Anti-Amyloid Agents

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: December 15, 2024

Expiration Date: December 15, 2025

Estimated Time of Completion: 28 minutes

Anti-Amyloid Agents

Charles Bernick, MD

Description

Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience

Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

ACCREDITATION

In support of improving patient care, Cleveland Clinic Center for Continuing Education is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

CREDIT DESIGNATION

• American Medical Association (AMA)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
  
  Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

• Certificate of Participation
  A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

• American Board of Surgery (ABS)
  Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Credit will be reported within 30 days of claiming credit.

Podcast Series Director

Imad Najm, MD
Epilepsy Center

Additional Planner/Reviewer

Cindy Willis, DNP

Faculty

Charles Bernick, MD
Lou Ruvo Center for Brain Health

Host

Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Anti-Amyloid Agents

Charles Bernick, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

The following faculty have indicated they have no relationship which, in the context of their presentation(s), could be perceived as a potential conflict of interest: Cindy Willis, DNP and Charles Bernick, MD.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

HOW TO OBTAIN AMA PRA Category 1 Credits™, ANCC Contact Hours, OR CERTIFICATE OF PARTICIPATION:

Go to: Neuro Pathways Podcast December 15, 2024 to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at myCME@ccf.org

Copyright © 2024 The Cleveland Clinic Foundation. All Rights Reserved.

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neurorehab, and psychiatry.

Glen Stevens, DO, PhD: In recent years, we've seen the advent and sunset of the first anti-amyloid agents, a new and evolving landscape for Alzheimer's disease management. As treatments like adacanumab phase out, it's crucial to understand the advancements and challenges of these agents. In today's episode, we're discussing efficacy, patient selection and safety surveillance for anti-amyloid agents and explore their profound impact on patient care.

I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm pleased to be joined by Dr. Charles Bernick, a neurologist and researcher in Cleveland Clinic's Lou Ruvo Center for Brain Health. Charlie, welcome to Neuro Pathways.

Charles Bernick, MD: Well, thanks, Glen. It's really a pleasure to be with you today.

Glen Stevens, DO, PhD: So I was just looking at the intranet today and congratulations. I see that you're the new holder of the Lee Pascal Endowed Chair for Clinical Research in Vegas. So congratulations on that.

Charles Bernick, MD: Thank you very much. Thank you.

Glen Stevens, DO, PhD: Outside of that, why don't you tell us a little bit about yourself? Tell us about your background, how you made your way to Vegas.

Charles Bernick, MD: Yeah, so I'm a neurologist as well, your colleague at the Cleveland Clinic and have been involved in actually the field of Alzheimer's disease since the mid-1980s, which at the time there wasn't much known about this condition. Really the advancements we've made within even the last 10 years have been amazing, and I have been part of that here at the Cleveland Clinic since 2009 here in Las Vegas.

Glen Stevens, DO, PhD: Okay, welcome. So we're going to talk about amyloid today, but I think it's probably just to set the stage, tell us what amyloid is as it relates to Alzheimer's disease and why we target it or why we're interested. I know that people will have some understanding of plaques and tangles, but tell us about amyloid.

Charles Bernick, MD: Well, there you have it. The heart of Alzheimer's disease pathology is these plaques which are made up of the amyloid protein, which accumulates and then clumps together, and tangles, which are deposits of a different protein called tau. This is the characteristic pathology of Alzheimer's disease.

What we think happens is that the amyloid gets deposited in the brain. That's probably the earliest feature, and then sets off a chain reaction. A chain reaction, meaning that there's inflammation, there's modification of the tau protein, which is a normal protein, but gets modified and then can spread. It can spread throughout the brain, although this is a process that takes years to decades to occur.

Glen Stevens, DO, PhD: So it sounds like it's probably a good idea to treat this amyloid. Of course in the last few years there's been a movement in that direction in the FDA, sort of fast-track medications. So let's talk a little bit about maybe aducanumab and then the agents that are currently available and their mechanism of action or what they're thought to do.

Charles Bernick, MD: Absolutely. So aducanumab was the first drug approved by the FDA for a disease modification of Alzheimer's disease. What aducanumab does, as do the other drugs that are currently on the market now, lecanemab and donanemab, is that they target the amyloid protein. They're monoclonal antibodies, so they have to be infused intravenously and will attach to amyloid plaques, and then your immune system then removes the plaques.

So these have been shown all three of them to be very effective at removing plaques and actually changing the trajectory of the disease. People don't improve with them necessarily, but we believe it can actually slow down the progression as what you'd expect from a disease modifying therapy.

Glen Stevens, DO, PhD: Help me understand why aducanumab is now off the market.

Charles Bernick, MD: This is completely a business decision. So aducanumab is probably as effective as any of them. Except when it came out initially, even though it was approved by the FDA, it was not covered by CMS or Medicare and has not been ever covered by that. So from a feasibility standpoint, it's just not available to people. So I think it was a business decision by the company that makes it, Biogen, to cut their losses and move out of that space.

Glen Stevens, DO, PhD: Tell us what evidence shows us about the effectiveness of these drugs, because I guess there's two sides of it, right? Yes, they can remove the amyloid, but does removing the amyloid then result in any improvement?

Charles Bernick, MD: Yeah, I think the evidence is really pretty overwhelming that it does, that what you mentioned, the latter it does happen. That is they all effectively remove amyloid plaques and it comes out to after a treatment period of about 18 months, 80% of people will have all their plaques as far as we can tell from imaging, gone. That is you can make a scan, a PET amyloid scan look normal.

Now does that translate then to clinical benefit? People argue about this, but I think again, there's such a consistency in all these drugs. We know that on average the decline they've seen over 18 months, about a little under 30% on cognitive measures, close to 40% less decline on functional measures. We know after 18 months that about 50% of people on drug don't change at all. That is they stay stable, compared to close to 25% of people on the placebo.

So these drugs definitely change the trajectory of the disease. People can quibble about, oh, is that meaningful? Keep in mind the whole idea of a disease modified therapy is the effect will get greater over time. So as it's changing the slope of the disease, the longer you go out, theoretically the more effect you're going to have.

Glen Stevens, DO, PhD: I'd also think that finding earlier before damage is done would be better. So if I'm having some mild cognitive impairment and I come and see you, what type of test do you run on me to determine if I might be a candidate for one of these anti-amyloid drugs?

Charles Bernick, MD: So the drugs are really indicated for people with mild symptoms of Alzheimer's disease. So either what we categorize as mild cognitive impairment, that is people who are having memory problems more than you'd expect, but yet function normally. And even with people who have mild Alzheimer's disease, dementia. So yes, they don't function independently, but they're pretty functional. They can do most of their activities with prompts, cues, a little supervision. So those are the people that we believe will benefit the most. We do know that people who are further along in the disease, moderate to severe symptoms, are likely to get no benefit. So it does have to be in somebody earlier in the disease process.

As far as the testing part, we do have to confirm they have amyloid plaques in their brain, and this is done in two different ways at the moment. So one is PET amyloid imaging, which is now covered by Medicare, and CSF studies of the amyloid and tau proteins. So those are two ways to confirm the presence.

I'll just add parenthetically that the really exciting part in our field is these blood tests that are coming up for Alzheimer's disease. I don't know if people accept that they're reliable enough to use as a single measure at the moment, but we're heading in that direction. So we have to be sure they have mild symptoms, they have amyloid in their brain, and of course most importantly, there's no contraindications. That is from a safety standpoint, they're not at any very high risk of the side effects of these drugs, which primarily boil down to the fact when you pull out amyloid from the brain, a percentage of people will have amyloid in their blood vessels, and then you can incite some inflammation in the blood vessels and basically fluid can leak out and into the brain and cause some edema. Even then, most of the time those people are asymptomatic, but that's the biggest risk and we want to make sure a person does not have any other medical conditions that would make them more prone for that to happen.

Glen Stevens, DO, PhD: So since you brought up the ARIA, the amyloid-related imaging abnormalities, how do we monitor for that? So you've got to do regular imaging studies. How often do you do it? I believe my recollection is that depending on your APOE status, there's a little more risk and you have two main variants, the ARIA-E, which is more cerebral edema and ARIA-H, which is more hemorrhagic risk. Why don't you go through that with us?

Charles Bernick, MD: Well, we began again by trying to weed out people who are more likely to develop ARIA, which we know are people who have amyloid angiopathy. There's features on their baseline scan that can help us determine that who would be at the highest risk. So that's one major risk factor.

The other major risk factors, as you mentioned, is their genetic status. So the apolipoprotein E genotype. If you carry one copy of the E4 gene, that puts you at an elevated risk of ARIA occurring. If you carry two copies, it increases it significantly. Now that doesn't mean those people can't be treated, but it's just they have to understand that they're at a higher risk.

As far as our surveillance of that, once somebody starts treatment, there's just a schedule. So we know that if ARIA is going to occur, it will occur early. So usually within the first three, four months, certainly the first six months is the most vulnerable time. So we have MRI scans scheduled on a somewhat regular basis after, for example, with lecanemab, it's after the second month, then the third month, then the fifth month. So you have a number of these MRI scans loaded up front. Or if somebody has a symptom that will trigger usually an off schedule MRI scan to, again, be sure that they don't have ARIA.

Glen Stevens, DO, PhD: So I'm on the medication, you're following me, you do an MRI scan on me, you see an increase in edema. You think I might have ARIA-E, but I'm clinically doing okay, do I need to stop the drug? Or you just continue the drug?

Charles Bernick, MD: Yeah. Well, it turns out there's an algorithm for that based on what was done in the studies. So people who have minimal or mild ARIA actually can continue to dose, but if the ARIA is significant, if it's multifocal, again, there's a whole, if it's bigger than a certain amount, then we stop the drug. We do know that usually there'll be complete resolution of the ARIA within three months, four months.

As far as we know, looking at people, some of the long-term open label phase of these studies, having ARIA doesn't necessarily change the disease process. In other words, it doesn't worsen your prognosis in the long run. So the problem with ARIA is the symptoms that if you do have symptoms, which is again only about a quarter of people who have ARIA actually have symptoms, but it's really the symptoms at the time and the severity of the ARIA at the time that that occurs.

Glen Stevens, DO, PhD: Okay, so I'm taking the drug, you do a scan on me, I have a little blood products or a little edema that's there. I'm clinically doing fine. You make the decision based on the algorithm to stop the medication for three months. You re-scan me, things are better. Can I restart the drug?

Charles Bernick, MD: Some can. Again, this is a discussion I think that is really between the physician and the patient. There are definitely instances where you just would not start the drug. If the ARIA was severe or if the symptoms were severe, that probably is not a great idea to restart the medicine. Or people who have had recurrent ARIA, that is they have it, then you challenge them, they have it again. Those people probably should not be re-challenged with the drug. But, on the other hand, if you've had ARIA, it's resolved, if it was mild to begin with, then they could be re-challenged with the medication.

Glen Stevens, DO, PhD: Do you check the APOE status on all the patients before starting or not necessary?

Charles Bernick, MD: No, no. We do check APOE status on everyone. It's kind of almost a requirement prior to starting the drug.

Glen Stevens, DO, PhD: Just to go back to something we discussed earlier, for the diagnosis you do the amyloid PET scan, and you mentioned the CSF as well, looking at the amyloid and the tau, and you can do some ratios to help figure things out. I guess the benefit of the CSF is it looks at tau, where the amyloid PET just looks at the amyloid. So most patients will get both.

Charles Bernick, MD: No, usually actually you'll choose one or the other, and it's often based on insurance issues and so on. Or I guess if there is other things in the differential diagnosis that you would be looking for in the CSF. It's interesting, the blood tau measures and the CSF tau measures are really not a great measure of the tau burden in the brain. It seems that at the moment, really the best indicator of that is called PET tau imaging, which is available but not commercially. So really these tests we're doing measuring tau even in the CSF is an indicator primarily of the likelihood of amyloid being present. Ideally, we would like to have a blood marker that truly represents the tau amount or burden in the brain, but that's just not available at the moment.

Glen Stevens, DO, PhD: Okay. So I think you mentioned this a little bit, but who's not a candidate for therapy? I take it someone whose imaging is negative, has more severe disease and has MRI images of blood products or something else. Is that kind of the...

Charles Bernick, MD: Yeah, I would say the main exclusionary criteria, certainly if they don't have amyloid. Or if there are really obvious signs of amyloid angiopathy, if they're on anticoagulants, we're often very careful about that. I mean, most people would not treat somebody on an anticoagulant. Or if they have very severe cerebrovascular disease.

Again, it's just thought that these groups may be the highest likelihood of either ARIA edema or the other concern would be ARIA-H, which is the microhemorrhages that may not just be microhemorrhages, that is you might transform something into a major hemorrhage. So those are primarily the contraindications to use the drug.

Glen Stevens, DO, PhD: So I come in to see you with my family. I guess you've gone through some of the things you'll discuss with us, but what's the discussion like?

Charles Bernick, MD: Yeah, I think it's really just going over the benefits and the risks of the drug so people understand what it can do and what it's not going to do. Again, it's not going to improve people. It's not going to stop progression. So people have to understand that.

There needs to be a discussion on really how it's going to change their quality of life. In other words, if somebody's in their late '80s and they may have mild symptoms and it's likely the disease's progression is going to be slow anyway, it's not worth taking the risk of a drug like this. So I think it is that type of discussion.

And then finally, just that the patient has an understanding of what type of surveillance is going to be necessary as far as the treatment. So I think it's like every decision in medicine that we do with our patients, it's just sharing our knowledge of benefits, risks, and trying to come up with really the best decision for them.

Glen Stevens, DO, PhD: Is cigarette smoking a contraindication to taking the drug?

Charles Bernick, MD: I wish it was, but no, it's not. Unless again, unless they have some underlying, more severe cerebrovascular disease.

Glen Stevens, DO, PhD: Yeah, it's interesting because from a surgical standpoint, cigarette smoking can decrease wound healing, a little more of a bleed risk. So I was just curious with these types of drugs that can cause hemorrhage if there's any contraindication to it, but sounds like there's not.

Charles Bernick, MD: Actually, I don't know if anybody's really looked at it. Maybe we should.

Glen Stevens, DO, PhD: There you go. A research project for you as the new head. So I come to see you, I agree to therapy. How do you decide which of the two drugs that's approved you put me on, what's the differences?

Charles Bernick, MD: So they both remove plaque and even though there's no head-to-head trials, it seems like the benefit that they provide is very similar just based on these scales and such that are done. So then it comes to practical and theoretical reasons. So the practical part is that donanemab is a once-a-month therapy and it is stopped once all the amyloid is removed. That is based on the studies, the idea is that you would check an amyloid scan maybe after the first year and see if the amyloid's gone, and if it is, you could stop it.

Whereas lecanemab is a twice a month therapy for 18 months. Now the other differences that the ARIA rate with donanemab is higher. Although the significant ARIA, which is a more severe ARIA is the same. So I mean I guess if you're just worried about the worst of the worst, it's about the same between both of them.

Then there's the theoretical aspects, which is that donanemab is targeted strictly to the amyloid plaques. There is some belief that really the toxic form of amyloid is not the plaques themselves, but is actually what are called protofibrils or a soluble form of amyloid, which actually lecanemab binds to. So if you kind of go that route you'd say, well, lecanemab is not only removing plaques, but it also is removing this toxic soluble form. Which is why actually the company Eisai who produces lecanemab has gone to the FDA and is awaiting decision for a maintenance therapy, approval for maintenance therapy. So once you remove the plaque, of course the disease is still there, you're going to start producing amyloid again. Things are going to continue. The rationale that lecanemab is making is that their drug could actually help in a maintenance phase after you've removed the plaque.

Glen Stevens, DO, PhD: Yeah, I'm glad you brought that up because I'm sure families to some regard just get into the motion of the treatment and feel some comfort. I'm doing treatment. Then one day you come to them and go, "We're stopping." I'm sure there's a little bit of panic when you do that. So it's good to hear that more to come and maybe there'll be a decision on some maintenance treatment, but how do patients take the, "We're going to stop your treatment now"?

Charles Bernick, MD: Often they're thrilled. We haven't actually, to be honest with you, Glen, it's because these drugs really were approved just last year. Now we're just getting people who are finishing their therapeutic regimen with lecanemab. We don't know how they'll take it, how many people truly have had the amyloid removed.

I think there probably is a certain comfort to know that yes, the treatment has removed your amyloid plaques. Then it really brings up this whole issue of, yes, amyloid is... We think it's an important part of the disease, but it's only one target of a very complex disease. So there's a lot of work of course, going on in looking at drugs that target other mechanisms in the disease. It's likely there'll be some combination therapy type approach at a certain point.

Glen Stevens, DO, PhD: So I assume because the treatments aren't that frequent that people don't need a central line in general unless they have very bad access. Is that right?

Charles Bernick, MD: That's correct. We haven't had anyone really who's had any central line or in-dwelling port. So yeah, usually they just come in, get the IV going, and it takes about an hour to infuse. At least here in Las Vegas, we work with infusion centers throughout the valley.

Glen Stevens, DO, PhD: Okay, do you pre-medicate? Are there infusion reactions?

Charles Bernick, MD: Yes. Now there can be infusion reactions. The common things such as pruritus or things like that, rash. So yeah, if a person has that, that's possible, if they have it then we would pretreat them.

Glen Stevens, DO, PhD: So I come to see you and my amyloid PET is negative, so that's not going to be a therapy for me. So what do you have to offer for me for the amyloid negative person with Alzheimer's disease?

Charles Bernick, MD: The amyloid negative person has a further journey to go, which is to try to understand than what is the cause. The second most common neurodegenerative cause of cognitive impairment is Lewy body disease, the one in the Parkinson family. They may have underlying vascular disease that need to be more aggressively treated. For the very old people, there's this condition called late limbic predominant age-related TDP-43 encephalopathy. So it really would depend what we thought the underlying cause of their memory problems are.

Now, for those who have amyloid but yet are not candidates for lecanemab or donanemab, then the choices are somewhat limited. There's certainly the symptomatic therapies that are available that have been on the market for 20 years almost. Then the other option is clinical trials. As you know here at the Cleveland Clinic, both in Cleveland and here, we've been very actively involved in trials of other drugs that don't carry the risk of ARIA and attack the disease in different ways. So I think a person has to make that decision if they want to participate in something like that. Certainly there are plenty of clinical trials going around of new approaches.

Glen Stevens, DO, PhD: Just as an aside, do you see behavioral improvement with patients on these medications? The memory's one thing, but is there quality of life affected in a different way on these medications?

Charles Bernick, MD: Yeah, I don't know if that's been really shown that it has in general a positive effect on behavior, which of course as you bring up is common even early in the disease, behavioral changes are common. So I don't know if we have a good handle on that as an affect of the drug. Although I will say it's very common to have a person on symptomatic therapy while they're undergoing the anti-amyloid treatments.

Glen Stevens, DO, PhD: So as a brain tumor guy and what I know about the disease, it would seem logical to me that put me on an anti-amyloid and an anti-tau drug at the same time. Is that available? Is this something that's being looked at?

Charles Bernick, MD: Well, great minds are thinking like yours. I mean, so there have been some anti-tau drugs that have been tested that have not been successful. However, that doesn't mean we've stopped trying. So there's a big initiative. There's a tau, what they call tau platform, which is looking at various drugs that can influence tau. I think the thought would be that either be done in combination or sequentially, that you would have an anti-amyloid agent, maybe initially, and then an anti-tau agent or both at the same time. Again, they're both fundamental parts of the disease process.

Glen Stevens, DO, PhD: In terms of reality of life, insurance coverage for these medications.

Charles Bernick, MD: That's the good news actually, because CMS or Medicare has approved anti-amyloid therapy, so both donanemab and lecanemab are covered by Medicare. Coverage should be pretty good for almost anybody who's a candidate.

Glen Stevens, DO, PhD: Any trials you guys are involved in that you'd like to highlight?

Charles Bernick, MD: I think this is just as an example. So we are involved in a study, it's called the START study, but it's looking at the same population, mild cognitive impairment, mild AD dementia. It's looking at a drug that doesn't remove plaques, but it actually blocks the adherence of amyloid to the neuron, the cell itself. So the good news to that is it doesn't have the risk of ARIA, edema, or micro hemorrhages, now whether it works who knows? We’ll find that out because it’s an early stage study. But I think this is just an example of products that are being tested that could be the complementary to anti-amyloid drugs or used in combination. So I think it really is an exciting time in our field and particularly in a field that where there was no progress for so long, and now we're moving ahead again.

Glen Stevens, DO, PhD: Maybe it's my simplistic way of looking at it, but my recollection was that amyloid outside the neurons, tau inside the neurons. Is that...

Charles Bernick, MD: That's correct. That's what makes it so difficult to find anti-tau agents that can penetrate, that affect the tau that you want because tau is a normal protein. Or that can ideally prevent tau from spreading.

Glen Stevens, DO, PhD: Yeah. Too many things to go through.

Charles Bernick, MD: Yeah, that's right. There you go.

Glen Stevens, DO, PhD: All right, well listen, it's been a pleasure having you. Any closing thoughts for the audience?

Charles Bernick, MD: Only to say that hopefully these new treatments will change the paradigm about Alzheimer's disease and early detection and this kind of therapeutic nihilism I think we've had for a long time in the disease will change because certainly the earlier you start these drugs, if a person's a candidate, more likely they're going to get a benefit from them.

Glen Stevens, DO, PhD: Well, I find that as I get older, I dislike the term nihilism even more, so I'm glad that some breakthroughs or at least some innovative thinking is going on in terms of how to manage and maybe something that I and others out there will need down the road. So I appreciate your joining us today. Congratulations again on the chair and appreciate all the research and fine work you're doing.

Charles Bernick, MD: Well, thanks, Glen. It's really a pleasure to be with you today.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's @CleClinicMD, all one word. And thank you for listening.