On July 6, 2023, the U.S. Food and Drug Administration (FDA) granted full approval to lecanemab, marketed as Leqembi, for the treatment of Alzheimer’s disease. The University of Kentucky’s Sanders-Brown Center on Aging has been working with this drug and others like it for more than a decade.
In January, the FDA approved the drug via the accelerated approval pathway for the treatment of Alzheimer’s disease. Its move from accelerated approval to traditional approval makes it the first disease-modifying therapy approved for the treatment of Alzheimer’s disease in the United States. This marks what researchers believe is a huge step towards finding a cure for the disease.
Greg Jicha, MD, PhD, director of clinical trials at Sanders-Brown, answered some common questions about the drug following its full FDA approval.
Question: How does the drug work?
Dr. Jicha: So that is very, very important. We know that in Alzheimer’s disease, the process begins with a buildup of amyloid that forms plaques in the brain. That is followed by the development of neurofibrillary tangles, then the nerve cells die, and we start to have memory problems. At the heart of this is this early buildup of amyloid.
So, the thought process has been if we can get rid of that amyloid then we should be able to slow or stop Alzheimer’s disease. Lecanemab is an antibody made in a pharmaceutical plant that directly binds to and allows the brain to remove the amyloid that is building up in a patient with Alzheimer’s. It does this to the point where it becomes completely undetectable by about 12 to 18 months.
We’ve really been trying to balance how effective we are at removing amyloid with the safety of the medicine. That balance really was achieved here. The validation of that is this eventual FDA approval, that not only do we remove amyloid from the brain — but it actually has a clinical impact — with a slowing in the clinical trials of about 27 percent to 40 percent, slowing of the disease process.
I wish it were a cure. We’re not there yet. But this is the first medicine — ever — that actually changes the disease in the brain. It removes a component of the disease and can extend quality of life for patients who are developing and who are in the early stages of Alzheimer’s disease.
Question: Since this is the first medicine of this kind, when do you see a potential cure coming? Is that still far away? Or is that something we could see in our lifetime?
Dr. Jicha: We are going to continue to work. We are not going to give up, we are not going to rest on laurels. This is the beginning, it’s the first crack in the wall.
Now, we’re really approaching this issue of Alzheimer’s in in a two-pronged approach. First, are there other medicines and many of them in development that we need to add to? So we are beginning to think about elimination therapy trials where we started to use medicines and attack the tangles in conjunction with these medicines that can remove plaques. The other is, what if we can remove the plaques even earlier? What about if we looked at people long before they have memory problems before they develop tangles?
I suspect in the next decade or two, Alzheimer’s will become a thing of the past. If we can get everybody educated on it, get early detection and early intervention. But it’s not going to happen overnight. It’s going to require a lot more work a lot more elbow grease, a lot more people standing up joining the fight, and really working to make these discoveries a reality in day in day out medical care for patients around the globe.
Question: What did the 18 months of treatment in this clinical trial look like for patients?
Dr. Jicha: It is a lot of work to receive this medicine. Right now, this medicine is an intravenous infusion. So to receive the medicine, the patient needs to come in every two weeks to a medical center, have an IV placed and receive an infusion that takes about an hour. That is a big commitment every two weeks.
In addition, we do have to monitor for safety with regular examinations, blood tests, frequent MRI scans, and brain imaging studies to make sure that we’re not developing any problems or creating any side effects.
We do have several folks that have been on the medicine for years now and so we’ll get those answers about long-term use soon. Certainly, a lot of work put into it, but potentially a lot of benefit coming out the other end.
Question: Who is eligible for lecanemab? And do you see it being more effective and certain groups than others? Can anyone with a diagnosis talk to their doctor now about getting this?
Dr. Jicha: This medicine is not going to be for everyone, and the FDA and the Center for Medicare Services have made that quite clear. In the approved package label that was released, this medicine is only for those with mild memory problems — what we call mild cognitive impairment. Or for folks that are in the mild stage of Alzheimer’s. Once the disease progresses to a more moderate or severe stage, we no longer understand if there could be benefit or not. The benefit is probably dramatically reduced and the risks potentially increased at later stages of Alzheimer’s.
It’s also important to note that people that are at risk for Alzheimer’s disease, the medicine is not approved for them either. We are working still in experimental clinical trials, to test the medicine in folks that are normal, but clinically at risk because they have a family member or other risk factor for Alzheimer’s.
To prescribe the medicine, doctors are going to have to verify that there actually is a buildup of amyloid in the brain. There are currently only two ways to do that. One is with amyloid PET scans, which we use in research a lot and are FDA approved, but currently not covered by Medicare. The other is to check one’s spinal fluid which is typically covered by insurance. It’s a very easy test to do and it’s highly reliable, to tell us whether or not there’s a buildup of amyloid in the brain.
Question: What side effects or concerns have been seen with this medicine?
Dr. Jicha: If we remove the amyloid too rapidly, it can cause swelling in the brain or bleeding into the brain. We call these amyloid related imaging abnormalities (ARIA). We look with MRI scans for evidence of either of these, and if one has evidence that they have previously had significant bleeding in the brain, they would not be eligible for the medicine either because their risks of receiving it and having a repeat bleed would be too great.
I do think that I that it’s important that in the package label and from the FDA approval as well as CMS, they’ve come out quite strongly that centers or health care facilities that are going to administer this medication have to demonstrate expertise and the ability to monitor for safety.
Here at UK, we’ve been working with this particular medicine and with medicines like it for well over a decade, almost two decades when we take into account medicines like this and have a wealth of experience here. That has been very helpful for us. While we have had folks at times develop swelling in the brain, and or microscopic hemorrhages in the brain, we’ve been able to see that on the MRI scans, hold the medicine for a few weeks, a month or so, let the brain return to normal and then resume the removal of amyloid. It does require a partnership and a clinical team that’s well experienced to keep folks safe. I think that’s the biggest issue.
Across the board there, have been three deaths associated with this medicine during its clinical testing which took place at numerous sites throughout the U.S. and involved around 1,800 people. Those deaths, primarily associated with people who have received anticoagulants, which are very strong blood thinners or medicines for the removing blood clots in the acute setting of stroke. So again, folks do need to understand that when we do see bleeding in the brain even though it’s typically microscopic or if you’re on a blood thinner, that could turn into a big bleed. A lot of caution, a lot of expertise is going to be needed to make sure that people stay safe.
Question: How early can lecanemab be used to mitigate symptoms? How late it could be introduced before it’s no longer effective?
Dr. Jicha: The beginning of early memory problems is an appropriate time to evaluate and to potentially prescribe this medication. The latest that we would prescribe it is once one enters a more moderate stage of disease. Typically by moderate stage of disease, we’re looking at folks that are having trouble getting dressed and performing more basic activities of daily living. We have a pretty good range in the early stage of disease and the goal of the medicine is to keep people doing well. For a patient in this range, this is valuable time.
Question: How do you feel this treatment compares to others currently being used to treat Alzheimer’s?
Dr. Jicha: There are four that are commonly used. These other approved medicines for Alzheimer’s are not disease modifying, they don’t change the plaques and tangles. They don’t stop nerve cells from dying, but they do provide symptomatic benefit. So the medicines are not really comparable, because they work in completely different ways. We would use the medicines in clinical practice together. So, we would still continue to use our traditional medicines to help with the symptoms of memory and thinking. Then we would simply combine it with the new medicines, trying to remove that amyloid and slow down the disease process.
Question: What does the full FDA approval mean for your research on this drug going forward?
Dr. Jicha: I already mentioned one avenue that we’re looking at is looking at folks over the age of 60-65 that are still normal with memory. We know that that buildup of amyloid can occur 10 to 20 years before memory problems occur. Whether or not we can remove amyloid at that stage and prevent Alzheimer’s from ever really taking hold in the brain. That is a major study with this medicine funded by the National Institutes of Health the National Institute on Aging, called the AHEAD study.
The second area of investigation that we’re exploring currently is whether or not once we remove the amyloid from the brain, we can allow folks to do self-injections at home. Just like someone with diabetes might inject insulin at home. Many of the folks that have been in our clinical studies now have the opportunity in ongoing clinical studies to receive the real medicine at home, so they don’t have to drive to Lexington every two weeks.
Question: Does this approval mean that Medicaid and other insurances will cover the treatment or will it be out of pocket?
Dr. Jicha: Medicare has already made it quite clear that with FDA full approval, they are going to cover the medicine. Now people do need to be aware that there may still be a copay, your standard Medicare copay, especially if you do not have a Medicare supplemental plan that covers your copay. So that’s very, very important. Typically, if Medicare covers it, Medicaid covers it, and almost every third-party insurer will cover it.
So, we really do think that this is an opportunity for widespread use of the medicine where people should not be restricted on the basis. I hope that we hear about supplemental patient assistance programs coming from the pharmaceutical company behind the drug. I would really like to see that and have for our folks that may not be able to afford a copay have that fee waived. Because I really think it behooves all of us to ensure that this medicine is accessible to everybody, no matter what their socioeconomic status, no matter what their geographic limitations are.
Everyone who has early Alzheimer’s disease deserves the opportunity to receive this drug as long as the medicine is going to be safe for them. I’m really, really excited right now with how the stars have aligned for us to really begin to impact Alzheimer’s disease.
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG054029 and R01AG061848. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The AHEAD study (Clinical Trial number NCT04468659) received funding from NIH and from nongovernmental sources.
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