In a special episode of Dementia Matters, Drs. Cynthia Carlsson and Sterling Johnson join the podcast to discuss what they know from lecanemab’s clinical trials following the U.S. Food and Drug Administration’s (FDA) accelerated approval, granted on January 6, 2023.
Guests: Cynthia Carlsson, MD, MS, director, Wisconsin Alzheimer’s Institute, and Sterling Johnson, PhD, leader, Wisconsin Registry for Alzheimer’s Prevention (WRAP), associate director, Wisconsin Alzheimer’s Disease Research Center and Wisconsin Alzheimer’s Institute
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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.
Disclaimer: Before today’s episode, a quick disclaimer. The statements from Drs. Nathaniel Chin, Cynthia Carlsson and Sterling Johnson do not reflect the opinions of the University of Wisconsin–Madison, UW Health or the Veterans Affairs Healthcare System.
The University of Wisconsin–Madison is one of 100 locations worldwide that are a part of the AHEAD study and one of approximately 63 sites across North America that are a part of the A4 study. Both are clinical studies of the investigational treatment lecanemab in people who may be at risk for memory problems. Dr. Carlsson serves as the principal investigator for the AHEAD and A4 studies at UW–Madison, and Drs. Chin and Johnson serve on the study teams. The AHEAD study is funded by the National Institutes of Health (NIH), in partnership with the pharmaceutical company Eisai, and is being conducted by the NIH-funded Alzheimer’s Clinical Trial Consortium (ACTC). The A4 study is funded by the National Institute on Aging (NIA), NIH, Eli Lilly and Company, and several philanthropic organizations. Read more about the AHEAD and A4 studies in the episode description.
Dementia Matters and Drs. Chin, Carlsson and Johnson receive funding from the National Institute on Aging (NIA) and the National Institutes of Health (NIH). Dr. Johnson has served on advisory boards for Roche Diagnostics, Prothena, Merck and Eisai in the past two years. He receives research funding to the University of Wisconsin from Cerveau Technologies.
Dr. Nathaniel Chin: Welcome back to Dementia Matters. On today's episode, I'm following up on a conversation I started back on January 17 regarding the FDA Accelerated Approval of the medication lecanemab. For those who have not listened to that episode, I encourage you to do so as we will be going more in depth on this medication now, particularly the results of the Clarity AD clinical trial which featured lecanemab. While the FDA Accelerated Approval was not based on the results we'll be discussing today, the findings are critical in helping the scientific field, the FDA, and Medicare determine if this medication is clinically meaningful, a phrase I think you will be hearing a lot of in the future. Joining me today to discuss this clinical trial and new drug are two returning guests, Drs. Cynthia Carlsson and Sterling Johnson. Dr. Carlsson is the director of the Wisconsin Alzheimer's Institute, as well as a professor, geriatrician and Alzheimer's disease researcher at the University of Wisconsin School of Medicine and Public Health. Dr. Johnson is a professor, clinical neuropsychologist, leader of the Wisconsin Registry for Alzheimer's Prevention study, known as WRAP, and the associate director of the Wisconsin Alzheimer's Institute. Thank you both for joining me on Dementia Matters.
Dr. Sterling Johnson: Thanks Nate. It's good to be here.
Dr. Cynthia Carlsson: Thank you, Dr. Chin.
Chin: Oh, Cindy, you can call me Nate. (laughs)
Carlsson: (laughs) Thank you, Nate!
Chin: So Sterling, let's talk about the results of Clarity AD. For our listeners, there's one primary outcome or endpoint and then there are multiple secondary outcomes, but the primary outcome is an important one and a very important one in improving the efficacy of a drug and the one that's often talked about, although I would argue the secondary outcomes are very important too. What was the primary outcome, Sterling, and what was this result?
Johnson: Thanks Nate. For this study, they chose the Clinical Dementia Rating as their primary outcome. There's a particular measure from this called the sum of boxes, which is just as it sounds. It's adding up the points on this rating and reporting out those points. When they did that, they showed that the treatment group on lecanemab slowed down their rate of change on this – on their score, on this Clinical Dementia Rating sum of boxes. They slowed down by 27% versus the placebo group that did not get the therapy.
Chin: Cindy, can you briefly explain this concept, this tool – the sum of boxes – and tell us what is meant? Sterling mentioned 27% reduced decline. The number .452 is also mentioned as a part of the score. Can you explain that to us?
Carlsson: Yeah, so with these studies, what they try to do is to get a kind of a full picture of the person's function. This Clinical Dementia Rating scale looks at six different domains, so it looks at memory, orientation, their judgment, how well they're able to problem solve, how they function in community affairs, how they function at home and in their hobbies, and then their personal care. There's different areas. They ask the participant or the patient and the family member or caregiver or someone who knows the person well how well they're doing in these. It's a very standardized approach and then trying to see how well people are functioning in these different areas. With the lecanemab therapy, again this sum of boxes improved, so kind of the sum of all these added up or improved by about .5. So that reduction – again, people are questioning, is it that clinically meaningful? But again, some of the ratings – to go from mild impairment to questionable impairment or to go from moderate impairment to benign forgetfulness can be within that range. Again, I think each person's different how they would interpret how clinically meaningful this was but for some people it may be clinically meaningful. You know, it could be clinically meaningful to them or to their family members. Both groups are still declining because they do still have Alzheimer's disease. The drug doesn't stop the disease but it slows down the progression.
Chin: And thank you for emphasizing that last point too. Just for our listeners, this is not a cure for Alzheimer's disease and people are still progressing but they are noticing less change based on being on this medication versus this placebo. That was the primary outcome. Sterling, one of the secondary outcomes dealt with amyloid PET scans. Can you tell our listeners, what were they looking for and was it significant what they were finding?
Johnson: Yeah, this is a great question. This drug is an anti-amyloid kind of a drug and its target is the amyloid plaques in the brain. The experiment looked at amyloid in the brain and the way they could do that was with PET scans. These are really a fancy way of doing imaging that is very specific to imaging the amyloid plaques in the brain if in fact amyloid is there. That was an entry criteria to being in the study, so we know that everybody had amyloid in their brain who was in this study. The experimenters used this scale called the Centiloid scale. It's kind of a play on words of the centigrade temperature scale which goes from zero to 100, zero being where water is frozen and 100 being where water boils. Those are the reference points. For the Centiloid scale on this amyloid PET scan, zero means you don't have any evidence of amyloid and 100 means you have a level of amyloid that's very much like others who have dementia due to Alzheimer's disease. In this study the average Centiloid was about 75, which is about three quarters of the way there to being an AD-like level of amyloid plaques in the brain. What the study did was, by targeting amyloid, it lowered the amount of plaques in the brain from this starting point, on average of 75, 59 points, down to an average of about 18. This was over a period of 18 months
Chin: And so, is it abnormal then? I mean you've said 100 is an abnormal Centiloid, like that's what someone with dementia with Alzheimer's disease. Is there a lower threshold, though, that one would consider, okay now you've technically amyloid-elevated. And then my second question to you –
Chin: – is in removing amyloid, do you have to get to that level, do you think?
Johnson: Well, the group level data show that nearly everybody declined who was on the treatment. In fact, as a group, they declined by 59 points, from 75 down to 18. What was intriguing was this particular study used a threshold of 30 as their cut point or their threshold, so to speak, of being amyloid positive. After 18 months on the drug it seems like not everybody but a good chunk of these people were below that level of 30 Centiloids. One year, it was 54. I don't recall what the number was at the end of the trial but it was a substantial number – oh it was 68% actually became normal based on getting below this 30 Centiloid level. So that's pretty pretty remarkable. Most people were reverted to normal by this drug.
Chin: And so, Cindy, in addition to amyloid PET scans there were other really important secondary outcomes. Can you go over a few of these and what the results were?
Carlsson: Yeah. Again, the study really tries to look at a variety of factors. They look at things that are important to see if the drug's working, so things like amyloid levels in the brain. They look at things like does it help them think better, so looking at cognitive outcomes. Then the fuller picture, does it make a difference on their quality of life, how well they're functioning, so things that we really care about as people who may be living with this disease. Again, the primary outcome was this Clinical Dementia Rating scale but they also had other measures. Another measure was the Alzheimer's Disease Composite Score that looked at cognition and how it relates to function. There's another Activities of Daily Living Scale too, that looked at more functional outcomes. There are a variety of measures that showed that not only did it, again, improve how much amyloid there was in the brain but also it improved their daily function. It also improved their thinking abilities across a variety of types of thinking abilities. That's partly what made this study more exciting is that there was consistency across these things. Instead of just saying the one measure of amyloid in the brain improves without any impact on the person, this study shows that there was consistent improvement in a lot of these measures.
Chin: And so, Cindy, I'm going to ask you a tough question but as a physician in a memory clinic who treats people living with thinking changes and who works with many other disciplines in doing so, do you think your colleagues and the patients that you see – would they find these results clinically meaningful?
Carlsson: I think there are some patients who would find this clinically meaningful. I think they really want to keep – protect their cognition, protect it from declining at all costs. So I think there's other decision-making that's going to come into play, so the clinical meaningfulness and also how the person views their time. Do they want to spend every two weeks coming in to get a therapy? Some patients don't want to see their doctor every three months because it's too much time taken away from gardening or fishing or other things they're enjoying. I think it's going to not only be a matter of do they think it's clinically meaningful but is the benefit enough to counteract the time it is going to take them to have the infusions done? I think some clinicians say it's not very clinically meaningful. Others say we don't have anything that's better and that they're encouraged. Some people are encouraged by the continued improvement over time for the duration of the study. Will it have even more effect after 18 months? Those are questions we don't know yet.
Chin: I appreciate your answer because certainly risk benefit is something that matters a great deal. I'm sure Medicare will be thinking about that too, but then also cost-benefit. Cost doesn't have to be money; cost can be time and the hassle factor. It's not something I had considered so thank you for sharing that. There were other biomarker analyses that were done in addition to the amyloid PET scan. Sterling, can you just provide a brief overview of some of the other key findings from the study?
Johnson: Sure yeah. Our field really has several biomarkers now that are indicative of AD or indicative of having neuronal damage happening in the brain as a result of AD. This study looked at something called Aβ42/40 which is something you can get out of the spinal fluid or also out of the plasma. It's an indicator of the amount of amyloid that might be present in those fluids. That measure became more normal-like with treatment of lecanemab. Similarly they measured something called p-tau181 both in the spinal fluid and in plasma in the blood. They found, also with that, that it normalized it. It became more normal-like or it was reduced with treatment I should say. Then they also looked at another PET scan called a tau PET scan. What they found with that is that the people on the drug had lower levels of tau especially in the temporal lobe, which is the area that's most concentrated for tau proteins on these PET scans. They looked at a few other things too, measures of neurodegeneration. One is called Neurofilament light. One's called GFAP, which is a measure of astrocyte function. Then there was finally one more called neurogranin, which is another measure of how well the neurons are functioning and how well the synapses are communicating. They found some mixed results with these. The Neurofilament light measure didn't really change all that much. It was a slight trend that wasn't significant. The GFAP, which is this measure of inflammation-related change, improved significantly on lecanemab. Neurogranin, this measure of synapse function and how well neurons are communicating, that also improved. There was one other measure they did which was MRI, just looking at the – quantitatively at the amount of brain tissue before and after treatment. What they found was a little bit curious. They found that there was slightly more atrophy in the group that had the lecanemab treatment. We don't know why that is. I think there'll be lots of research on this over the next coming months and years to help us understand why there would be this kind of paradoxical effect.
Chin: That's helpful for our listeners to understand, if they weren't familiar with this particular clinical trial or clinical trials in general. It's not just about amyloid protein or even tau protein. There are other mechanisms or pathways of thinking change that these studies are looking at, inflammation being one of them. What does all that mean though, when you think about all of these biomarkers either showing this expected result of change, reduction in change, or even trending in that way, what does that tell you about the amyloid cascade hypothesis or or this ATN framework of amyloid, tau and neurodegeneration?
Johnson: I think when you look at the overall pattern here, the overall preponderance of the evidence with the primary outcome being kind of clinical cognitive symptoms and the secondaries being other cognitive symptoms and Activities of Daily Living and the biomarker evidence, all of this is pointing to a drug that looks like it's working. It was most pronounced – the most pronounced effect looked like it was on amyloid. I think that means that it's engaging the target. It's actually finding the amyloid plaque that's in the brain and reducing it. That seems to be the narrative that I'm seeing. As a result of that, here's a reduction in symptoms. It's not complete, but at least there's a significant difference in symptoms and in these other biomarkers on this drug. I think the preponderance and overall pattern here is that we have a favorable profile with this drug that looks like it's truly modifying the disease. It's not stopping it but it's modifying it and that's really, really incredible.
Chin: Now, Cindy, you hinted to this earlier in one of your answers but there are researchers talking about potential cumulative effects of disease-modifying therapy, just the way Sterling mentioned it. What does that mean though, a cumulative effect in a drug like lecanemab?
Carlsson: Well these types of studies are short, short studies. Again, they're studying people over an 18 month period of time and obviously many people with dementia due to Alzheimer's disease are going to be living beyond that, so they’re trying to figure out what's going to happen beyond the 18 month period of time. Sometimes we'll have additional information from what they call open-label extension components of the studies where people are able to get the true medication beyond the duration of the study but sometimes they have to kind of guess what would happen if we kept the person on the study for four years, five years, etcetera. Because of the way the graphs look and the results look so far, it looked like people were continuing to have improvement in cognition and in these functions and their quality of life. So because – again, both groups are declining but the group that's declining without the medication is declining at a faster rate. Again if there's greater effect down the road then, for example, they're estimating that there may be a preservation of about seven months of time of cognitive – stabilizing the cognitive function of someone. How clinically meaningful is that to have seven more months of preserved cognitive function? If that seven months includes your granddaughter's wedding or other big life events, that might be clinically meaningful for someone. They also, again, may progress to the next stage of dementia at a later point in time. Does that mean they can stay home longer, that their family can support them longer in their own home setting? Those things are sometimes really important questions for patients and families. You know, we know that institutionalization, which is when someone moves from home to a nursing home or a higher level of care, varies from person to person. You have a patient who happens to live next door to his daughter who's a nurse and his son’s an EMT and they've been in the neighborhood for 50 years and know everyone – that person might be able to stay in their home longer than somebody who maybe is new to their surroundings or doesn't have as many children nearby. It's not just the fact of the drug on the person that's going to determine if someone moves to higher level care but if the drug can help keep that person in their home setting then that's valuable to patients, families, and economics as well, the cost of providing care for people with dementia.
Chin: Well and you're leading me to my next question, which is that the study did look at other things such as well-being and quality of life. What did they find, Cindy?
Carlsson: Yeah, so they found that quality of life did seem to improve. Another thing which influences the care of the person with dementia is the care of the caregiver, so the person who's caring for that person. If they feel less stressed because the person's doing better. They're thinking better and able to engage in their own cares better. Maybe they're sleeping better. So if the medicine helps with some of those aspects then the caregiver may be sleeping better and functioning better, so their what we call caregiver burden is less. They did some measures on a Zarit Caregiver Inventory Scale that looks at some of those factors. That seemed to improve as well, so a lot of different factors moving in the right direction, which is encouraging.
Chin: Sterling, can you tell our audience what subgroup analyses are, just in general, and then why they're done in a study?
Johnson: Yeah, subgroup analysis is when you just look at a subset of people who are on the treatment or the placebo. You look at those individuals to see if there was a difference there. An example would be looking at older people versus younger people in the trial or men versus women.
Chin: Well, you kind of took my thunder with this question though, Sterling, because the reason I'm bringing it up is that in the news people are commenting that lecanemab may be more effective in older people versus younger people and in men versus women. From your scientific perspective, should we be looking at this cautiously and why?
Johnson: Well, these subgroups are really important for raising questions for further study. We have a habit in our field of looking at subgroups because we've had, what, two decades of negative trials. We've squinted at these little subgroups of certain demographics to see if there was any glimmer of hope in any of these subgroups. That's kind of been our habit as a field to try to learn from these failed trials over the years to see what the next trial might look like. In this case, the study was not really – they didn't plan on these things ahead of time. They – these studies are after the fact and so there's not enough statistical firepower, if you will, to really have confidence in any of these subgroups. What they do is, as I said before, they just raise questions for the next study where we might want to look at men versus women with more intention on that in the future or older versus younger subjects with more intention of balancing those groups and really having a proper study on age. That's a question that we can now ask and maybe the next study will answer it.
Chin: So instead of conclusions, these things should raise more important scientific questions.
Johnson: Yes, yeah.
Chin: So Cindy, you talked about risk benefit, cost-benefit. I'd like to talk a little bit about safety of the medication, particularly ARIA. I did go into some ARIA in my introduction episode from January 17, but I want to hear from you with a little bit more data that you have. How did lecanemab do in this regard?
Carlsson: Right. So again, people have raised the questions, rightly so, as that lecanemab does have side effects, and some of them are very serious. Again, having good conversations about the side effects is really important for clinicians with the patients. That's going to go into the decision-making. ARIA are these amyloid-related imaging abnormalities that you've talked about before. There’s two types. There's one that's called hemorrhagic versus edema, so you have the -H versus -E. Hemorrhagic is more of the microhemorrhages, so tiny mini bleeds, and then the edema is just little bits of swelling in the brain. Calling them the eye of the ARIA means that they are imaging. These are things that we see on the brain's scan. Not all of them does the person with these changes experience any symptoms of those. Again, we have to distinguish between what are we just seeing as kind of incidental findings on brain scans versus what are causing symptoms in the person that's going to affect their day-to-day life. With ARIA, they broke it down into the edema and the hemorrhage, or the microhemorrhages, the mini bleeds. What they found was that about 12.6 percent of people in the treatment group compared to 1.7 percent in the placebo group, or the ones without active medication, had the ARIA that had little edema with it, so the ARIA-E. Again, a very small percentage of those had symptoms so it was only 2.8 percent of those who were on the treatment had ARIA-E with symptoms and none of the participants on placebo did. Again, it's not very common unless you have the medication. The hemorrhagic findings, about 17 percent of people who are on the treatment had the ARIA-H and about 9 percent in the placebo group had the ARIA-H so just to know that the amyloid itself in the blood vessels can lead to little microbleeds. Just having the disease in and of itself can lead to microbleeds, so that's why we're seeing some of these changes in a placebo group as well as a treatment group but a higher percentage in the treatment groups. Again many of these were not symptomatic either. If you look down at the symptomatic – the people who were symptomatic of the microbleeds. It was extremely small, like .7 percent in the treatment group and like almost .2 percent in the placebo group. A lot of these factors have to be taken into context for, you know, did they have edema – the ARIA-E – with them or ARIA-H? Were they just on the scan? Did the person have any symptoms with that? Kind of teasing apart a lot of those factors. The other thing that influences it is that people who have a genetic risk called apolipoprotein E epsilon 4 or ApoE 4, something that increases our risk but doesn't necessarily mean for sure we'll get dementia. The ApoE 4 carriers tended to have a greater risk of having some of the hemorrhages and the edema, so had more side effects. Again, as people are coming into these trials a lot of times for these studies they're doing genetic testing to see are they more prone to getting these side effects. That'll probably become part of clinical practice, is that you may have to screen to see what their genetic risk factor is so you can decide what's your risk of having one of these microbleeds versus a micro edema and causing you symptoms where you would have some clinical consequences.
Chin: And it's a very unfortunate reality that ApoE 4 increases risk for having Alzheimer's disease and that's the population we're trying to help with this drug but then you're also at a higher risk of just having some of the side effects. It does seem like an important piece of information for people potentially to know in the context of therapy, but it's good for us to be able to identify these things. Moving on from that, Cindy, I was hoping you could share with us how Clarity AD did as far as representation of the people who were actually in the study.
Carlsson: Yeah. It's one thing that clinical trials across the board but especially Alzheimer's disease clinical trials have not done a good job of is making sure that the people who are included in the clinical trials are representative of those who are at risk for developing dementia due to Alzheimer's disease. Again, for a variety of reasons – probably a lot of social determinants of health – persons who are from African American descent or persons who are Hispanic, Latino background and Native American have higher risks of developing dementia to Alzheimer's, but yet they tend to be very underrepresented in these clinical trials. This study made a concerted effort. Again, they did the study internationally so they had participants from North America, Europe, Asia. Obviously they had the larger Asian population, but within North America they were able to increase the number of Hispanic participants and slightly increased the number of African Americans. They had about 12 percent who were Hispanic. It was about two to three percent who are African American, then the larger Asian population chiefly from the cohort in Asia. So again, the representation was improved but still not where we'd liked it to be because we want to make sure that people from different backgrounds who have different constellations of risk factors, vascular risk factors and other things, are represented so we can see if these drugs are safe and effective in these different kind of subgroups of individuals.
Chin: We've talked about the results, the primary results, the secondary outcomes. We've talked about the significance of those as well as the potential side effects and the people being studied. That's all within – that's all being reviewed by the bodies that determine approval. Sterling, what happens next? Where do we go from here?
Johnson: Yeah, that's we're all waiting to know what's going to happen with these reviews, but it's in the FDA’s hands, like you said. They're reviewing the line item data and going over everything with a fine detail and they'll make their decision sometime in the late spring or summer of 2023. Then the Center for Medicaid Studies – that's the wrong word. What's the right word for this?
Chin: Services, right? Center for Medicare and Medicaid Services.
Johnson: They will also be reviewing this, probably after the FDA makes their decision. The Center for Medicare and Medicaid studies will be reviewing this as well and they'll be making decisions about whether this can be administered clinically and then whether it'll be reimbursed. It's an exciting time.
Chin: A lot but a lot of waiting going on here and so we'll make sure to provide updates as things happen. To end, Cindy I'm going to ask you another hard question and that is, let's say everything moves forward, the approvals happen. What actually needs to happen within healthcare in order for this medication to reach a patient?
Carlsson: That's a great question. A lot of discussions are happening around this because right now dementia's underdiagnosed in our country. You know, there's estimates that about 50 to 60 percent of people with dementia are diagnosed. Biomarkers are not widespread use – do not have widespread use in clinical practice so a lot of clinicians are not comfortable using biomarkers, using these amyloid PET scans or CSF levels or blood tests to decide if someone has elevated amyloid to see if they're eligible to get the study drug. Then so from there, again, improving diagnoses, improving understanding how to use biomarkers, and then from there the clinicians have to understand who's a good candidate for this. What is their ApoE genotyping? Do they have other risks for cerebral hemorrhages? There's questions about whether someone on anticoagulation should get this medication. Then they have to be able to have enough infusion centers for people to come in every two weeks. Infusions take about an hour but there's some prep time before and after and some monitoring for allergic reactions. Again there’s that time. There's also careful monitoring that has to be done. People have to be able to have an MRI scan before they have the infusion done and also for monitoring afterwards. Those MRI scans have to be done on a regular basis to make sure these ARIA changes, these microhemorrhages or micro edemas, aren't occurring. We also need to have emergency room personnel who are comfortable when somebody comes in with a headache after getting an infusion, when to worry about a side effect versus just somebody having a headache. There's a lot of training, infrastructure, follow up that needs to happen and this is happening in the context of clinicians who aren't super comfortable many times managing dementia, caregivers who are already overburdened, and the patients who have memory loss. That's why they're being evaluated. It adds extra layers of complexity to help kind of get this therapy into practice and then, again, in addition to healthcare systems having to decide if they're going to cover this expensive therapy and all the extra costs that come with administering it.
Chin: Well, with that said, so very exciting results, landscape-changing kind of study, but a lot still to understand and a lot still to determine.
Chin: Well I’d like to thank you both, Dr. Carlsson, Dr. Johnson, for joining me on Dementia Matters. I'm certain we'll be having more conversations as time progresses and we are learning more about this approval or not approval of lecanemab.
Carlsson: Thank you, Nate.
Johnson: Thanks Nate.
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