumps together in plaques that are toxic to the brain. Normally, beta-amyloid plays an important role in keeping the brain functioning, constantly being made and broken down by brain cells as it is needed. When there is an imbalance between the creation of beta-amyloid and its break down and it begins to accumulate, it can then form those plaques that have long been thought to be a key feature of Alzheimer’s disease.
Aducanumab is an antibody – just like the antibodies made by the immune system to fight off bacteria and viruses – that enters the brain and sticks to beta-amyloid plaques, signaling to the immune system to remove whatever the antibody is stuck to.
So far, aducanumab has shown to be effective in removing beta-amyloid from the brains of persons with early stages of Alzheimer’s disease. However, the evidence is not quite so clear on whether it improves cognition or slows cognitive decline. In the clinical trials that have been completed, only a portion of the participants showed clinical benefit over the full 18 months of the trial. These participants were in a part of the trial where they received a higher dose of aducanumab than other participants.
As a result, the FDA issued their approval based on the fact that the drug removes beta-amyloid plaques but required that another clinical trial be completed where Biogen – the company that makes aducanumab – must reproduce the improvements seen at the higher dose in a different set of participants. If Biogen cannot reproduce the positive effect, the FDA could reverse its approval of aducanumab.
Approval of the drug based on its impact on a biological marker only – beta-amyloid plaques – without a clear clinical benefit is controversial and not supported by all scientists and clinicians. The controversy is also in part due to the fact that a drug typically needs to be proven to be clinically beneficial in at least two independent studies to demonstrate replication and show that a positive result from one study is not due to chance only. This requirement is needed usually before approval given the potential sides effects of drugs and personal and economic costs of drugs. For aducanumab, the concerning side effect was a form of “brain swelling,” and its estimated cost per year is US $56,000.
Aducanumab works as it was designed to – removing beta-amyloid – so why is it not showing a benefit in all patients? The answer, as one could expect, is not so simple.
Alzheimer’s disease is a very complicated disease, with other factors at play in its manifestation. Another protein known as Tau, which is also required for a healthy brain, can stick to other Tau proteins and form long tangled chains known as neurofibrillary tangles. These tangles are also found in Alzheimer’s disease, with the beta-amyloid plaques, and are toxic to brain cells.
It is also important to note that one should not equate Alzheimer’s disease with dementia. Alzheimer’s disease is thought to be one of the most common causes of dementia but there are other causes of dementia such as vascular disease dementia or frontotemporal dementia.
Furthermore, there are also several other factors that contribute to the risk and manifestation of dementia, including genetics, age, smoking, alcoholism, sedentary lifestyle, brain injury, chronic depression. These can all potentially affect the disease process, as well as affect the ability of the brain to cope and compensate for the disease, referred to sometimes as cognitive reserve.
While we welcome a potentially clinically beneficial and disease-modifying treatment for Alzheimer’s disease, much more work is needed at the bench and the bedside towards understanding what causes Alzheimer’s disease, and what the most effective treatment will be.
The Tanz Centre for Research in Neurodegenerative Diseases (Tanz CRND)
Tarek K. Rajji
Toronto Dementia Research Alliance (TDRA)