Aduhelm (aducanumab) Approved for the Treatment of Alzheimer’s Dementia
On June 7, 2021, Biogen announced FDA approval for its product, Aduhelm (aducanumab–pronounced add-yoo-CAN-yoo-mab), to treat Alzheimers disease. This is a time of hope and optimism for many people living with dementia and their family caregivers. However, there is still controversy around the FDA’s decision to approve the drug. Why?
What is Aduhelm?
Aduhelm is a monoclonal antibody Monoclonal antibodies are made from “antigens”, proteins that mammals make to fight off bacteria, cancers, and other diseases. Antigens can be developed from the immune responses of other animals, such as mice. Some antigens are removed from human blood and then combined with mouse proteins. Some antigens are not combined with mouse proteins, but still have to be mass produced, a process that is very expensive. Aduhelm is 100% human antigen and works by reducing the amount of beta-amyloid plaques, or clumps, from the brain.
Although Aduhelm was tested in people diagnosed with either mild cognitive impairment or mild dementia, the FDA has approved the use of Aduhelm for Alzheimer’s dementia regardless of the stage.
Does Aduhelm Reverse the Disease?
No. Aduhelm was tested in 2 Phase 3 studies, ENGAGE and EMERGE. The people enrolled in the study were diagnosed with either mild cognitive impairment or mild dementia. In EMERGE, Aduhelm SLOWED DOWN memory problems in persons receiving higher dosages of the drug compared to those receiving the placebo. In ENGAGE, no differences were found between those receiving the drug and those receiving the placebo.
When Biogen first started testing the drug, they used lower dosages because of concern about side effects–especially brain swelling and small bleeding (see below). Over time, the researchers began using higher dosages and seeing better results. However, when they analyzed all of the results together, the statistics indicated no improvement–because the people receiving lower dosages were mixed in with the people who had received higher dosages. Biogen initially reported that Aduhelm did not work. When the researchers re-ran the statistics and compared the groups (higher dosage versus lower dosage), they discovered that Aduhelm did demonstrate positive changes. Some scientists are still skeptical of Biogen’s claims because these scientists argue that the EMERGE trials were not well-designed, and the positive results could have been affected by the number of people dropping out of the study.
Surrogate Endpoints Vs. Clinical Benefits
Per Biogen and the FDA, Aduhelm was approved using the “Accelerated Approval Program.” Biogen received temporary FDA approval based on studies that used a “surrogate endpoint.” Surrogate endpoints are NOT necessarily measures of clinical improvement. For example, Biogen reported that patients receiving higher doses of Aduhelm performed better on a clincial dementia scale than patients receiving a placebo–by 0.89 points. That is, those getting the drug scored an average of 1 point higher than those receiving the placebo. What does that 1 point difference mean in the real world? Hard to say right now.
Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.Dr. Patrizia Cavazzoni
However, the drop in beta-amyloid plaque did not always occur with better scores on clinical dementia scales. Under the conditions of the accelerated approval program, Biogen is still required to continue testing Aduhelm to demonstrate actual clinical benefit–this is known as Phase 4 confirmatory trials. If these trials do not show that Aduhelm produces clinical benefits, the FDA can take Aduhelm off of the market.
How Much Will Aduhelm Cost?
Aduhelm has to be given intravenously every 4 weeks. The dosage is based on weight–the heavier a person, the larger the dosage. Biogen has currently set the cost at $4312 per infusion for a 74 kg person (163 pounds). Yearly costs will be around $56k. Out-of-pocket cost for persons with insurance will vary, assuming one’s insurance will pay for the treatment. Plus, one will have to have proof of beta-amyloid in the brain, meaning that the individual will require specific types of imaging, like PET-scans. MRIs will also be needed to monitor for side effects.
What Are the Side Effects?
Amyloid Related Imaging Abnormalities (ARIA) were the most frequently reported side effects . The two types of ARIAs were brain swelling or small hemorrhages, and happened in 41% of the patients. Those with ApoE 4 alleles were most at risk for brain swelling detected by imaging. These changes resolved over time. Clinical symptoms were detected for 24% of the people who developed ARIA: headache, dizziness, confusion, and nausea. These symptoms resolved for 88% of the patients.
FDA approval of Aduhelm is cause for cautious optimism in the Alzheimers community—especially for persons with mild cognitive impairment and mild dementia. However, there are some things to consider. Even though the FDA has approved Aduhelm to be used in anyone with AD, regardless of stage, Aduhelm was not tested in people with moderate to severe dementia. Aduhelm slowed decline–it did not reverse the disease. If given to a person with mild cognitive impairment or mild dementia, Aduhelm may prolong independence, delay the need for paid caregivers/higher levels of care, and provide greater quality of life for people living with AD and their caregivers. On the other hand, if given to someone with moderate dementia who needs significant support and supervision, Aduhelm will increase the amount of time that the person requires care. This could mean that the caregiver, instead of providing an average of 10 years of care, could be facing 15 or 20 years in the caregiver role. Aduhelm may increase the need for even more caregiver support systems.
The best approach is to discuss your options with a trusted health care provider, especially neurologists skilled with dementia diagnosis and management.
Dr. Rita Jablonski
Rita Jablonski, PhD, CRNP, FAAN, FGSA is a nurse practitioner, researcher, tenured professor, and former family caregiver. Her research and practice involve all aspects of dementia management; she is best known for non-drug strategies to address dementia-related behaviors.