The ABCs of Alzheimer's Dementia
Steph’s Note: This week, we’re wandering into some heated territory. The pharmaceutical industry may have (more than) its fair share of controversies, but the approval of adacanumab for Alzheimer’s has caused quite the recent hullabaloo! In order to fully understand this, of course we’re going to back up a couple of steps and discuss the treatment playing field first, so expect some pharmacotherapy. I mean, it IS tl;dr!
Here to guide us through through this veritable minefield is the duo of Eselebor Okojie and Demi Oloye. Eselebor Okojie is a current P4 student at Howard University. He’s interested in medical information and communication. Next year he hopes to start a fellowship or join the workforce pursuing a career in medical/drug information. In his spare time, he likes reading, long walks on the beach and competes in powerlifting competitions. #SWOLEISTHEGOALSIZEISTHEPRIZE
Demi Oloye is a fourth year pharmacy student at Howard University College of Pharmacy. She has professional interests in both cardiology and diabetes. She is passionate about service and being heavily involved in underserved communities. Upon graduation, she hopes to start a fellowship in Medical Affairs. In her spare time, she enjoys traveling, spending time with family and friends and watching game shows.
What is Dementia versus Alzheimer’s Disease?
They say some things go away with time. The value of a car, skin elasticity, muscles, teeth, vision, patience, and weight (although obviously some of us are doing quite the opposite here! Probably all that pharmacy school stress…). Memory loss is also a common occurrence with time. Cognitive decline is directly correlated to age; everyone experiences it. Of course, once in a while you may forget where you put your keys, where you set the remote control down, or even forget to pick your kids up from school.
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But when does too much memory loss start to become an issue?
Dementia is more severe than normal age-related cognitive decline. Dementia progresses over time and eventually starts to significantly interfere with daily tasks and activities. But to be clear, dementia itself is not a specific disease. It’s an umbrella term that is used to describe the symptoms accompanying a decline in memory.
There are several different types of dementia including the following:
Alzheimer’s dementia, and
dementia associated with Parkinson’s disease (just to name a few).
However, the most common form of dementia (and the focus of today) is Alzheimer’s. Alzheimer’s disease makes up more than 50% of dementia cases in the United States.
Cramped quarters in the Alzheimer’s brain. (Image)
Imagine walking into someone’s brain and taking a look around a normal brain versus an Alzheimer’s disease brain. The Alzheimer’s disease brain would feel a lot more cramped inside.
This “shrink” of the brain is due to the loss/death of nerve cells. This process begins to happen more than a decade before symptoms begin to appear, which is part of what makes this so scary!
Alzheimer’s disease slowly destroys the memory and thinking portions of the brain. It is characterized by the presence of neuritic plaques comprised of bunches of beta amyloid proteins, as well as tangles of twisted strands of Tau proteins. The neuritic plaques and tangles present in the brain tissue interfere with the neurons and proper neurotransmitter signaling. There is also a decrease of acetylcholine associated with Alzheimer’s disease.
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Some Alzheimer’s disease symptoms include memory loss, agitation, irritability, difficulty communicating and depression. Unfortunately, the list goes on and on.
How do we treat Alzheimer’s Disease?
Like most types of dementia, Alzheimer’s disease is irreversible, and there’s no cure. There are some medications that help improve some of the symptoms or slow progression but nothing to actually “fix” it.
We mentioned earlier that Alzheimer’s is associated with a decrease in acetylcholine. It’s also associated with a loss of cholinergic neurons, which also contributes to the decline in memory and attention. So what drugs could be used to combat this lack of cholinergic activity?
If Napoleon Dynamite was a pharmacist, he would probably say, “Duh, acetylcholinesterase inhibitors.”
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Acetylcholinesterase Inhibitors for Alzheimer’s Dementia
Acetylcholinesterase inhibitors are the drugs of choice for this disease state because they increase levels of acetylcholine. As their name implies, these medications act by blocking the enzyme normally responsible for this neurotransmitter’s degradation. Fun fact, acetylcholine is pretty unique in the neurotransmitter world because unlike most other neuronal signaling molecules, it is degraded within the synaptic cleft to be “turned off” rather than experiencing reuptake into the neuron (like serotonin, for example).
What drugs belong to this backbone class of Alzheimer’s treatments?
Donepezil (Aricept) is most commonly used as first line treatment in Alzheimer’s. It is formulated as both a regular oral tablet as well as an orally disintegrating tablet (ODT). Donepezil is dosed once daily and does not need to be adjusted for renal or hepatic impairment (makes for a happy pharmacist!). On the other hand, it has a pretty high potential to cause nausea, so it’s usually dosed at night. The hope with this is that the patient will be asleep during the period of time that nausea would generally occur.
Since the highest donepezil tablet strength (23mg) has to be taken whole and not crushed or chewed, the ODT formulation may be highly favored in this patient population. For elderly patients who have a hard time swallowing pills, the ODT formulation starts to disintegrate in the mouth within seconds without water.
Rivastigmine (Exelon) is another acetylcholinesterase inhibitor used to help treat Alzheimer’s. Rivastigmine comes in a transdermal patch formulation and an oral capsule. The capsule is dosed twice a day while the patch is applied daily.
Just like the ODT formulation of donepezil can be useful for patients who have a hard time swallowing whole pills, the patch can be useful in a patient that doesn’t tolerate oral treatments at all or who already has a high oral pill burden, as is characteristic of this population. The patch formulation is also associated with less nausea and vomiting than its oral counterpart. As with any transdermal medication, it’s imperative to remove the old patch at the time the new patch is applied. (Makes sense. But you might be surprised to learn just how many times patients are admitted and found to have multiple patches still intact!)
Another necessary counseling point is to avoid using the same plot of skin more than once every 14 days for a rivastigmine patch. Skin irritation in the form of contact dermatitis is one of the tradeoffs of using the transdermal formulation as opposed to the oral capsule and can lead to discontinuation or medication switches. Finally, unlike donepezil, if a patient does have hepatic insufficiency, the patch dose needs to be adjusted.
The last acetylcholinesterase inhibitor that is used in Alzheimer’s is galantamine (Razadyne), which comes in tablet, capsule, and solution formulations. The IR tablet formulation is dosed twice a day while the ER capsule is dosed daily. Galantamine should be avoided if patients have either severe hepatic or severe renal impairment, but there are useful dosage adjustments for people with mild or moderate organ dysfunction.
The most common adverse effect with the acetylcholinesterase inhibitors is…drum roll…you guessed it…nausea and vomiting! Hence all of the various formulations including transdermal and ER capsules to try to product consistent medication levels and minimize this often deal-breaking side effect. Otherwise, patients may experience dizziness, bradycardia, weight loss, worsening peptic ulcer disease, and worsening urine outflow issues. Obviously some of these are highly undesirable in an elderly patient, so risk versus benefit discussions are key!
Now that we all know a little more about the role of acetylcholine and cholinergic neurons in the pathogenesis of Alzheimer’s, let’s chat about another possible angle: NMDA receptors.
NMDA Receptor Antagonists for Alzheimer’s Dementia
N-methyl-D-aspartate (NMDA) receptors are one type of glutamate receptor in the brain. Glutamate is the main excitatory neurotransmitter, and its excitation effects are largely mediated by influx of calcium into the neuron. When there’s excessive glutamate binding to its receptors, including the NMDA receptors, there’s too much calcium influx. This can lead to excitotoxicity and neurodegeneration.
Of course, we all need glutamate excitation to some degree. But sometimes there really is such a thing as too much of a good thing…
So how do we get the glutamate effects to simmer down, now?
When you can use some classic SNL memes for a post, it’s a good day. (Image)
Memantine (Namenda) is an NMDA receptor antagonist that is typically recommended as a second line therapy in patients with moderate to severe Alzheimer’s once progression is more apparent. Memantine can be used as monotherapy or dual therapy in Alzheimer’s, but we usually see it used in combination with donepezil. There’s even a combination pill formulation called Namzaric for this purpose!
Combinations of acetylcholinesterase inhibitors and memantine have shown modest improvements in cognition and global outcomes in patients with advanced disease. In a meta analysis that pulled data from multiple controlled trials researching the effectiveness of acetylcholinesterase inhibitors and memantine for treating dementia, the authors concluded that acetylcholinesterase inhibitors and memantine showed a statistically significant - but clinically marginal - effect in the improvement of cognitive function.
When the new kid on the block is trying to live up to expectations. (Image)
We would be remiss if we failed to mention at least a couple of the theorized non-prescription ways to treat Alzheimer’s. There’s some data that a few supplements such as vitamin E and ginkgo have benefits for Alzheimer’s. But both of those come with their own risks. Too much vitamin E can lead to an increased cardiovascular disease (CVD) risk, and too much ginkgo can pose a potential bleed risk.
However, there is a new kid on the block that’s causing quite a stir…
Aducanumab for Alzheimer’s Dementia
Aducanumab (Aduhelm) was approved by the Food and Drug Administration on June 7, 2021, using the accelerated approval pathway.
Aducanumab’s response to Alzheimer’s plaques. (Image)
So, what is this medication, and why was it approved through a special pathway?
Aducanumab is a monoclonal antibody that is administered intravenously once a month. It enters the brain, binds to the neuritic plaque, and facilitates degradation of the plaque. It’s thought to do this by stimulating the immune system to recognize the plaque as foreign and attack the plaque as if it was an intruder.
Why does this matter? What’s the big deal?
As we previously mentioned, there aren’t many treatments available for Alzheimer’s, and this is the first new one in a long time. The last time there was a new treatment for Alzheimer’s was 18 years ago in 2003! (Ah 2003, that was a good year. That was the same year that Lebron James, who some would argue is one of the greatest players of all time, was drafted out of high school as the number 1 NBA draft pick.)
Let’s not forget that Queen Bee released her first solo album that year too. Ah 2003… (Image)
Needless to say, aducanumab is a big deal as it is not only a new Alzheimer’s drug, but it also is the first in an entirely new drug class for Alzheimer’s. However, this drug has had a wild ride to approval that’s left some skeptics in its wake.
Enter the drama.
So here’s the deal. Aducanumab was studied in two identical, simultaneously conducted phase 3 studies, EMERGE and ENGAGE. Both trials were terminated in March 2019, when the data suggested that this treatment was not more efficacious than placebo.
According to the sponsor’s (Biogen’s) press release in March 2019, “Aducanumab was unlikely to meet primary endpoints,” and that is what ultimately led to the “decision to discontinue the trials.”
Fast forward to seven months later in October 2019.
After reviewing data which was unavailable at the original time of trial termination, investigators found that aducanumab reduced cognitive decline in the EMERGE study. Biogen stated that a subset of patients who were receiving a higher aducanumab dose in the EMERGE study met both the primary and secondary endpoints, and the drug did indeed show benefit compared to placebo. Biogen then submitted these results to the FDA for approval of aducanumab.
Check out this article for highlights about this difference. (Image)
However, if both studies were identical, how could the EMERGE trial have shown benefits when compared to placebo and yet the ENGAGE trial did not?
The EMERGE trial proved the benefits of aducanumab to be statistically significant at the higher dose when additional data with longer follow-up was analyzed. Biogen collaborated with the FDA to complete a subgroup analysis to attempt to explain why two similar trials came to different conclusions. Why did one have a positive clinical effect while its counterpart failed to show positive results?
There were two possible conclusions provided…
ENGAGE had more outliers than EMERGE with regards to patient characteristics, and these outliers experienced a more rapid decline of Alzheimer’s. When the FDA and Biogen removed these outliers from their analysis, it made the two study results more comparable. OR
“Patients in the EMERGE trial had a greater exposure to high dose aducanumab for a longer duration of time,” according to Alfred Sandrock, Biogen’s chief medical officer.
There was only one slight problem. Well, it’s more like a big one when the advisory committee looked over the NDA for this drug.
These conclusions of benefit and significance in favor of aducanumab were based on an incomplete trial. Most likely because of this, the FDA advisory board recommended the drug not be approved and actually voted against the drug’s approval. However, and here’s where it gets really hot, the FDA went against its own advisory board and approved aducanumab!
#DRAMA!!!!
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Why does this matter, and what are the bigger implications?
The FDA rarely goes against the recommendations of the advisory committee, so this is pretty shocking. Now, granted we don’t have many treatment options for Alzheimer’s, and the last approved drug was 18 years ago. So it’s understandable to consider that a drug with seemingly positive results would be welcomed - especially when thinking about those with family members affected by the disease.
But is this desire for a new treatment rationale enough to justify the issues with the data?
This controversial approval opens doors, both good and bad.
Yes, this opens the opportunity for more companies to consider research into Alzheimer’s and other less-understood disease states. But it also sets a precedent on the level of evidence required to gain FDA approval in these conditions, which may not be prudent.
So why did the FDA go against their own advisory committee?
As previously mentioned, there are probably thousands and thousands of patients that feel like this drug is beneficial. There’s no other drug like aducanumab on the market for Alzheimer’s. Maybe the FDA felt like its hands were tied, and they had to give the people what they wanted?
I mean everyone wants to find some cure or treatment to stop Alzheimer’s. So, when Biogen said that they had this super magical drug…then said it didn’t work…then said sike! just kidding, it works, one might say that the FDA lowered its standards and traded it in for this glimmer of hope when it granted accelerated approval to aducanumab.
What exactly does accelerated approval mean?
Well, in short, it’s basically saying that the FDA approval is conditional and that more hoops need to be jumped through. Biogen has to conduct another clinical trial to validate the data they claimed in the group of patients from the EMERGE trial receiving the higher dose. An accelerated approval drug means that this trial will be conducted after the drug becomes available on market, and the sponsor will then be able to use real world data to prove its hypothesis. So really there are two outcomes here at the end of this.
Option number 1: Aducanumab will have positive results in this post marketing clinical trial. Woo-hoo! The drug stays on market, and we have an additional treatment option for Alzheimer’s disease.
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Option number 2: Aducanumab fails to demonstrate a clinically significant effect, yet again, crashing and burning. If it fails, then aducanumab will be pulled from the market. But the aftermath would be where it gets really messy.
There may be some people who experience some type of beneficial effect, placebo or otherwise, and they may believe that the medication was actually working for them. After the drug gets pulled from the market, then what? That is a rabbit hole that would be terrible to have to explain!
But here we are now with aducanumab on the market. And it has a very hefty price tag. Aduhelm currently costs $56,000 per year per patient, according to FiercePharma.
Sales not so hot? Waah waaaaaaaah. (Image)
If we were to break this down into a monthly cost (since the patient is getting monthly infusions), the medication would cost about $4670 per month per patient! Some people don’t even get paid that much per month! But we digress.
Let’s look at it this way as well.
If the sponsor conducts a clinical trial that has 2500 patients, multiply that by the $56,000 and that is $140,000,000 per year. And who does a mere one-year clinical trial? No one. In two years, the drug costs for the trial would total more than a quarter of a billion dollars - all for a drug that may or may not be beneficial and may not stay on the market.
With this price tag, aducanumab sales haven’t been looking too great. Patients certainly can’t afford to pay out of pocket, and insurance companies aren't necessarily feeling inclined to offer coverage based on the data provided thus far.
So what now?
That is yet to be seen.
Aducanumab is now facing an uphill battle, as many facilities have not implemented it yet due to the surrounding controversy. Also, because it is a new class of drugs in Alzheimer’s with shaky data, it’s also facing reimbursement issues. On the bright side, hopefully aducanumab’s story will encourage other drug manufacturers to investigate less researched disease states, and we will begin to see more drugs in the pipeline!
The pros and cons of the aducanumab approval story… which side of the fence do you fall on? (Image)