What is Aduhelm and what is it used for?
On June 7, 2021, the United States Food and Drug Administration (FDA) granted accelerated approval for aducanumab (brand name Aduhelm), a new treatment for Alzheimer’s disease.
The FDA approval of aducanumab is only for managing mild cognitive impairment and mild dementia.
It’s a little unusual among the current list of approved Alzheimer medicines in that it’s actually a monoclonal antibody – the same things your own body makes to fight off infections when you get sick.
The difference here is that the human body doesn’t create Aduhelm – it was created in a lab by taking antibodies from animals and altering them to work in humans.
How does Aduhelm work?
It breaks up amyloid beta plaques in the brains of patients. Alzheimer’s patients almost always (if not always) have a large amount of this plaque growing in their brain cells.
Alzheimer’s is pretty widely known to cause memory loss, trouble talking, and decline in the ability to live on one’s own due to trouble eating, using the toilet, and other activities of daily living, but it also has another effect you can’t see directly without a brain scan.
We aren’t 100% sure whether Alzheimer’s disease’s development causes the plaques to grow, if they are themselves the cause of Alzheimer’s, or if they’re there by coincidence.
However, they’re unique enough to Alzheimer’s that they’re usually the target of new research – if we can get rid of the plaques, especially in the early stages of the disease, can we stop it, or at the very least slow cognitive decline typically seen with progression of Alzheimer?
That’s where Aduhelm comes in – it’s an antibody designed to break down these plaques in the brains of people.
Does Aduhelm work?
It does seem to break down plaques, confirmed via pet scans – a clinical trial with two different groups of patients who got Aduhelm checked the status of their amyloid plaques 78 weeks into the trial, and it does seem like everyone’s plaque levels went down.
So, yes, it reduces the plaques which are the pathological hallmarks of Alzheimer’s disease.
But does it help slow down memory loss or the other symptoms? Is there truly any clinical benefit?
That’s not as easy a question to answer, mostly because we aren’t really sure.
The shortest answer is: “it might.” You can find out more in the section below outlining the controversy of Aduhelm, but one of the clinical trials for Aduhelm gave patients random strengths of the drug.
Only patients who got the max dose (10 mg/kg of body weight) saw any result: memory loss seemed to slow down by about three months.
However, the other strengths didn’t show this result, and it didn’t happen to every patient. So, again, it’s possible, but we don’t know for sure.
How is Aduhelm given?
Aduhelm is administered as an intravenous infusion that takes about 60 minutes. A minimum of 21 days must elapse between each drug administration, but doses are typically given four weeks apart.
Doses of the medication are calculated based on a person’s weight. Patients start with 1mg/kg of Aduhelm, and in subsequent infusions, the provider will increase the amount of drug up to 10mg/kg by the 8th infusion.
The specific dosing regimens are 1mg/kg for infusions one and two, 3mg/kg for infusions three and four, 6mg/kg for infusions five and six, and 10mg/kg thereafter. See the table below:
Aduhelm Dosing Schedule
| IV Infusion (every 4 weeks) | Aduhelm Dosage (administered over approximately one hour) |
|---|---|
| Infusion 1 and 2 | 1 mg/kg |
| Infusion 3 and 4 | 3 mg/kg |
| Infusion 5 and 6 | 6 mg/kg |
| Infusion 7 and beyond | 10 mg/kg |
What are the adverse effects of Aduhelm?
In the clinical trial designed to test the safety of the drug, some of the side effects found in the 21 people who took the drug included diarrhea (5 patients out of 21), headaches (8 out of 21), and upper respiratory tract infections (4 out of 21).
These side effects were not linked to anything special with the patients and just seemed to happen by chance.
In some patients, hypersensitivity reactions such as angioedema and urticaria have occurred.
If you experience these reactions, your doctor will immediately stop the infusion and initiate appropriate medical treatment.
However, a more serious adverse drug reaction was found in some of the patients – Amyloid Related Imaging Abnormalities, or ARIA for short, were found in three patients.
In this case, an ARIA refers to something happening to the brain – there’s ARIA-E, where there is brain swelling, and ARIA-H, where blood vessels in and around the brain bleed slightly.
These side effects are considered serious, but they don’t seem to happen to everyone.
Instead, they mostly seem to happen in patients carrying a special gene type – its full name is Apolipoprotein ε E-4 (or just Apo E-4).
Patients who take this drug are tested to see if they carry this gene, and part of their therapy is to get magnetic resonance imaging (MRI scans) while they take Aduhelm to see if any of these potential side effects are occurring.
In the two large clinical studies, EMERGE and ENGAGE, the following adverse reactions were seen in study participants:
Adverse Reactions Reported in at Least 2% of Patients Treated with ADUHELM 10 mg/kg and at Least 2% Higher Than Placebo in EMERGE and ENGAGE
| Adverse Reaction | ADUHELM 10 mg/kg Number of participants = 1105 % | Placebo Number of participants = 1087 % |
|---|---|---|
| ARIA-E | 35 | 3 |
| Headache | 21 | 16 |
| ARIA-H microhemorrhage (microbleed) | 19 | 7 |
| ARIA-H superficial siderosis (slow bleeding in subarachnoid space of brain) | 15 | 2 |
| Fall | 15 | 12 |
| Diarrhea | 9 | 7 |
| Confusion/Delirium/Altered Mental Status/Disorientation | 8 | 4 |
Note: While all of these adverse reactions are serious, delirium and altered mental status can really complicate your loved one’s care since other medications and underlying cognitive impairment or a recent hospitalization can also cause these problems.
Who is at increased risk for developing serious side effects with Aduhelm use?
Carriers of the Apo E-4 gene (see above) may be at higher risk than other people for ARIA.
Genetic testing is part of treatment as a result.
What is the controversy surrounding Aduhelm?
The FDA recently approved Aduhelm in June of 2021 for treating mild/moderate Alzheimer’s Disease.
It is considered a controversial decision because this medication is the first of its kind, and scientists and experts have raised serious concerns about its safety and efficacy.
Backtracking to the two large clinical trials, ENGAGE and EMERGE, criteria were set that required both trials to achieve their primary outcome despite being conducted separately.
Unfortunately, the ENGAGE trial failed to reach its primary outcome, thus failing to prove its clinical efficacy, and the trials were halted early.
As a result, the method as to how this drug came to be approved is another topic of controversy.
As mentioned earlier in this article, Aduhelm was approved via the accelerated approval pathway, designed to grant early approval of drugs for serious conditions.
The basis for its approval was the drug’s ability to reduce amyloid levels.
However, it is still unsure if reducing these levels can reverse the disease state itself.
Additionally, ARIAs are a concerning adverse event, and more data is required to ensure the safety of this drug.
To date, follow-up studies are still being required of Aduhelm, and at any time, the FDA may withdraw its approval of the drug.
To add to the controversy further, the Cleveland Clinic, one of the most respected and largest medical centers in the country, has expressed concern over the safety and efficacy of Aduhelm based on a thorough review of all the scientific data by a panel of its experts.
Based on the panel’s recommendations, the Clinic will not prescribe the drug to its patients.
Another large medical center, Mount Sinai in New York City, has also decided not to prescribe Aduhelm to its patients, citing similar safety and efficacy concerns.
Aduhelm use in older adults
In the ENGAGE and EMERGE clinical trials, study participants’ ages ranged between 50 and 85 years, with a mean age of 70 years.
79% of the individuals were 65 and older. 32% were 75 and older.
The study investigators found no significant differences in adverse reactions between these age groups. They also noted no additional safety concerns in participants 65 and older compared to their younger counterparts.
These results do not seem to be significant warnings or considerations for administering Aduhelm to adults aged 65 and older.
That said, it will be a long time before I am fully convinced about the safety and efficacy of administering Aduhlem to older adults. In my opinion, the data is too early, and we do not have enough of it. We need more studies and more time to be absolutely sure about Aduhlem’s safety and efficacy.
As such, at this point in time, I will not be supporting its use in my own clinical practice.
How much does Aduhelm cost?
A lot. As of the date of this article, the price tag of one vial is about 340 dollars, and that vial isn’t very big – it holds roughly 2-3 mL, about the size of an eye drop bottle, or a little smaller!
Considering the number of infusions a patient would need a year, the cost of Aduhelm will be thousands of dollars.
This is true even after the drug manufacturer’s press release in December 2021, stating that the initial cost of $56,000 will be cut to approximately half to $28,200.
Since this medication has to be administered in a physician’s office, it would be covered under Centers for Medicare and Medicaid Services’ Part B, but there is a big caveat…it is only covered for people enrolled in qualifying clinical trials.
Even if you qualify, the cost is still staggering…with the co-insurance being 20%, the calculated out-of-pocket covered expense to Medicare beneficiaries is $5,600 per year!
And…this does not include the required blood test and PET scans that must be done to detect potential brain bleed and swelling.
Summary
- Aduhelm is the first drug in its class to break down amyloid-beta plaques in the brains of Alzheimer patients
- There may be some potential benefit for slowing down disease progression, but more studies are needed
- Controversy surrounds its use due to concerns being raised by medical experts about its safety and long-term efficacy – current data is lacking
- Only individuals enrolled in qualified clinical trials will be covered by Medicare Part B
- Even for qualifying individuals, the cost is prohibitive – approximately $5,600 per year, not including PET scan and blood test costs
References
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Hershey L, Tarawneh R. Clinical efficacy, drug safety, and surrogate endpoints: has aducanumab met all of its expectations? AAN. 2021, Sep 14;97(11). Available from: https://n.neurology.org/content/97/11/517.long
Budd HS, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimers Dis. 2022;9(2):197-210.
Ferrero J, Williams L, Stella H, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease. Alzheimer’s and dementia. 2016, Sep;2(3):169-176. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651340/
Sachs R, Bagley N. Medicare coverage of aducanumab – implications for state budgets. NEJM. 2021, Nov 25;385:2019-2021. Available from: https://www.nejm.org/doi/full/10.1056/NEJMp2115297
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