AGS Alzheimer’s Disease: New Diagnostic Technologies and Treatments Podcast

Evidence Review of FDA-Approved Monoclonal Antibody Treatments

• American Geriatrics Society • Season 1 • Episode 5

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Join Dr. Michael Harper, Professor of Medicine at the University of California, San Francisco and Dr. Eric Widera of  Professor of Clinical Medicine, Division of Geriatrics at UCSF and the Director of Hospice & Palliative Care at San Francisco VA Medical Center who, co-authored the module titled Evidence Review of FDA-Approved Monoclonal Antibody Treatments along with Kaitlin Willham, MD, Outpatient Geriatrics Clinic Medical Director at the San Francisco VA and Associate Professor of Medicine, at UCSF Division of Geriatrics.

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Michael Harper:

Hello and welcome. I'm Michael Harper. I'm a geriatrician and professor of medicine at the University of California, San Francisco. And I'm pleased to be moderating today's podcast, which is part of the American Geriatric Society's new educational curriculum on Alzheimer's disease, new diagnostic technologies and treatments. So we designed this curriculum for both practicing clinicians and for our fellows who are in training. Obviously, the world has changed a lot in terms of the way we think about Alzheimer's disease. And with the emergence of newer treatments, we want to make sure that all of our members and all of our learners are able to have conversations with our patients who are more than likely to bring up new ways we think about Alzheimer's disease, and particularly around the treatments. I'm really excited to be speaking today with my friend and colleague, Dr. Eric Widera. Eric's a geriatrician and a palliative medicine physician. He's also a professor of medicine at UCSF, and he works at the VA where he's the hospice and palliative care service director. And for many of our listeners, you probably know him best as the co-host of the Jerry Powell podcast and for his appearances at AGS with Dr. Ken Kavinsky and Alex Smith and their very creative presentations around the annual literature update. Today, uh Eric is here with me as a co-author of our module for this curriculum entitled Evidence Review of FDA approved monoclonal antibody treatments. So Eric, welcome. It's great to have you.

Eric Widera:

Thanks, Mike. It's nice being on the other end. I usually am the one asking the questions. So we'll see if I revert to that and start asking you questions.

Michael Harper:

I know I'm glad to have you on the hot seat here. So actually, we're going to do a kind of a deep dive into these clinical trials that led to the approval of these two currently FDA-approved monoclonal antibody treatments for Alzheimer's disease, lecanemab and donanemab. But before we do that, I wanted to read you an excerpt from a New York Times article published on the day lecanemab received FDA approval in January of 2023 and get your reaction. So here's the excerpt. It says the Food and Drug Administration on Friday approved a new Alzheimer's drug that may modestly slow the pace of cognitive decline early in the disease, but also carries risks of swelling and bleeding in the brain. Do you think they got this right?

Eric Widera:

I think that's a great summary. I think you could look at the two ends of the spectrum. You have some people that say, you know, these drugs don't do anything and they come with significant harm. And you have some people who say, oh my gosh, these are breakthrough drugs that will, you know, we're seeing a new era of Alzheimer's treatment. I like that statement because these drugs do something. They slow down the progression of a disease that most people are very fearful of if they develop it. With that said, that they don't stop it, they don't reverse it, they don't cure it, they mildly or moderately slow down the progression of the disease over the course of time that these studies were done in, which is about 18 months. So we only know data from 18 months what happens to the disease. We have to extrapolate or assume what happens after 18 months, but those are big assumptions. But we know from the two studies is that the disease continues to progress. But it seems to progress slightly less fast on these drugs than if they got the placebo. And it's also associated with cost, so these drugs are very expensive, and harms. They're associated with these amyloid-related imaging abnormalities, both edema and microhemorrhages that can be symptomatic, could be a reason to stop the drug, and that there were in both studies some deaths that may have been related to the drug, too. So this is not just like a statin. These are drugs that carry risk, but also some modest benefit.

Michael Harper:

All right. So I think that's a good overview. So let's talk a little bit more in detail about these studies to figure out how you reach those kind of conclusions. So let's the trials are Clarity AD for lecanemab and Trailblazer Alz- 2 for donanemab. What was the sort of the just the overall study of the study design for these trials?

Eric Widera:

Yeah, both are randomized control studies, and they both compared either the active drug, so lecanemab for Clarity AD donanemab for trailblazer alts to. I'm just gonna call it Trailblazer from now on. Uh they compared them to placebo. So those were some of the similarities between it. The timeline was about the same for both. They both looked about 18 months in Clarity AD and technically 76 weeks for Trailblazer, the donanemab study. So about the same. There were some interesting differences between the two groups, but again, big picture, both randomized controlled trials comparing to placebo.

Michael Harper:

Okay. And who did they actually study? Who who participated in these trials?

Eric Widera:

In the Clarity AD, lecanemab study, they included people with MCI, mild cognitive impairment, or mild dementia. They didn't include anybody with more severe dementia, and these were not asymptomatic individuals. These were people for MCI, they had objective cognitive impairment. So they had to meet the formal definition of MCI or mild dementia. For lecanemab trial, they were 50 to 90 years old, mean age was about 70, and everybody had to have amyloid in the brain. So they got PET, CSF fluid, and they saw amyloid in the brain. So again, MCI and mild dementia and amyloid in the brain. Now, I'll talk about so that was donanemab was slightly different. It was weirdly enough, they only included individuals 60 to 85. This is a pet peeve amongst every geriatrician. There is no justification for not including individuals greater than 85. I have not seen any FDA guidance or drug company guidance that we should not be using this in people older than agent 85. This was just outright ageism, um, not including individuals 85 because they sure are marketing to that group. But in that study, they they limited the age to 85. Mean age was around the same as the lecanemab trial. Everybody had to have MCI or mild dementia. So again, objective cognitive impairment, but not really, really bad. And everybody in the donanemab trial, trailblazer, had to have amyloid, but they also had to have tau. They had to have at least low levels of tau. So that was a one big difference between the two groups, kind of both the age and also the inclusion of Tau as a inclusion criteria.

Michael Harper:

Were these representative of the population that we take care of in the US?

Eric Widera:

They were representative of the population that we take care of in many academic memory centers where we do this type of research. Unfortunately, that's not representative of the general population of the United States. So I think there was like two or three percent black or African American. You know, the age is younger than the age of most people with Alzheimer's disease and Alzheimer's dementia, but it it wasn't too bad. Again, we we talked about the ageism with a cutoff of 85, but the inclusion of in the donanemab, I think over 90% were white.

Michael Harper:

This is an opportunity for me to make a plug for another podcast we did with Dr. Sharon Brangman and Dr. Sanchez Lopez, where they talk a little bit about how to counsel folks who may not have been represented in this trial. So if you get a chance, I'd encourage you to listen to that as well. Are there any important exclusion criteria, people that you couldn't get into this trial? Or are there any any reasons you couldn't be in other than those age limits you described?

Eric Widera:

Yeah, for me, when I think about it, I don't remember all the specific exclusion criteria, but for any clinical trial, you're looking at healthier individuals, people who are generally in every clinical trial healthier than the general population. They're usually wealthier than the general population. In this case, they were wider than the general population. So I think those were the big, big issues. They did look at things like APOE force status, which also puts people at risk for uh the harms, including ARIA. But those were kind of the the when I think about the exclusion. I think from a clinical practice perspective, the way I think about it is I think it's a very narrow definition of mostly individuals with mild cognitive impairment, which are kind of very hard to find in the general world. Um people who have noticed cognitive impairment, who are seeing a doctor, and then we are also getting objective cognitive impairment on testing, but not so bad that they're no longer MCI or mild dementia, but they're more moderate disease.

Michael Harper:

So that's the sort of the study design who they studied. What were the outcomes they were looking for?

Eric Widera:

This is always the biggest challenge in uh this type of research. So you have to use either functional scales, cognitive scales, a combination of both. When we looked at the outcome for Clarity A D, it's the CDRSB, the clinical dementia rating scale, some of boxes, which was also a secondary outcome in the Trailblazer donanemab study. But the primary outcome in donanemab study was the IADRS, which was the integrated Alzheimer's disease rating scale. The CDRSB is a 0 to 12 scale, and the IADRS is a 0 to 144-point scale. The biggest issue that you hear people complaining about the CDRSB is it spans the entire spectrum of Alzheimer's disease, from you know not having anything to MCI to all the way to very advanced end-stage Alzheimer's disease. But the study doesn't include that entire spectrum. It includes includes only people with MCI or mild dementia. So you also don't expect the to see the full kind of 12-point scale here is that if something is working, you're actually expecting a smaller point difference. Over time, you're hoping that you actually affect a lot more of that scale, but these are short studies, a year and a half. And we know dementia progresses slowly over a long period of time. So one of the biggest issues with these studies is that they are relatively short, a year and a half for a disease that may take many years, decades to develop and progress. Or decades, not decades.

Michael Harper:

One of the things that we think these drugs are supposed to do is remove amyloid. Were they successful in doing that?

Eric Widera:

Oh, they're really good at removing amyloid. They are so good. So in Clarity AD, it showed that you know it did a great job of removing amyloid. Interestingly enough, Trailblazer, the donanemab study. The other big difference between Clarity AD study is they actually stopped, stopped the infusion. They switched to placebo if they sufficiently cleared amyloid. And three out of four people on the drug were able to stop donanemab because it's sufficiently cleared amyloid, which makes sense. Like the the point of this, get rid of amyloid. If amyloid is there, do you still really need it? And again, both drugs did a great job of removing amyloid. That's that's the interesting thing, is uh if it completely or mostly sufficiently removes amyloid, and if amyloid is the primary driver of Alzheimer's disease, we'd hope that we'd see in the results it's would stop maybe not reverse, but at least halt the progression of the disease. And that gets us into the results where, and Mike already talked about this in the beginning, it didn't halt, it didn't stop the progression of the disease, but it slightly slowed down the progression of the disease.

Michael Harper:

Yeah, so I think this is a thing that we all as clinicians sort of struggle with, right? We we have these sort of so-called intermediate outcomes that are not hard outcomes. It's not as if people were not slowing the progression of admission to nursing homes or assisted living. So we're left to sort of interpret what this actually means. So given that this drug, these drugs are really good at reducing amyloid in the brain, it slows the progression, but not at all. It it seems to mean that there's something obviously else going on here, right?

Eric Widera:

Yeah, I think everybody would agree is that uh there is something else going on. There's something else besides amyloid going on there. Like we we we know that in the future, it may be you know targeting using these drugs, these types of drugs with other drugs that are targeting other pathways uh that may be responsible for the disease. But there is, I think for me, that the take-home is because it's not halting the progression of the disease, but it's doing something, it tells us amyloid is important, but it's not the end-all be-all of the disease. It it's somehow involved, and we got a lot of great researchers who would know a lot more than me on the different pathways, but I think it's a very clear like if you can do a really good job of sufficiently removing all amyloid, but the disease continues to progress, there's more going on besides amyloid for all cyber disease.

Michael Harper:

And I know there was there was things written about the amount of time that you sort of gain. Do you how do you interpret that, those numbers?

Eric Widera:

Yeah, uh, I would be cautious because that was not there, nobody walked into these studies saying, I am going to look at the amount of time gained. That was a kind of post hoc marketing. I'm gonna explain these results in a way where if if I say, you know, on this 12-point scale, there was a 0.4 difference for lecanemab between those who got the placebo and those didn't. Both groups progressed, but at 18 months there was a 0.4 difference between the group. Everybody is gonna look confused and wonder, like, what the heck does that that mean? Which is understandable. It doesn't really mean anything because we're using these scales. For donanemab, you know, I uh there was like a three-point difference on a hundred and for both groups worsened, but the donanemab group worsened by three points less on a hundred and for scale. Like, what does that mean? But if you can say, you know, it gave you this amount of extra months, man, that has such such a more emotional and practical difference that it works really well. I am from a, you know, from an evidence-based medicine perspective, I'm a little bit more skeptical on that. because that's not what they studied.

Michael Harper:

So we probably shouldn't be telling patients that if they take this drug, you can expect to gain so many more months of cognitive ability that you might not have otherwise gotten if you took this drug, if didn't take this drug.

Eric Widera:

No, because you can't even say that with these scales, right? These scales are measuring a lot of different things. So, what does this 0.4 difference in the CDRSB actually mean, or you know, a three-point difference in this uh IEDRS scale? Like you can't say, oh, you're gonna be driving for another three months. You can't say that. You can just say that there was this difference. And I think the hard part in evidence-based medicine is this is population-based numbers, right? This is of the people who got this drug. If you actually look at the individual changes in people, there was a lot of kind of um ups and downs for people. Some people did look like they improved a little bit on some of these numbers, some people looked like they worsened. Interesting, that's in both groups. So on a population, you see this progressive kind of decline. On an individual level, there's a lot more noise. Uh, but that's true for every single trial that we do. I do think that the key message here is that these drugs do not stop the disease. Okay, they don't halt the disease, but at best, they can help slow down the disease a little bit.. And that may be something that's really important to people, and that maybe not, given what people have to endure to get this. So the lecanemab study, lecanemab was given twice a week, or once every other week. And the donanemab was given once every month. And then you had to get MRIs and PET scans and all of this stuff in people with Alzheimer's disease. And the patients that we care for are generally not the patients included in clinical trials. So they have more than one thing going on. They may have heart fill, they may have all these things, they may be much sicker, they may be more complex. Um and doing things like getting frequent MRIs may be very challenging for them. Going to the infusion center every other week may be very challenging for them.

Michael Harper:

Yeah, I think that's an important point. This is not like going home with a pill bottle and taking a pill every day. There's a I think at least the perception for some people that there's a burden to the actual administration of this, uh, of these medications. So we talked about the sort of the what the potential benefits are of this, of this, of these medications. What about the harms?

Eric Widera:

Yeah, I mean, I think the biggest harms that we think about are is this ARIA, amyloid-related imaging abnormalities, which is this kind of newer term that was devised to explain kind of what we were seeing here with these drugs. And we saw higher rates of these amyloid-related imaging abnormalities, either edema or these microhemorrhages, these micro bleeds in the brain, significantly more so in the group that got the drug than that got the placebo. And they were not infrequently symptomatic. They frequently caused these drugs to be stopped. They may be restarted. The other big thing is that there were deaths associated with these drugs. So, again, it's these drugs are not benign. We also don't know what the longer-term impact is from having these microbleeds, these edemas. Again, we do know at 18 months that there is this difference in the group. What happens at three years or five years? Is the complications from all of this stuff will it get worse with time or will removing the amyloid continue to look better than having these complications like aria, um, which again tend to occur at the start of giving these medications? The other big risk is not just with these drugs, but older people with Alzheimer's disease tend to have other things and other complications that may develop in the future, like a stroke. So at least one of the deaths, if I remember correctly, was related to receiving um uh TPA in relation to stroke-like symptoms, um, which uh led to the death. And some would say, oh, that was that was the TPA, but it was really the resulting bleed was likely secondary to actually receiving the these these drugs. So again, not benign drugs. We have to have clear guidance and expectations that that there is a cost associated with it. And that cost is also having to see the medical system very frequently for MRIs, for tests, and also there is a risk of these microbleeds, this edema, and also potentially risk for death.

Michael Harper:

Yeah, I think it's important that you made that distinction that these are not just things that you saw on an image, right? These are real things that happened in the brain that potentially cause harm. You mentioned earlier something about ApoE status. Why might that be important in terms of counseling folks regarding these harms?

Eric Widera:

As far as we know, APE status, the homozygous are at much higher risk for developing this aria. So potentially not infusing these drugs for people who are APOE homozygous, people who are in anticoagulation, you know, really thinking about not using these medications on them because the risk starts increasing dramatically as well.

Michael Harper:

So I think we covered the design, who was studied, the outcomes and the results, and some of the harms. How do you sort of bottom line this for clinicians who are going to be potentially talking to their patients about this and potentially trying to advise them if this is something they should look to pursue or not?

Eric Widera:

My big take-homes are these drugs have only been shown to me mildly effective in people with MCI or mild dementia. I would not be talking to this, to anybody about these drugs or even doing any of the amyloid tests or tau tests, any of these Alzheimer's tests in people who don't fall into this category of MCI or mild dementia, where I'm strongly considering the use of these drugs. Because there is no evidence that these drugs work in people with subjective cognitive impairment, for people who are just amyloid positive or these Alzheimer's tests positive, these lab tests, or may have a you know, a PET scan that's positive, but they have only subjective cognitive complaints and no objective cognitive complaints. These drugs have not been shown to be effective in that. Our hope is there are trials ongoing and people with subjective cognitive impairment that hey, maybe these drugs may be effective for them, but currently we have no evidence for that. So the first off is eligibility. Like these are people with mild cognitive impairment or mild dementia. They're also the only people I would consider doing these Alzheimer's lab tests on if I'm also considering using these drugs. I would have a clear understanding with the the patient and myself similar to the colon acid inhibitors, there is a mild benefit, but different than the colon acid inhibitors, it's potentially disease modifying, but you know, different than colon ester inhibitors, the risk-benefit ratio um gets kind of distorted because these are there are real harms, including death, that we see in both of these studies and this this aria, this edema, these bleeds. So it does require a lot of discussion. I think the other big thing, it requires systems of care. This is not something you just start with somebody and assume everything is going to be okay. Like if you start these drugs, you have to have like radiologists who know how to read an MRI for ARIA. You have to have EDs that are aware, like if somebody comes with a stroke-like symptoms on these drugs, you're gonna care for that patient differently because of the risk associated. If somebody develops AFib on these drugs, you're gonna have to think about that. Like, which is worse for somebody in the long run, you know, not using anticoagulation for atrial fibrillation to prevent stroke, which will worsen cognitive issues, or to continue these drugs. So it adds complexity to the healthcare system and to the care of the patient.

Michael Harper:

Eric, I want to thank you for your willingness to go on the other side of the microphone and the interview for this series, and to thank you for your contribution of this module for this educational series. It's really been great talking with you. And uh and thanks again.

Eric Widera:

Wonderful. Thank you for having me and wonderful series.