The Bottom Line On The New Alzheimer's Drug

When the Food and Drug Administration (FDA) approved the Alzheimer’s medication aducanumab in June 2021, many people cheered. They were excited that for the first time in nearly two decades, there was finally a new drug to treat this devastating neurological disease that affects an estimated 6 million Americans. But since its approval, many have raised serious concerns about the effectiveness and safety of the medication.

We sat down with Luca Gilberto, MD, PhD, a neurologist and neuroscientist at Northwell Health, to find out more about aducanumab, including why it’s so controversial and who should—and shouldn’t—use the medication.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that doctors and researchers are still trying to figure out. We do know that with AD there are excess deposits of beta amyloid, an abnormal protein, in the brain, which researchers believe contributes to the destruction of neuronal cells. 

Enter Aducanumab (brand name Aduhelm). It is an antibody, a protein produced by the immune system, which works by reducing the formation of and clearing beta amyloid deposits in the brain, potentially slowing disease progression. The idea behind this drug is that healthy people, who do not develop AD when they age, have an immune system that efficiently fights the pathology: antibodies derived from these subjects have been engineered and used as a therapeutic tool.

The drug is given as a monthly injection that patients would take indefinitely. Current therapies only treat symptoms of the disease, so a drug that could treat the underlying process could be life-changing for many.

The approval of Aducanumab has become a hot topic for several reasons. First and foremost, the data may not be as good as it sounds. As a final step on the path toward FDA approval, the drug’s manufacturer, Biogen, conducted two separate phase three clinical trials of patients with either mild cognitive impairment or mild AD. Both clinical trials were stopped early because the drug was found to have no significant clinical benefit. But after the trials concluded, Biogen pulled more data from a subset of patients who were exposed to the highest dose of the drug for the longest period, and that data did show some clinical benefit. However, a closer look at that data reveals that the clinical changes were very small. We’re talking about a 0.6% to 0.7% difference in one of the commonly used clinical scales, for example, which is quite small. These types of variations in results can easily happen in clinical trials and are not always necessarily related to the effect of the drug. 

Additionally, the drug was authorized under the FDA’s Accelerated Approval Pathway, which allows manufacturers to get drugs into patients faster, essentially because the benefit is thought to be too great to wait for a long, drawn-out process.

Finally, the approval itself was granted, however, not based on the clinical benefits of the drug itself, but rather on the finding that it reduced the amount of amyloid in the brain, as ascertained by imaging (PET scan). Several scientists have found fault with the premise that slowing or halting amyloid accumulation is all that is needed to translate into a cognitive benefit. The development of AD is extremely complex and while amyloid is considered a feature of the disease, it is not well correlated with the clinical progression or state of the disease. What’s more, reducing amyloid plaques doesn’t necessarily mean that you are automatically improving clinical outcomes. This concept has been proven time and time again in the past, where prior clinical trials have similarly failed to grant a clinical benefit, despite reducing amyloid in the brain. Brain amyloid plaque reduction is a good measure of how the drug works, but not of the drug’s clinical efficacy.

Like any medication, aducanumab can have some side effects. Besides a small percentage of patients who dropped out of the trials because of allergic reactions to the drug, several patients reported headaches, confusion, and other stroke-like symptoms. Importantly, the occurrence of brain swelling and even hemorrhages is a known side effect of this treatment, which requires strict monitoring and may lead to stopping the drug.

The FDA has recommended that only patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease be treated but has not provided clinicians with other guidelines, for example, contraindications. It makes sense that this type of approach is pursued in the earliest stages of the disease, where the damage is not so widespread. In the later stages, the disruption of the brain environment is often so advanced that this type of strategy has practically no role. But we must remember that the data from the clinical trials only showed minimal benefit even in patients with mild forms of the disease. We also need to be careful of other diseases, such as stroke, that can contribute to cognitive decline, and where this medication would be useless and pose more risks than benefits.

It should also be noted that the drug is expensive. With an expected annual price tag of around $56,000, this is not something that will be available to all who need or want it. And, at this point, we do not have a clear indication from Medicare and other payers on their plans to cover the drug.

Our approach, which stems from the available clinical trial data, is that patients who have surpassed mild cognitive impairment or who have other conditions that may cause cognitive decline (such as other forms of dementia, strokes, substance abuse, etc.) would not be good candidates for this drug. This also excludes patients at risk for adverse events, such as a history of stroke, significant cerebrovascular disease, or brain hemorrhage, as well as patients who take an anticoagulant.

Aducanumab is certainly an important step in the approach to treating this disease. And while it may not be the wonder drug we’ve all been hoping for, it may be appropriate for a select group of patients. In early July, Acting FDA Commissioner Dr. Janet Woodcock called for an investigation into the approval that would analyze interactions between the agency and Biogen prior to aducanumab’s approval. As we await the results of that inquiry, many of us will remain wary of the drug’s limitations while hoping to be able to more fully embrace the advance brought forward by its approval.

Scientists are still working on this and other therapeutic avenues, and the pipeline of clinical trials for AD is rich with exciting possibilities. After all, we are all looking forward to new developments and anything we can do to improve the life and livelihood of our patients. 

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