A Revolution in the Treatment Landscape of Alzheimer's Disease

Andrew N. Wilner, MD; Richard J. Caselli, MD


March 02, 2023

This transcript has been edited for clarity.

Andrew N. Wilner, MD: Welcome to Medscape. I'm your host, Dr Andrew Wilner. It's my pleasure today to introduce Dr Richard Caselli, professor of neurology at the Mayo Clinic and an expert in Alzheimer's disease. Welcome, Dr Caselli.

Richard J. Caselli, MD: Pleasure to be here. Thank you, Dr Wilner.

Wilner: Dr Caselli, as you know, there's been quite a revolution in the treatment landscape of Alzheimer's disease. First, aducanumab in 2021, and then just a few weeks ago, lecanemab. Two monoclonal antibodies that are approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer's disease.

I've listened to podcasts and I've read about these drugs, and there seems to be a fair amount of controversy that, even though they're FDA approved, there are many pros and cons. I need some help to figure out what to do with my patients with Alzheimer's disease, and I figured out you were the go-to guy. What do I do?

Caselli: I'm happy to share some thoughts. As you correctly point out, there is a fair amount of controversy, probably more than I've seen for anything else in my career, in our field regarding these medications.

The first thing to point out is both of these drugs, and others that are in the pipeline, have been far more effective in moving a biomarker than their predecessors. The biomarker in these studies has been an imaging biomarker, an amyloid PET scan. It really has been quite remarkable to see the difference between the amount of amyloid in the brains of people with Alzheimer's disease before treatment and the relative reduction and almost depletion of amyloid following treatment.

Treatment typically takes a while — months, at a minimum, to a year, not uncommonly. It became a type of human experiment, testing the amyloid cascade hypothesis that was formulated in 1991. For the past 30 years, we've been aiming for this. What was the outcome of achieving what the amyloid hypothesis predicted would essentially cure Alzheimer's disease?

The answer was that it helped a little. Now, you can be a glass-half-full or a glass-half-empty kind of person. To give you some specifics, in the aducanumab trials — without going into all the controversy of that — you'll recall that initially, Biogen, which sponsored those trials, stopped them after doing a futility analysis and concluding that aducanumab was really not clinically effective.

They then changed that by analyzing further data and subdividing their patients into milder cases and found that, in one of the two trials they were conducting at the time, the patients with the mildest-stage disease — meaning mild cognitive impairment and mild dementia — who'd been on the highest dose for the longest time, did actually hit their clinical target that was statistically significant.

What did that amount to in terms that many of your viewers might recognize? They had a number of outcome measures, but one that's familiar to many of us is the Folstein Mini-Mental State Examination.

After about a year and a half, which is unusually long for a trial but is necessary for these disease-modification trials for Alzheimer's disease, the difference between the high-dose group and the low-dose and placebo groups is only about half a point on the Folstein Mini-Mental State Exam.

In the lecanemab trial, there was a little bit less controversy in that there was only one trial that did not have discrepant results like the aducanumab trial. The usual leading soundbite, if you will, when you hear about the benefits of lecanemab, was that it slowed disease progression as measured by the CDR Sum of Boxes by 27%.

What is the CDR Sum of Boxes, and is 27% meaningful? CDR stands for Clinical Dementia Rating Scale. It's not something that you do in your office. It's not something I do in my office, although we do it in our research program as do other research centers.

It's not a test. It's really an interview. It involves separate interviews done with the patient and with their informant, typically the spouse. They're asked questions that are relevant to six different domains of functioning, or what are called boxes — memory, judgment, problem-solving, home and hobbies, and some others as well.

The best you can do in any of these categories is 0. That means there's essentially nothing wrong. The worst you can do in any one of these categories is 3, which means things are severely wrong. Therefore, 3 times 6 would be 18, which is the maximum score one could get on the CDR Sum of the Boxes.

The difference in the treatment group and the placebo group in the lecanemab trial was 0.45 at the end of about a year and a half. Again, that doesn't sound like much to those of us who view the glass as half-empty. To those who view the glass as half-full, that's a 27% reduction in degree of decline compared with the placebo group.

When we look at another trial, which you haven't mentioned because it hasn't been in the news because it hasn't hit its endpoints, was the gantenerumab trial. The gantenerumab trial was another monoclonal antibody directed against amyloid, this one delivered subcutaneously. It performed better in previous studies, but in the phase 3 trials, it didn't hit its endpoints.

What does that amount to? A difference of 0.31 in one of the two trials in the CDR Sum of Boxes. Here, you have 0.45, P < .0001. Here, you've got a CDR difference of 0.31, and the P value was around 0.09. Is that a huge difference? It doesn't sound like a huge difference, absolutely.

If this was a little capsule you could pop in your mouth, I'd say everybody should take it, but it's not. It's an intravenous infusion. Aducanumab was once a month. Lecanemab is every 2 weeks. Another one in the pipeline, donanemab, is once a month.

With both aducanumab and lecanemab, there's no upper limit to the amount of time a person could continue to receive this. It is taken for as long as somebody would be considered to be at a mild stage. That could be for a year, or it could be for 3 or 4 years.

Donanemab is setting the bar, saying you're done at 1 year. One of the thoughts behind that, I suppose, is that it seems to be a little bit more rapid in the clearance of amyloid from the brain.

It wouldn't surprise me if, at the end of all of this, this becomes kind of a winner-take-all, in that why would you do something every 2 weeks when you could do it once a month? Thinking about gantenerumab for a minute because there are trials looking at subcutaneous versions of some of these things, why would you do anything intravenously if you could do it subcutaneously at home? From the administration standpoint and the effectiveness standpoint, those are a couple of big considerations.

Finally, I'd be remiss not to mention adverse effects. The way these work as your viewership knows, is by causing inflammation in the brain. I mean, that's the whole point.

You're getting monoclonal antibodies that are binding to amyloid at some point along the pathway and inciting an immune response to clear amyloid from the brain. That is inflammation. In some cases, it's a robust enough inflammation that one can see cerebral edema on an MRI scan of the brain, also called ARIA or amyloid-related imaging abnormality — which in my opinion, is a somewhat obfuscatory term that makes it sound like an imaging artifact.

It's not an imaging artifact. There's nothing artifactual about it. It is cerebral edema. In some patients, it has a hemorrhagic component as well. The risk involved is very related to a person's APOE genotype. APOE homozygotes, who comprise 2% of the general population but about 10% of the Alzheimer's population, are at lowest risk of benefiting from lecanemab. They actually got worse in the trials. They're at the highest risk of developing serious adverse events, like I was just mentioning.

There are sex differences as well. Men seem to respond much better than women, but we don't know the reason. There are age differences. Older people over 75 seem to respond much better than younger people under 65. I don't really know why.

There are a number of considerations here, not the least of which is cost, which I haven't even mentioned. That's kind of where we are in terms of what effects these things have, how they are administered, what the potential benefits are, and what the potential risks are.

Wilner: Wow. I asked a great question, because this is a complicated answer. I want to follow up on a few of those things.

Clinical benefit is really the key. When you're sitting in front of the patient who asks if they should take this medicine, in their mind, they want to get better or they want their loved one to get better.

There were these statistically significant improvements. I grew up using the Folstein Mini-Mental State Examination, and half a point, in my mind, is within the margin of error of testing.

If it came out that that's the only benefit, that's an answer for me. The trial may have been much more consistent, but a half a point out of 30 is not much.

I'd really be interested in whether there were any patients who were in a nursing home, for example, who were now able to go home? Were there any patients who were at home but needed assistance, for example, with activities of daily living and were now independent?

That's an endpoint that I think, in my patients, would be very significant. Did they see anything of that magnitude?

Caselli: The short answer is no. The longer answer is the target patient population for these treatments are people with mild cognitive impairment and mild-stage dementia. These are not the people that you're referring to. Those more severely impaired people, to the extent they were even enrolled in any of these trials, to my knowledge, did not demonstrate any significant benefit.

Wilner: Clarify something for me: In the old days anyway, when a drug was FDA approved, it meant that there was clinical benefit. From what I understood, the FDA approval for this drug — and maybe for others — was based on a biomarker.

Is this a new thing the FDA is doing? Is this something everybody is on board with — that if the biomarker gets better, then the patient's better and that's good enough? Is that what's happening here?

Caselli: Again, the short answer is yes. I'm not an FDA expert, so I can't speak to how long they've had this program called the Accelerated Approval Program. "Accelerated" sounds good, but what it basically means is what you've described. They're approving something before they're totally convinced that it's clinically beneficial.

Again, there's a large amount of history behind the amyloid cascade hypothesis and the strategy that led up to these studies and their results. I imagine between that momentum behind this whole strategy and, not to be ignored, the understandable vested interests of groups like the Alzheimer's Association, many people are looking for something.

Alzheimer's disease is probably in a class by itself in terms of the lack of progress that's been made in advancing care. Prior to aducanumab, the most recently approved drug was memantine, which was 20 years ago or more. I don't remember the exact date, but it's been a long time.

When we look at things like mortality rates and diseases, mortality rates in heart disease and cancers have gone down. Not so in Alzheimer's disease. You can understand why the FDA might have been willing to give it the benefit of the doubt. The idea behind the Accelerated Approval Program is that they're supposed to come back with more data postmarketing.

Medicare is assisting with that, if you will (not everybody looks at it as assistance), in that their decision was that they were not going to simply cover the cost of this except within the context of a further clinical trial. There are people getting it within the context of a clinical trial, and registering results to eventually show or disprove whether this is, in fact, helping people.

Wilner: That helps because it takes some of the burden off me. I don't have to just sit there and say, I'm going to write the prescription for you or not, then you're going to come every 2 weeks, I'm going to do MRIs every 3-6 months, and we're going to follow you very closely.

Now, I can say, this is a tricky drug, and I'm going to send you to a Center of Excellence where, if you really want it, you can enroll in a clinical trial. Is that right?

Caselli: At the moment, that is correct, and it may stay that way. There has been expressed interest by a number of people in the field petitioning Medicare to reconsider their stance because when they came out with that statement, at the time of aducanumab, they made it more of a blanket statement for all monoclonal antibody therapies directed against amyloid.

As you may know, Eisai, who is the primary company behind lecanemab, is also applying for full FDA approval. If they get that, it would put more pressure on Medicare to simply offer blanket coverage for that drug. Again, how that will play out, we are still waiting to see.

Wilner: I want to follow up on a small point just for my own information. The way these drugs work is to remove amyloid from the brain. Sometimes, there's amyloid in the blood vessels themselves. What happens in that situation?

Caselli: To my knowledge, it does work on the amyloid angiopathy component as well. I believe it's thought that's the likely source of, at a minimum, the microbleeds that I mentioned earlier, the hemorrhagic component of the cerebral edema, and maybe even the cerebral edema itself. I'm not sure if there's more than one source for the edema, but blood vessels would also be a candidate in that regard. Yes, it does also work on blood vessels.

Wilner: Dr Caselli, you have given us a large amount of terrific information in a very brief period of time. I want to thank you. Is there anything you'd like to add before we close?

Caselli: It has been a pleasure to be here. You've asked some very good questions. As you can tell, we're all challenged by this. This is not going to be easy for anybody. I imagine, even at a Center of Excellence, one of the challenges is having sufficient resources to offer this to enough people should many people want to receive it.

That's not going to be a simple thing for anyone, given how prevalent Alzheimer's disease is and the fact that it's being diagnosed earlier and earlier these days.

Wilner: Dr Caselli, many thanks for sharing your expertise about the diagnosis and treatment of Alzheimer's disease with Medscape.

Caselli: My pleasure. Thank you.

Wilner: I'm Dr Andrew Wilner, reporting for Medscape. Thanks for watching.

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