Host Nathaniel Chin, MD, gives an overview of the new Alzheimer’s treatment Leqembi (lecanemab), and highlights results from the second and third phases of its clinical trials. On January 6, 2023, the U.S. Food and Drug Administration (FDA) approved Leqembi (lecanemab-irmb) via the Accelerated Approval pathway for the treatment of Alzheimer’s disease.
In the coming weeks, host Nathaniel Chin will be joined by Cynthia Carlsson, MD, MS, and Sterling Johnson, PhD, to further discuss lecanemab and the clinical trials’ results. A link to that episode will be added here following its release.
Read the FDA’s news release regarding lecanemab’s accelerated approval on their website.
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Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.
Dr. Nathaniel Chin: Welcome back to Dementia Matters. I'm your host, Nathaniel Chin. I'm a geriatrician and the associate director of the University of Wisconsin Geriatric Memory program where I see patients who are experiencing memory and thinking symptoms. I'm also the medical director of the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention study known as WRAP, led by Dr. Sterling Johnson. This is a special episode in response to the recent FDA accelerated approval of lecanemab for people living with early Alzheimer's disease. This medication has received a lot of media coverage since the Phase 3 clinical trial results were released at the Clinical Trials in Alzheimer's Disease conference, known as CTAD, in December 2022 and again at the present moment with the FDA Accelerated Approval. I'd like to use this episode to address some common questions that may arise as you're hearing and reading more about lecanemab. I'm also excited to be doing a podcast with Drs. Sterling Johnson and Cindy Carlsson from our own University of Wisconsin Alzheimer's Disease Research Program, which you will be able to listen to or see in the near future.
To begin, the drug that we're talking about is called lecanemab, or the trade name is now called Leqembi. It is in the same family of drugs as aducanumab, which was FDA approved in 2021. That family is known as monoclonal antibodies and I will explain some of that in a bit. Lecanemab is different than aducanumab and the clinical trial results are different as well. When you read early Alzheimer's disease, what that means is people with memory and thinking symptoms plus cognitive impairment. By cognitive impairment, those are people with memory and thinking test scores that are lower than those of someone at the same age or within the same age range. Now, early Alzheimer's disease refers to people living with mild cognitive impairment and mild stage dementia. These individuals also in this study had to know that they had at least the first protein of Alzheimer's disease called amyloid for this drug to actually be effective since other diseases can cause mild cognitive impairment and dementia.
The FDA approval was based on a process known as Accelerated Approval, which means it's a conditional okay to use this drug based on the fact that it did remove amyloid protein from the brain. It is not fully approved by the FDA. With this FDA approval, insurers like Medicare won't pay for it unless you're in a clinical trial. Medicare can always change its mind but as of now that has been the position since aducanumab's approval. Now private insurers can make their own decision and certainly people could pay for it out of pocket. The approval that happened is actually based on the Phase 2 trial data and not the most recent ones that came out in December 2022. The Phase 2 trial data was also considered positive. It was done in a smaller number of people, around 800 or so, whereas Phase 3 was done in roughly 1,800 people. Now the FDA will likely review the Phase 3 trial data in the near future, in the next month or so. It's possible that the FDA may change their approval based on the results of combining these two studies or the Phase 3 study alone but that remains to be determined. The Center for Medicare and Medicaid Services, the paying agency of Medicare, will also be reviewing the data and making their own determination of coverage. CMS has released their own statement and it states that if the FDA does give full approval and not just the accelerated one, then CMS would provide broader coverage. It goes on to say that full approval will require, and I'm going to quote here, “evidence of efficacy from a direct measure of clinical benefit,” and that's the end of the quote. As you'll see going forward, this idea of clinical benefit is an important one and one that will be debated or discussed going forward. They also will have to heavily consider the risks and the benefits of this medication and how they may change over time. Some news reports have cited a yearly cost of $26,500 for lecanemab, or even $28,500. This is based on a person weighing 165 pounds, and that is because the drug is weight-based.
Now, the treatment duration of the study itself was 18 months, or one and a half years, and so you can do the math. It's unclear if people will need to be on this drug at intervals – sort of like chemotherapy, not just one 18 month period but perhaps multiple – or what the interval will be in between these periods, how long the interval treatments will be. A lot is still unclear, and so scientific study is going to be needed to determine this but also needed to determine the safety profile for people who are taking blood thinners or who have other brain conditions. The one commonly mentioned in the news is cerebral amyloid angiopathy. You have this amyloid protein but it's in the blood vessel lining and not just in the brain tissue.
With that in mind, lecanemab works by targeting soluble, toxic amyloid proteins that are in this kind of formation called a protofibril. That is important because it's not the end result. We often refer to amyloid in its plaque formation. That's when a whole bunch of amyloid comes together. It's very fixated and it's cemented sort of in the brain tissue; that is the end result but it takes a while to get to that. It starts with smaller proteins and kind of a longer protein called an oligomer and then eventually it forms this protofibril. The significance for us as potential researchers, clinicians or patients, participants is that this drug, lecanemab, is targeting an earlier part of this amyloid process. Things like or a drug like aducanumab targeted the plaque, the end result, or at least that was its primary target. Ultimately, these monoclonal antibodies work by attaching to their amyloid protein part that they're looking at and they stimulate our own immune response to then attach to those and break it down and clear it out of the body. Lecanemab is given by an infusion, so through an IV line every other week or twice a month roughly. The dose is started low and then increased over time, over the course of months probably, until it reaches its target dose. Then it's given at that high dose or target dose until the conclusion. This whole process takes 18 months. Again, we don't know what happens after the drug is stopped and that is why the scientific trials are still looking at what happens to individuals six months, 12 months, 18 months later. Some studies suggest that perhaps a medication is needed again after that but we don't know at this time.
In this trial, the one – the Phase 3 trial – the people who are involved, knowing and understanding who they are is really important because we need to know if it applies to the general public, to our patient panels, to us as individuals. The individuals included were those that were 50 to 90 years old. They had a diagnosis of mild cognitive impairment or mild stage dementia due to Alzheimer's disease. They had to know if they had amyloid in their brain and that was based on a PET scan or a lumbar puncture, and they had to have impairment on their memory testing specifically. One other important fact is you have to be able to have an MRI scan. That is because of the monitoring that is needed while on this medication, getting a good look at the structure and the blood vessels in the brain, and that can be only done right now through the MRI. Patients, or participants rather, came from North America, Europe, and Asia. This study was trying to be more inclusive than prior studies and so they have released data showing that, of the United States participants, 25 percent were Black or Hispanic. The numbers are different when you look at the whole study based on the whole international population but one other important fact is they are trying to be as inclusive as possible when it came to chronic medical conditions. They did not exclude people because they had high blood pressure, diabetes, or heart disease, or cholesterol issues, or obesity and then they were able to then see does the medication work differently in certain individuals. Again, more analysis will be needed for that.
The primary outcome, the primary goal, the metric, that they were using in the Phase 3 study was really to see if there was a change in this survey or this research tool, this instrument, called a Clinical Dementia Rating scale and, in particular, a component of it called the Sum of Boxes. I think what's important for you, as a listener or someone who's watching this, is that this is a validated tool that is commonly used in research studies. It's not commonly done in clinic. It's really asking and testing an individual with symptoms and then also asking important questions to someone who knows that individual, so this could be a family member, a close friend. We call them a collateral informant because they know them well enough to know if there's any change.
The scale itself – I'm going to go into much more detail about this with Drs. Carlsson and Johnson, but the numbers that you might see when you read this or hear about it in the news is that there was a reduction in the score of 0.452, which sounds small. However, that came to about a 27 percent slowing of decline. Statisticians have been able to translate that nicely for us, that perhaps we're prolonging a certain stage of this disease by four to six months, so someone with mild cognitive impairment might stay in that stage for an additional four to six months or the same thing with mild stage dementia. We don't know what happens downstream, what happens later in the disease. Perhaps it extends those stages as well. To be clear, this drug does not cure Alzheimer's disease. It does not stop Alzheimer's disease in its tracks. It slows the progression of Alzheimer's disease, so people are continuing to decline but they're doing so at a slower rate. That is where you're going to hear people discussing, is this clinically meaningful? Is this beneficial for the person? Is this worth the risk of giving the medication?
Now there are other outcomes, results that the trial was looking at. Again, this is the Phase 3. One in particular, the important one, amyloid PET scan. This is really to show, does the drug actually remove amyloid from the brain? In fact, it does, and I will be asking Dr. Sterling Johnson for more details about that. It did show that when people came in they had a higher amount of amyloid and it reduced that amount pretty significantly over 18 months. In fact, it reduced it even at the six month period, and for some individuals it reduced it below a detectable threshold, what we would consider to be even amyloid positive. It looked like it was very successful at doing it. It didn't do it for every single individual. Looking at the results that they've shared, 68 percent of people went to that lowest threshold, that largest amount of removal, but not everyone experienced that benefit.
There were other outcomes that the study looked at and these are more clinically relevant. Dr. Cindy Carlsson will speak to this in more detail, but three of those outcomes that I just wanted to highlight for you are that one of them – again, a survey instrument – was looking at cognitive symptoms, which for those with impairment know that this is a really meaningful outcome because you would prefer to not have the symptoms. It showed a reduction in the decline. So again, people are noticing more symptoms but there's less of a decline in those individuals on lecanemab. Again, this was noticed at six months, as well as at 18 months. There is a combined scale that we will talk about called ADCOMS and this is looking at both cognition and function. Again, at six and 18 months there seemed to be a reduced decline in the report of both cognitive and functional change. Then lastly, there's a functional scale that is commonly used in research that also showed a slowing of decline. Actually in this regard it's 37 percent slowing at eighteen months, which seems significant and again will be discussed by experts in the field. Certainly I will be asking Dr. Carlsson more about that.
Other biomarker results were looked at so not just amyloid PET scans but tau PET scans, spinal fluid analyses, and blood tests. These are all very important biomarkers to be studying in a research setting. Potentially we will be translating this to the clinical setting. Many of them show what was not only statistically significant but positive, that people had improved results, however you want to look at that. Some of them were equivocal but trended to look better. We'll find out more about that from Dr. Johnson, but I did want people to know this idea of a downstream effect seemed very real. Removing amyloid with this drug seemed to affect processes that we commonly see later on afterwards in people who are developing the disease or declining overall.
Clinically there were other aspects that the study looked at, which I think are really important as a geriatrician and someone in a memory clinic. One of which was the quality of life experienced by the participant, the person with symptoms. That showed a 49 percent to 50 percent less of a decline in quality of life. For the caregiver, the person who's also involved in this process, there's a questionnaire called the ZARIT Burden Inventory and that showed that there was 38 percent less decline in the caregiver burden. There's less burden, I should say, and then also less of a decline in caregiver well-being. These are meaningful, important things to consider and that were looked at by the study.
Now not everything is about benefits. We also have to talk about risks. The most common one that you will read about is called ARIA – Amyloid-related imaging abnormality. It's a mouthful, but what that is and what that's been shown in clinical studies is there are two components to this. It is seen both in imaging but also potentially reported by the person in the study. One is called ARIA-E for effusion or edema. That's swelling that occurs in the brain that can be seen on an MRI scan. The other one is ARIA-H, standing for hemorrhage or small bleeding that occurs in the brain. That also has made the news depending on potential adverse effects for some of our some of the participants. When they look at the statistics of this, what the percentages are, those that we're taking lecanemab had – 12.6 percent of them had ARIA-E, so the effusion, whereas 1.7 percent that were on the placebo, not the medication, also developed the ARIA-E. They were saying that of those that developed this, most of them were mild or moderate based on the imaging itself. 78 percent were asymptomatic, so the participants didn't even know that they were having this. The common symptoms though, if they did experience them, were headache, visual disturbance, and confusion. Pretty significant still. For those with hemorrhages – now just looking at the hemorrhage itself – if you on lecanemab, 8.9 percent developed ARIA with hemorrhages and 7.8 percent on the placebo. That's not as huge of a difference but it's still a large number and so we have to be considerate of that and make sure that a medication like this is appropriate and that we are weighing the risk of this along with the benefit.
What they found that was seen in other studies, but also important to know, is that for ARIA-H, for the bleeding in the brain, it happened more often in those that had ApoE4. That's the genetic risk for developing Alzheimer's disease and so that perhaps suggests that people should know their genetic risk before they receive this medication. That, too, is going to be discussed and debated, but it is a consistent finding. So having that genetic risk – it doesn't mean you cannot receive that medication but perhaps that increases one's risk for bleeding.
Other things were looked at for safety – blood work, EKGs of the heart, and vital signs. There was no difference between lecanemab and the placebo. The other most common reaction was called an infusion-related reaction. They said 26.4 percent of those receiving lecanemab experienced that versus 7.4 who were on the placebo. That’s almost a fourfold increase. 96 percent who experienced that reaction, it was considered mild or moderate. It mostly happened just in the first dose and it seemed not to happen in subsequent doses. However, those are real symptoms and so people who have not experienced that just so you know this is considered a headache, nausea, vomiting, flu-like symptoms, fever, chills, decreased appetite and so that is what was commonly reported.
That's where I'm going to stop. I'm going to defer the other really important aspects of this discussion to Drs. Cindy Carlsson and Sterling Johnson when I interview them next on the podcast. I'd like to conclude by really sharing that I feel like this is a very exciting time in the field, whether you think this medication should be approved or not. It certainly shows that removing amyloid can be done and that there are potential positive ripple effects of that when you look at other biomarkers and you ask people who receive the drug and those who are close – the caregiver or family member. The current approval by the FDA is conditional, meaning Medicare will only pay for it if you're in a clinical trial or if you have private insurance, you pay out of pocket. We have not received the full approval. That has not yet been determined although the FDA and CMS, Medicare will be reviewing the full data from the Phase 3 study in the near future. The idea of clinical meaningfulness is one that will continue to be discussed and debated and one that we really need to determine both as clinical organizations but also in the research field. Certainly at the end of this, the landscape is changing. These medications are here and, for good or bad, these are important things for us to be considering and talking to our clinicians about, talking to our researchers about. It is going to require a lot of infrastructure change within healthcare and certainly even within clinical trials. I'll be asking Drs. Carlsson and Johnson about that.
I'd like to end with a feeling that I think many of my listeners already know; this medication doesn't change the importance of living a healthy life, so the things that we still have control over regardless of medications – exercise, healthy foods, good sleep, being mentally stimulated, socializing with others, feeling supported, reducing our stress, addressing hearing loss, addressing vision loss, addressing our chronic health, certainly addressing our mental health especially now. These things matter and they continue to matter. They will always matter regardless of the medication. We can do something about that now while we're waiting for FDA and Medicare approval. I still believe that is the foundation of our care, that is the foundation of our well-being. I encourage everyone to really think about that, especially in the new year, that there are things we can do now while we're waiting. Let's optimize our brain. Let's live the best lives possible and when we need help, let's get that help. With that, I'd like to thank you for listening and I certainly hope you tune in again when I meet with Drs. Carlsson and Johnson.
Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin--Madison. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode of Dementia Matters was produced by Amy Lambright Murphy and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at firstname.lastname@example.org. Thanks for listening.