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In this episode of Minding Memory, we dive into the newest FDA-approved drug to treat Alzheimer’s – Lecanemab – with Ohio State University stroke neurologist Jim Burke. Dr. Burke discusses the benefits and drawbacks of the new Alzheimer’s drug and also the paradigm shift of how people (clinicians, patients, and the general population) are thinking about these news Alzheimer’s medications.  

Resources:

• Jim Burke Faculty Profile: https://wexnermedical.osu.edu/find-a-doctor/james-burke-md-128794  
• Article referenced in podcast: Burke JF, Richard S, Langa KM, Albin RL, Kotagal V. Lecanemab: Looking Before We Leap. Neurology. 2023 Jul 21: doi: 10.1212/WNL.0000000000207505. Epub ahead of print. PMID: 37479527. 
• CAPRA Website: http://capra.med.umich.edu/ 
• You can subscribe to Minding Memory on Apple Podcasts, Spotify, Google Podcasts or wherever you listen to podcasts.

Transcript

Jim Burke:

The paradigm change is more meaningful, I think, in terms of how people are thinking and feeling about it than the specific effect of this medication. I think the enthusiasm I've heard for it from providers, to the extent I've heard that has been more about we're shifting to an era of weak Alzheimer's disease as a treatable illness as opposed to, I think Lecanemab is an amazing medication.

Matt Davis:

I'm Matt Davis.

Donovan Maust:

And I'm Donovan Maust.

Matt Davis:

You are listening to Minding Memory, a podcast devoted to exploring research on Alzheimer's disease and other related dementias.

Matt Davis:

In a previous episode, we discussed the FDA's approval of the drug Aducanumab for treating Alzheimer's disease. Those of us who research dementia are now feeling a sense of deja vu with the recent approval of the new drug Lecanemab. I mean, how many mabs do we need? Lecanemab is a new drug designed to target amyloid reduction that has received a lot of attention in the media, and this drug like its wayward sibling also comes with a fair amount of controversy. In this episode, we'll speak with a neurologist and health services researcher who's put some thought into the benefits and drawbacks of Lecanemab.

Matt Davis:

Today we're joined by Dr. Jim Burke. Dr. Burke is a neurologist and health services researcher at the Ohio State University. Previously he was here at the University of Michigan and we're proud to consider him one of our own. His research has been continually funded by the NIH, and he's worked in a variety of areas including studying treatment decisions, understanding racial disparities in stroke endpoints, and exploring how patient preferences affect health outcomes. He's here today to speak with us about the new drug Lecanemab that was recently approved by the FDA for treating mild cognitive impairment and Alzheimer's disease dementia. Jim, welcome to the podcast.

Jim Burke:

Hey, thanks for having me.

Matt Davis:

To set the stage for the discussion today. Dr. Burke was the lead author of a commentary that was recently published in the journal Neurology titled Lecanemab: Looking Before We Leap. The article raised some interesting and important issues regarding the drug's effectiveness, risks and cost. We'll include a link to the article, make sure to check it out. So to start things off, many of our listeners are already familiar with Aducanumab. I was wondering if you could talk a little bit about the degree to which the two drugs are similar in terms of how they work and their general outcomes and side effects.

Jim Burke:

I think I would say that they are generally more similar than different. If we went back when these medications were first in the development pipeline before we had any data on how well they work, you would've said both of them are monoclonal antibodies targeting the same pathologic protein in the Alzheimer's cascade, amyloid. They go about how they are going to reduce amyloid in slightly different ways, although that difference is probably relatively small. And if we were going to judge how well they work, we would probably do it by saying how much did they lower amyloid in your brain? And that's the other thing where before we ever had clinical outcome data from trials, we had early data in terms of phase two data that told us that these medicines both reduce amyloid in your brain by a lot. Lecanemab may be a little better than Aducanumab, but not a lot better.

Certainly we're not talking about twice as much amyloid reduction, maybe like 10% more. So before we ever had a trial outcome for either of these medications, I would've said yeah, probably pretty similar. I would've guessed that if one of them works, the other one would work. If one of them worked great, the other one would work great. If one of them worked a little, the other one would probably work a little. It would've been surprising if they had radically different effects.

Then when we ran the trials, that's more or less what we saw. Both medications... Well, I guess you'd say before we get to these two specific medicines, we've tried a lot of different ideas for lowering amyloid in the brain. These are hardly the first two molecules to come along that have targeted this strategy. And so when you look back over the last couple of decades, we've tried lots of different medicines for lowering amyloid in the brain. And other researchers have sort of looked at this question and if amyloid lowering is a really good strategy for Alzheimer's disease, then we'd expect that medicines that robustly lower amyloid would also have big effects on cognition.

They would really improve cognition or slow cognitive worsening. And when you look at all of the data that's been published before, you have some medicines that lower amyloid a little, some that lower a lot, and generally the ones that lower it a lot have better effects on cognition, but they're still pretty small. And so I think that would've been kind of where I started with these medicines. I would've said, Hey, if they lower amyloid, even if they lower it a lot, it's unlikely they're going to have a home run effect on cognition.

So then we ran phase three trials, and we don't need to rehash the Aducanumab story, but we have a couple big trials there and one big trial for Lecanemab. And in those trials, their effects come out pretty well aligned with those priors, which is to say both of them have trends towards improving cognition and in the case of Lecanemab, a very clearly robustly statistically significant effect. In the case of Aducanumab, a much debated, was there any effect at all. But if you look at the size of those effects, they're probably more similar than different.

I guess that was long answer to a short question, but mechanistically, they're pretty similar. In terms of their effects on the pathway that is of putative biologic interest, amyloid lowering, pretty similar effects. And in terms of their effect on cognition, probably also in the same ballpark.

Matt Davis:

And that amyloid lowering part is an important component of this whole story because part of the FDA accelerated approval, the fact that it's a surrogate marker, not necessarily a clinical endpoint, which is important.

Jim Burke:

Yes, I think that's probably right. So I think that's the part that's extremely clear about both of them is they're both very good amyloid lowering medicines. They both lower amyloid and they lower amyloid a lot. If the whole trick was just lowering amyloid, then these medicines would probably be great for Alzheimer's disease. But I think what we're learning is that's not the whole trick.

Donovan Maust:

Just a couple maybe follow-ups. First, in your answer you mentioned the phrase clinical improvement. So I think it's important for listeners to know, we don't actually mean that their cognition improved, it's just that the rate of the decline was slightly lower than in the placebo group. Is that correct?

Jim Burke:

No, that's absolutely right. So in treated arms of both drugs and in every trial, the people who are treated on average have worse cognition after a year, after 18 months with them when they started. It's just that the extent to which they got worse is less than the extent to which the placebo arm got worse. Yeah, absolutely. Good point.

Donovan Maust:

Which is just what makes the messaging around all of these so tricky. So you put Lecanemab in context of Aducanumab, if we take even a step back further and put Lecanemab in context relative to the cholinesterase inhibitors in terms of the clinical effect. Similar, different? What would you say for that?

Jim Burke:

Yeah. Well, this is where I started to become... So that question is the question that made me somewhat more skeptical about Lecanemab. My experience of this new medicine was I had sort of been through the Aducanumab debates, I did not follow and know that this trial was coming down the pipeline, all of a sudden I see the New York Times landmark new Alzheimer's drug, robust effect. It made it sound like we were suddenly going to change the story with dementia. So I was really excited when the trial came out in the New England Journal and I pulled the paper and the primary outcome is something called the clinical dementia rating sum of boxes. Which is basically a way of trying to sum up how is somebody functioning with dementia? And the trial shows that at 18 months, people that are treated have a score that has declined by 0.54 less than people who weren't treated.

And you said, "Well, is that good? Is that bad?" What does 0.54 clinical dementia rating sum of boxes mean? And then so I pull up the clinical dementia rating sum of boxes and refresh my recollection of what that is. And I look at it and I go, well, I can't really tell if it's important just by looking at the scale. So then it was doing exactly what you said. Well, we've got other drugs that we've had approved for Alzheimer's disease. So the cholinesterase inhibitors, and the most widely used one is donepezil or the trade name, Aricept has been around for forever. And most neurologists, most doctors that interact with this medicine don't tend to think it works great. Maybe it works a little bit.

And when you look back at its trials, we have meta-analyses of its trials, its effect on reducing the decline in the CDR sum of boxes is probably a little bit bigger than what you see for Lecanemab. And it's not just that one measure. There's a bunch of different measures of cognition. And when you look at all of these measures, if anything donepezil seems like it's working a little bit better than these new medicines. And that for me was the part where it was really sort of tapped the brakes on this medicine. Up until that point, I was like, "Oh, great, fantastic. This is maybe a breakthrough. Maybe this is the one that's really going to work great." And you said, "Oh, it might not work as well as donepezil." That is certainly not aligned with the impression I got from those New York Times headlines.

Donovan Maust:

Yeah, it seems like part of the excitement is because it's so effective at that surrogate endpoint of reducing the amyloid burden, but then when you actually look at the clinical outcome, it's not really that much of an improvement over what we already have. So is it time to just give up on amyloid as a meaningful outcome proxy of anything in dementia?

Jim Burke:

I mean, I was almost thinking that before this drug came along. So I don't know. I think there's sort of two parallel tracks of Aducanumab in terms of the story. There's the clinical story, which is relatively disappointing and I think something that has gotten popular media attention that is misaligned with its actual clinical effect. And then there is the scientific story, which is up till this point in time, almost every version of the amyloid hypothesis, if we can make all the amyloid go away in your brain and we can do that clinically safely, we really think that that should help. That should make a meaningful difference. And up until Lecanemab, we were able to get amyloid down a lot in your brain and it had no discernible effect on cognition that we are confident about. And so now we finally have something. So I think this is telling us the amyloid hypothesis probably isn't totally out in left field.

However, the extent to which the amyloid hypothesis as we've operationalized it for the last couple of decades is going to be the story that gets us the home run for Alzheimer's disease or even the solid double. That I'm probably more skeptical about. But I think this is a medicine that is scientifically pretty important because it anchors us back on the idea that this medicine might really be doing something.

I think there's another difference with Aducanumab, and it's not just the amyloid lowering because Aducanumab was pretty good at lowering amyloid too. I think there's a big clinical trial interpretation point here, which is Aducanumab did not give us that clean and clear P is less than 0.05 in your primary intention to treat analysis and Lecanemab did, right?

So with Aducanumab, we had debates about whether or not that effect existed at all, whether or not that was just random error, statistical noise, how you slice the data, data dredging. That was a credible interpretation or a worrisome interpretation of what might be happening with Aducanumab. With Lecanemab, that's not the case. We've got slam dunk statistical evidence that cognition moved in the right direction. Every measure that you look at goes the right way and unless there's some complex placebo effect that we're not capturing correctly, probably that's real and that's true. It's just that it's not that big. It's really the perfect example of very clearly statistically significant. But I'm not entirely sure how clinically significant it is.

Matt Davis:

That story that came out about that person who uncovered the falsification around some of the early seminal papers with looking at amyloid as sort of one of the main drivers of Alzheimer's dementia. Did that move the field at all or have any impact whatsoever?

Jim Burke:

I'm not super familiar with that narrative, so you'd have to inform me. I haven't heard a lot about that. I am not a cognitive neurologist and I'm also not a basic scientist, so I'm not living in amyloid, but I'm a clinical neurologist and I am regularly hearing talks about amyloid and Alzheimer's. And I have not perceived a huge shift in terms of how the field's thinking about the pathophysiology of Alzheimer's disease over time.

So my guess is that certainly I don't think changed it tremendously. Maybe it nudged it, and I think probably there's been a nudge with these serial negative trials to have a little more skepticism. I think that the field has moved from prioritizing amyloid as the key pathologic molecule to thinking more about tau. I think there's been more thinking about is this biologic story more complicated than what we would get from the pathologic story that we've been looking at it over time? But I don't think there's been a sea change yet. So maybe this is one of those things where the paradigm hasn't fully shifted, but we might be having the rumblings of some tension in the plates over time and maybe we're getting towards that more seismic shift in paradigm.

Donovan Maust:

Can you talk a little bit about, say, what are the concerning adverse events or side effects related to Lecanemab?

Jim Burke:

So this is basically the same story as every other, or I should say all of the other antibody-based stories, treatments for reducing amyloid, although generally a little better. So Aducanumab is probably a good anchor here, and Lecanemab is same story but not as worrisome. So the really common story, and this happens in a very sizable fraction of treated patients, something like a quarter or a third of patients will, when we serially image their brain with MRIs, they'll have areas of edema that is probably related to amyloid clearance in the brain and we'll see areas of swelling. Not infrequently, so of those people who have those changes, some chunk of the time those will cause symptoms. So they won't just be a change that we see on the scan of your brain that is as best we can tell not clinically meaningful. It's something where it will cause people some neurologic symptom that we're able to detect.

Usually those aren't terrible. Usually they're relatively transient. If that was the only thing these medicines caused, they probably wouldn't be a big deal as long as those subtle areas of edema did not cause any lasting injury to the brain. I think the real trick is that these medicines also predispose you to bleeding in the brain. This is much less common and it looks to be less common with Lecanemab than it was with Aducanumab. But the idea here is probably the same is that it's about lowering amyloid in the brain, increasing your brain's propensity to have bleeding and then potentially causing a severe problem there.

In the trial, severe bleeding in the brain that caused symptoms was something like a one in two hundred outcome. So it wasn't common, but for a medicine that doesn't have a huge benefit, a one in two hundred risk of a really bad outcome is something that is non-trivially worrisome. So I think that for me as a prescriber would be the big one. I would talk with patients a lot about the edema in your brain and how that might cause symptoms and whether or not you'd be able to tolerate the medicine. But then the real worrisome risk benefit calculus, should we talk about this medicine, is on the one side, here's the benefit that we know it'll have on your cognition and the downside is this potentially really serious bleeding risk.

Donovan Maust:

Is there any sort of routine neuroimaging monitoring recommended or is it like you're just on the lookout for symptoms?

Jim Burke:

I think this will be a really interesting question about what ends up happening with this in the world. And this is going to be the standard sort of thing where the trial had a protocol for serial imaging. My guess is when it's implemented in the world, it's going to start off being implemented in centers that were in the trial or similar centers and they'll follow the trial protocol, which is going to be a lot of MRI scans. And I think that probably most of the prescribers are going to be looking at those scans and if they see asymptomatic bleeding, that is likely going to be a thing that gets people to stop the medicine before it causes symptomatic bleeding. But that was also happening in the trial. And in spite of that happening in the trial, we still had a non-trivial rate of clinically detectable bleeding.

I think this is also one of those, the trial might be the tip of the iceberg. And so a common story about trials is the people who are in the trial are not always well representative of the people you want to treat. And that is for me, probably the biggest worry with the safety of these medicines, which is the median age in the trial was 71 and the median age in the US population of adults who have mild Alzheimer's disease or mild cognitive impairment and amyloid in their brain is more like 84, 85. And for every other medicine we've ever studied this in, bleeding risk goes up oftentimes a lot with age. So if in the real world target population, the risk of bleeding with this medicine isn't one in two hundred but one in 50, all of a sudden you would go from a medicine and say, boy, that risk benefit calculus is tough to one where you say it'd be really hard to recommend that medicine for anybody who had anything that would increase their bleeding risk.

Matt Davis:

I think you just got at my next question about the study population in the trial, and I guess in terms of how pharmaceutical companies sort of think about where to focus. I suppose it makes a lot of sense to focus on the mild cognitive impairment, early stages of dementia population, but there is a bit of a disconnect between the people that really need the medication and want it and are looking for an answer versus the ones that they're looking at in the trials.

Jim Burke:

Yeah, while I'll often be a skeptic of drug company motivations and choices, this is one that I think is just really hard. I don't know who you start off with trying to treat and tell if one of these medicines really works. And I think that one of the arguments that I think is valid for starting with the relatively mild population is that it's easier to see differences, that our outcome measures are more sensitive and sort of as step one for a trial, you say, let's run that in the population where if it works, we can see it, right? And if you have something that works there, then you could talk about running a follow-up trial that would generalize to people with potentially more severe disease. So I have really no confident idea about where they should start these trials. I can sort of see this rationale.

The rationale that I wish would've been a bigger focus of these medicines is I think the clinical effect that would be really meaningful to people is can we prevent Alzheimer's disease? Can we take people with mild cognitive impairment, which is to say we can measure problems with their thinking, but we can't tell that it's getting in the way of their life at all, and keep those cognitive problems from ever getting in the way of their life. That's the type of effect size that I would said, "Oh, that's potentially clinically meaningful. That's the thing I could talk to a patient about." I could say, "Look, right now you're having some thinking problems. If you take this medicine, we can reduce your odds of those thinking problems getting in the way of your life by half." And if I could tell people that, that would be I think something that would've made me much more favorable to this medicine. And I'm not sure it doesn't do that based off of the data that we have. It's conceivable that it does. We just don't have enough data to be able to tell.

Donovan Maust:

So I should know this and I'm embarrassed that I don't, but so once FDA's approved Lecanemab, what's the pathway then to Medicare covering it, and does Medicare currently cover it?

Jim Burke:

So this is going to get really complicated, and I think the answer is it will be, but this is sort of a saga on its own. And so once FDA gave Aducanumab provisional or accelerated approval, I forget which, CMS, the Center for Medicare and Medicaid Services basically made a decision that they would not pay for the medication outside the context of a trial. And that determination was not labeled directed at Aducanumab specifically, it was for monoclonal antibodies targeting Alzheimer's disease with amyloid lowering. So that decision I think would've hit Lecanemab. My understanding is that CMS has said that with Lecanemab that if FDA gives it approval, it will get paid for. And so I presume that they're making some other independent determination. That is my understanding and I'm not entirely sure of it. So don't take that one to the bank, but I believe that to be the case.

Matt Davis:

So what's your sense in terms of what clinicians think about these so far?

Jim Burke:

It's really interesting. I think I've heard a pretty substantial diversity of viewpoints. I think unlike the sort of initial mass media response, I haven't really found anybody who's talked about this like, "Oh my goodness, we finally found a home run." I think I've talked to some cognitive neurologists who are really excited to say it really feels like we have a biologically meaningful treatment. So if you're a cognitive neurologist, you've been taking care of really sick patients for a long time and it's really challenging and tough, and now you've got a medicine that comes along, that fits with the biology you've been understanding all this time, lowers that amyloid which you've been measuring on scans and clearly moves things in the right direction.

So I think it kind of feels good, but when I've had conversations with those people about, boy, that effect size doesn't look real huge. Most of them are like, "Yeah." I think this is one of those, the paradigm change is more meaningful I think in terms of how people are thinking and feeling about it than the specific effect of this medication. I think the enthusiasm I've heard for it from providers, to the extent I've heard that has been more about we're shifting to an era of weak Alzheimer's disease as a treatable illness as opposed to, I think Lecanemab is an amazing medication.

I've also heard a lot of people that are relatively skeptical. So as a health services researcher, the clinicians I tend to communicate with probably fall from the more skeptical side of the clinical audience. And I think there's a lot of people who looked at this medicine and said, "This is just totally worthless. This is something I would never recommend for any patient, and certainly not with those downsides."

Matt Davis:

The drug is really expensive and you make some really interesting cost estimates in your commentary. Could you tell us about those?

Jim Burke:

Yeah, so there's at least a couple interesting cost stories here. Let me start with the positive story first, it's a potentially positive story that ultimately I personally found really disappointing and frustrating. So I've been involved in a bunch of debates in neurology for the last couple of years about what's an appropriate price for a medication? So if you have a new medicine that treats a previously untreatable illness and has a gigantic benefit, but it's a small population of people, what's a fair price for a drug company to be able to charge for it? And one answer to that question, and I probably would've advocated for it more before seeing what happened here was to say, "Hey, let's do a cost-effectiveness analysis. You can charge a price that hits a reasonable societal cost-effectiveness threshold."

That's exactly what Lecanemab did. They said, "Given the effect we observed in the trial and a whole lot of other assumptions, we think this medication would have a societally beneficial net effect at a price of $26,500 a year." So if you had a home run drug for Alzheimer's disease, you could charge a ton for it and be cost-effective. The reason that is sort of disappointing is when you kind of delve into that analysis, I think what I learned was the problems with the paradigm that I proposed, which is you have to make a lot of assumptions to be able to do that analysis. And the assumptions they made were very favorable to the medicine. So the main tricky assumption that they made was that they kept extrapolating the effect of the medicine would increase over time. And so rather than a 0.54 increase in the CDR sum of the boxes at 18 months, that was going up to something like one and then two as you got years and years down the road.

So they started off modeling a pretty small effect, but an effect that they were going to imagine gets bigger over time, and that's one assumption that really works in their favor. The other one is they started with a population that was the trial population as opposed to the population you'd treat. So they started with a population with a mean age of 71. Now if you take somebody with mild Alzheimer's disease who's 71, they're probably going to live for a long time, which means if you meaningfully improve their cognition, you get big gains and quality of life over time. If instead you start with somebody with Alzheimer's disease who's 84, you can't get that much benefit from the medicine because they're likely to die from some other reason before they would've ever have lived through the period of time when they would've gotten the benefit.

And so those two tricky assumptions probably interacted to allow them to get a number that would've been much more favorable. I suspect that if I had run that cost-effectiveness analysis, you would not have come up with a price of 26,500. You would've come up with something a lot higher in order for that to, or should I say much, much lower, not higher, lower. You have to go the other way by a lot for this to have been cost-effective, I suspect if I ran the analysis, and thus my reduced enthusiasm for the paradigm of pricing medications on cost-effectiveness analysis, I think that is too fraught of a territory for that to really work well for us. So that's sort of the boring technical part of the story in terms of how do they come up with that price and how should we set prices for high price drugs generally.

The real story to this medicine though is that when we talk about the costs of care in the United States generally, and we talk about the costs of neurologic care, this medication is the potential elephant in the room. This is really the question that got me thinking about these medications like a decade ago was say, all of these monoclonal antibodies that we were developing for all kinds of different conditions are expensive, but most of them are relatively uncommon illnesses. So we're going to treat rheumatoid arthritis or multiple sclerosis with a medicine that costs $50,000 a year, $70,000 a year. And if we really only treat the bad cases, that doesn't add up to that big of a number at the societal level. But Alzheimer's disease is the condition where now you take a prevalent condition and multiply it by a gigantic cost. And the back of the envelope numbers you get here are utterly staggering.

So you take that $26,500 and you say, as we should, "We've got a new medicine. If we really believe it works, we should treat the whole target population." That's four or five million people. We're talking about something over a hundred billion dollars a year for the medication alone. It's one of those, I have to go back every time I've done this back at the envelope math and count zeros like three times. Is that seriously 120 billion? The number is utterly staggering. 120 billion is what we spend on all medicines in Medicare Part D. Now, are we ever going to spend that on this medicine? Assuredly not. Well, I shouldn't say assuredly, not, probably not. Very, very unlikely we'd actually get to that number but when that's the type of scope of expenditure that we're talking about where this would fit in, that has been the real societal trick.

For me what this medicine is about is in the United States, we don't talk about the cost of medications. We just treat people. And when we talk about the cost, we talk about the cost inconvenience to individuals. Insurance companies worry about costs a little bit. But this is the type of medicine where the societal cost problem that we largely ignore away, I think kind of points to it being unignorable. You just can't look at that number and ignore it. We could have a couple extra NIHs a year for what we would potentially be paying for this one medication.

Donovan Maust:

All right, so we've come to the end of our planned questions except for one where I was supposed to ask you about football, but I don't want to end on a contentious note. And so I'm going to skip that and just say, is there anything we haven't talked about that you think we should have talked about?

Jim Burke:

So the one thing as I was talking that maybe might've been useful to sort of kick this conversation off was sort of I think kind of where this all came from. So I'm a stroke neurologist, I'm not a cognitive neurologist, and it was more my research thinking and the research questions that I think about that got me into thinking about these medicines and collaborating with people who are cognitive neurologists and who are geriatricians to think about these societal trade-offs for these medicines. And we did a bunch of simulation work, maybe a decade ago now, that tried to play with this question. Because treating Alzheimer's disease with a preventative medication's really tricky.

We're not going to now go out there and give people a medication with harm, and the harm starts right away. So as soon as we start the medication, you're at risk for the harm. But the benefits are likely to slowly accrue over time, and a lot of people are likely to die of some other cause before they ever got to those benefits in the first place. We worked with, what are the assumptions of how well do you have to treat this illness to have a meaningful benefit? How well do these medicines have to work? And the answer was, Alzheimer's disease is such a big problem and it leads to so much disability that if you can really move the needle on how this disease progresses, if we can reduce disease progression by half, you could tolerate a ton of harm of these medicines. You could have a medicine that causes a one in 50 bleeding risk and have net societal benefit, but it has to have that really big effect on are we slowing the disease down?

And having had that perspective in my head and generalizing from other medicines, then the potential problem that Lecanemab is now presenting for us has been sort of sitting there and making me worry about it for the last decade. The medicine that I was terrified of was a really expensive medicine that works a tiny bit, right? This is now the thing where you say, we're not going to move the needle on net societal benefit, and if we're going to treat five million people with it, we could spend an astronomical amount of money on it. I think the other interesting question here is this is a really interesting space about who will actually get treated with this medicine. While for most new medicines, we don't get anywhere near treating our whole target population and so the aggregate societal expenditure probably is not going to be over near 120 billion, the potential for who could get treated for these types of medicines is huge.

The number of people with amyloid in their brain is like 40 million. So it is a ton of people who have some amyloid in their brain. This is very common in aging. And if we get to the point where people get worried about cognition, this becomes a really, people are already worried about cognition, but we sort of have the idea that this is now a treatable thing. The stories about billionaires going to their doctors and asking for their amyloid scan and seem to have one molecule and taking Lecanemab and telling all their friends to do that, that doesn't seem like it's a crazy possibility.

So probably we're not going to treat four or five million people with this medicine, but would I really totally rule out the possibility we end up treating 10 million? Could we end up treating half of the people in the country who have amyloid in their brain? We've overused a lot of medicines, including a lot of really expensive ones. So I don't know what's out of bounds of possibility here.

Matt Davis:

I think that's an important note to end on. So Jim, thanks so much for joining us today, and thanks to all of you who listened in.

If you enjoyed our discussion today, please consider subscribing to our podcast. Other episodes can be found on Apple Podcasts, Spotify, and SoundCloud, as well as directly from us at capra.med.umich.edu, where a full transcript of this episode is also available, On our website, you'll also find links to our seminar series and the data products we've created for dementia research.

Music and engineering for this podcast was provided by Dan Langa. More information available at www.danlanga.com. Minding Memory is part of the Michigan Medicine podcast network. Find more shows at uofmhealth.org/podcast.

Support for this podcast comes from the National Institute on Aging and the National Institutes of Health, as well as the Institute for Healthcare Policy and Innovation at the University of Michigan. The views expressed in this podcast do not necessarily represent the views of the NIH or the University of Michigan.

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