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

Amyloid-Targeted Therapies (ATTs) and Their Adverse Effects - What Should Geriatricians Know

• American Geriatrics Society • Season 1 • Episode 4

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Join Dr. Michael Harper, Professor of Medicine at the University of California, San Francisco and Dr. Daniel Parker, Associate Professor of Medicine in the Division of Geriatrics, Assistant Professor of Neurology and Medical Director at the Duke Memory Disorders Clinic at Duke University School of Medicine, as they discuss Amyloid-Targeted Therapies (ATTs) and Their Adverse Effects.

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Michael Harper:

Hello and welcome. My name is Dr. Michael Harper. I'm a geriatrician and a professor of medicine at the University of California, San Francisco. And I'm really happy today 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. And this curriculum was designed for our members, both experienced clinicians and geriatrics fellows, as a way to sort of keep up with this really pretty quickly changing landscape around Alzheimer's disease diagnosis and treatment. So we figured as new technology and therapies are continuing to emerge, we wanted to make sure that our members and our learners are keeping up with what's happening so that we can really best advise our patients. So today I'm really happy to have the pleasure of speaking with Dr. Daniel Parker about a module that he created titled Amyloid Targeted Therapies and Their Adverse Effects. Before we get started, let me introduce you to Dr. Parker. He's a geriatrician and an associate professor of medicine with a joint appointment in neurology at the Duke University School of Medicine. He's also a senior fellow of the Duke Center for the Study of Aging and Human Development and Medical Director of the Duke Memory Disorders Clinic. So some of his research and clinical interests are focused on these disease-modifying treatments for Alzheimer's disease and related dementias. And specifically, and one of the reasons we're talking to him today is he actually has some experience in the use of Lecanemab and Donanemab, the two FDA-approved anti-amyloid therapies for MCI and mild dementia due to Alzheimer's disease. So really great to have you here, Dr. Parker. thanks for being with us.

Daniel Parker:

Yeah, thanks for having me. Great to be here.

Michael Harper:

So I've been really looking forward to talking to you in large part because you have a lot of experience with using these medications. And it's really important that we've can certainly have a lot of sort of theoretical discussions, but really having someone who's actually used these medications, I think, is really important. So I was thinking maybe a good place to start is to ask you to share maybe some of the history about the development of these therapies. How did we get to this point? This didn't happen overnight.

Daniel Parker:

Yeah. Um so at the Duke Memory Disorders Clinic, we have uh currently around 250 patients on treatment. Um, and about 110 of those patients are my patients. So yeah, I have quite a bit of familiarity with these treatments. And I think one thing that's really important for people to understand, um, especially given some of the controversy around these treatments and some of the past failures, is just a little bit of the history of this approach to targeting Alzheimer's disease. So for around 25 years now, people have been working to harness the immune system to target the amyloid plaque that accumulates in Alzheimer's disease. And that began uh actually in the late 90s with the development of vaccine against the full-length amyloid that was used in a mouse model of Alzheimer's disease. And that was shown to uh lead to a really marked reduction in amyloid plaque burden. And so in 2001, uh this approach of using an active immunization strategy with a vaccine was uh trialed in humans. Unfortunately, that trial had to be terminated early because about 6% of participants developed what was at that time described as meningoencephalitis. We would now characterize as a one of the main side effects of these medication treatments for Alzheimer's. But looking at the brains of those brave participants, many of them showed a really significant reduction in amyloid plaque burden as well as tau pathology. And some of them had persistent clearance for the remainder of their life. And so, given the kind of harms associated with this active immunization strategy, the field shifted to using a passive immunization strategy. So using antibodies targeted against the amyloid that are delivered via infusion as kind of a gentler way of engaging the immune system against the amyloid pathology. For many years, these trials all failed. There was no benefit clinically with this approach. And I think that led to some significant pessimism. And also, I think that led to people uh starting to question whether or not amyloid was really an important driver of Alzheimer's disease. I think if you dive into the trials uh and look at uh the effects of the drugs that were tested, many of them didn't actually do anything to get rid of amyloid. Um they maybe stopped amyloid from uh amyloid burden from getting worse, if anything at all. Some of them didn't even do that. Uh it wasn't until Aducanumab, which was the first anti-amyloid drug that got partial FDA approval in 2021. That one entered human clinical trials in 2015. And that was the first anti-amyloid treatment to actually show a significant reduction of amyloid burden in the brain to the point where many participants became amyloid PET negative. And that was the first drug that gave us a hint that there might be some clinical benefit with respect to stopping the progression of cognitive decline using this approach. And then we subsequently had the result of the clarity AD phase three trial of Lacanomab, followed by the results of the Trailblazer ALZ2 trial of Donanemab , that also showed significant amyloid flat clearance and an even greater benefit than compared with Aducanumab. So it turned out that for this approach, the treatment to work, we really needed rapid and robust clearance of amyloid. And Aducanumab, Lecanemab, Donanemab were the first three anti-amyloid drugs to demonstrate that they could do that. And as a result of that, we saw uh this modest uh clinical benefit with respect to slowing progression of memory and thinking changes.

Michael Harper:

Uh that's a that's a really great summary to get us sort of up to speed. And I and I want to sort of now dive a little bit into so you you mentioned that the way these you know these drugs work by clearing amyloid. How do they actually do that? What what's the what's the sort of mechanisms behind these drugs?

Daniel Parker:

Yeah, so um these drugs are all uh antibodies that target different forms of amyloid that build up an Alzheimer's disease. Um so amyloid biology is pretty complex, um, but basically it starts with an amyloid monomer, and then that amyloid monomer can oligomerize, and those amyloid oligomers can then aggregate into protofibrils and fibrils, and then finally form the amyloid plaques uh that we think of in combination with the tau tangles that are the pathologic hallmark of Alzheimer's disease. And so the way these treatments work is they bind to amyloid, and so Lacanamab binds to the protofibrils of amyloid, and donanemab binds to the Pyroglutamate form of amyloid that's found in the mature plaques, and they trigger an immune response, primarily mediated by microglia in the brain, to clear that amyloid and so these antibodies basically harness the brain's immune system to uh make it aware of this pathology and then trigger an immune response to get rid of it.

Michael Harper:

And how good are they at doing that?

Daniel Parker:

Yeah, so um they're pretty effective at doing that. Um, so in the clarity AD trial of Lacanamab, about two-thirds of participants were amyloid negative by a visual read of an amyloid PET scan at 18 months. Um, Donanemab was a little more effective at clearing amyloid. Um, in the Trailblazer ALZ2 trial, uh, where participants actually started out with a higher amyloid burden uh compared to the clarity AD trial of Lacanamab, about three-fourths of participants were amyloid negative at the conclusion of the trial after 18 months.

Michael Harper:

So I think you're pretty clear that these drugs are actually good at what they're targeting. Why do you think, or why do we think that clearing amyloid from the brain is important? Why can it be beneficial?

Daniel Parker:

Yeah, so um, you know, according to the amyloid cascade theory of all or hypothesis of Alzheimer's disease, um, the first change uh that leads to the loss of memory and thinking skills that we see in Alzheimer's disease is this accumulation of amyloid pathology. And that process happens slowly. Uh typically takes you know 10 to 20 years before people uh have a significant amyloid pathology that's then as visible on an amyloid PET scan. It's not really the amyloid pathology that causes the significant changes in memory and thinking that we see with Alzheimer's disease, but rather that amyloid pathology triggers changes in the microtubule associated protein tau, initiates a process whereby tau is hyperphosphorylated, which then predisposes tau to start aggregating and forming the tau tangles that we think of as the other part of the equation in Alzheimer's besides the amyloid plaques. And those tau tangles first appear in the medial temporal structures of the brain, which are important for memory and thinking, the hippocampus and rhinocortex. And that's when patients first become symptomatic in Alzheimer's disease. And then as that tau pathology accumulates, it spreads further into the neocortical structures of the brain. And that's where we see a more precipitous decline in memory and thinking and a more rapid progression of symptoms. And so the idea behind targeting amyloid is if we're able to clear that amyloid early in the disease process before there's a substantial tau burden, then essentially we're getting rid of the stimulus for tau production. Whatever tau will still be there, it can still spread. So we still expect to see progression even with treatment with these drugs. But if we're able to get rid of the stimulus for the production of that tau, then we can slow down the rate of progression of clinical decline in people with Alzheimer's disease.

Michael Harper:

So you had already brought up some of the clinical trials. And I just want to say as background, we did a separate podcast with Eric Widera. We kind of did a kind of a deep dive into the review of the trial data. But for the purpose of this talk, where we're we're talking about the mechanisms, what do you think are some sort of highlights of the trials we should take away, or maybe a more succinctly way to say it is who might benefit from these treatments and how do these two treatments sort of differ?

Daniel Parker:

Yeah, so you know, I think the takeaway from the clinical trials is that there's a modest benefit in terms of slowing progression of memory and thinking changes with these treatments. But the key takeaway for me at least is that all of the evidence, especially from the Trailblazer ALZ2 trial, where they had participants stratified by TAL pathology, all the evidence points to earlier treatment yielding a substantially greater benefit compared to treating when symptoms are more significant. In the Trailblazer ALZ 2 trial, um, investigators stratified participants based on their Tau burden. And while the overall benefit looking at you know everyone in the trial was pretty modest, um, about a 29% slowing of progression on the CDR sum of boxes. When you look at participants in the low to medium Tau group, we saw a greater benefit, around 36% slowing. Still not, you know, what we would hope for, but uh nonetheless a greater benefit. In the Clarity AD trial, they didn't do a pre-specified analysis stratifying participants by Tau status, but they did have a Tau substudy where a subset of participants also had Tau PET scans. Uh, and they did do an analysis looking at participants who started out with the low or no Tau burden. And those participants also did substantially better uh with respect to progression compared to those who started treatment with a greater Tau burden. Um, so I think all the evidence at this point is telling us that we really need to start these treatments early in the disease process when symptoms are mild, which means that there's likely a low Tau burden in the brain.

Michael Harper:

Yeah, that was gonna be my sort of my follow-up question is you know, now given your experience with these medications, are you seeing is that sort of bearing out in your sort of anecdotal following of these folks? And and or is it changing how you're thinking about who you recommend to potentially get started on one of these?

Daniel Parker:

Yeah, absolutely. Um I think, you know, just anecdotally in our experience and my personal experience, um, it's really the patients that were able to diagnose early and start early on treatment, who appear to be getting the most benefit. Um, obviously, it's very difficult to assess given that we don't know how these patients would be doing had they not started the treatment. Um, but I think I've seen many patients where I would have expected to see more progression, uh, who appear essentially to be stable in terms of both their cognitive status as well as their functional status. And I think that has impacted the way I counsel patients when they're thinking about starting these treatments. Um, certainly for patients who are in that mild dementia category where symptoms are more advanced, where uh they're less likely to get benefits from treatment, you know, I'm letting them know that, you know, this really may not do much for you. I think another thing that I think we'll probably get to later is the risk of side effects. And there's some evidence that people who have more advanced symptoms are also at a higher risk of side effects. So I'm telling patients that, you know, in your situation, given where we are, you know, this may be all risk and very little to no reward. So I really try to help patients understand that these treatments are really most effective when we get people very early and when their symptoms are very mild, and that the further along in the disease process, benefits are going to be less and the risk of side effects is probably gonna be higher.

Michael Harper:

Yes, that's a nice summary of I of the benefits. I appreciate your sort of putting it into that context. You know, I think for many of it it's still been challenging to know how to help people make these decisions. And it sounds like based on both the science and also your clinical experience, it sounds like we're getting better at maybe helping to target who might be more likely to benefit and who may be more at risk of the burdens, which is what I want to get to next. So let's talk a little bit about the potential harms of these. You mentioned this what initially was thought it was meningo encephalitis, and now what we would call aria. What can you tell us about aria? This you know, so-called uh amyloid-related imaging abnormalities. Sounds kind of benign, right? Just something you see on a picture, but I'm guessing there's more to it than that.

Daniel Parker:

Yes. So um aria is the very pleasant sounding term that we use to describe some potentially scary and life-threatening side effects that can go along uh with anti-amyloid therapy. And aria basically refers to kind of two categories of side effects. So the first is swelling or edema that occurs with treatment, and the other is hemorrhage or bleeding that occurs. And um these side effects we think are uh mediated by vascular amyloid, which is the first amyloid that these drugs encounter, particularly amyloid that's built up in the arteries and arterioles of the brain. And you can imagine if you're giving someone an antibody that targets amyloid, and some of that amyloid is embedded in the blood vessels of the brain, if you trigger an immune response in those blood vessels, that could certainly lead to weakening of the blood vessels, can lead to the edema, and certainly the bleeding or microhemorrhages, which are the most common manifestation of that bleeding. And so that's the major side effect of these treatments. I think, at least in our hands, uh in our experience here at Duke, the side effects have been generally pretty manageable. And I think that's because we do a good job of one patient selection and then two uh counseling patients about the side effects so we can catch them early. Um, so the biggest risk factor for these side effects is having uh one or two copies of the APOE4 allele. And so um, if someone has one copy, the risk of these side effects is modestly increased. And it's really in patients with two copies where we see the highest risk of these side effects. And the reason for that as well is because with the APOE4 variant, you have a higher risk of developing that vascular amyloid, another name for which is cerebral amyloid angiopathy. And we also do a good job, I think, of making sure we identify patients who already have signs of CAA on their baseline MRIs before we start. So we make sure that all our baseline MRIs are obtained at least a year before starting treatment, ideally a little bit sooner. And we also look for findings on the MRI that would tell us that those patients already have that cerebral amyloid angiopathy, which would include things like multiple microhemorrhages, uh, superficial siderosis, significant white matter changes, those can all tell us that that patient may have that CAA and maybe an increased risk of side effects with these treatments.

Michael Harper:

So at Duke, I'm wondering, do you have any strict contraindications or is it still, no matter what, sort of shared decision making? I'm imagining, say, a young person with very mild symptoms, maybe MCI, who has two copies but says, hey, you know, I think this is worth the risk for me. How how are you guys thinking about that?

Daniel Parker:

Yeah, so um, at least in my practice, you know, I generally do a lot of shared decision making. I do have some hard cutoffs where I absolutely think the risk of treatment is too dangerous to consider. Um so certainly if someone already has multiple microhemorrhages and the cutoff we use is more than four, which comes from the appropriate use recommendations. Oftentimes, you know, that's gonna be a hard stop for me. Any superficial siderosis that's present on that baseline MRI, gonna be a hard stop for me. Um certainly at patients who have you know severe white matter changes, physique is three, and I have treated patients with that finding, and they've done well. Um, so that's not been an absolute exclusion for me. But generally, if people are starting out with more than four microhemorrhages, if they have any superficial siderosis, then I think the risk is just unacceptably high.

Michael Harper:

And how about how do you think about APOE?

Daniel Parker:

Yeah, so I know some centers will not treat ApoE4 homozygotes. That's not our policy. We will treat them. And I've had many ApoE4 homozygotes who've done really well with the treatment. Have not had significant side effects, or if they have, you know, they've been mild. And so, you know, I don't think that that should be a barrier to treatment. And, you know, we've had good experience uh treating those patients here at Duke.

Michael Harper:

So obviously we know we monitor for these with, you know, MRIs at particular intervals. How might folks manifest these complications clinically? Or, you know, what are you seeing or what do we know about that?

Daniel Parker:

One thing is these side effects that they're gonna occur typically occur in the first six months of treatment. So after the first six months, the risk of side effects drops pretty substantially. And within the first six months, the risk of side effects is really highest around the two to three month time point. And so that's when we cluster our monitoring MRIs to try to catch these side effects early. Most of the time, if people develop the RAE, the swelling, the edema, there are no symptoms associated with that. Um, so typically 70 to 80 percent of people who develop RAE are going to be asymptomatic. If people do develop symptoms, the most common symptom is gonna be a headache. Other symptoms that can develop uh that can be a sign of RAE are worse than confusion, vision changes like double vision, balance problems, falls. Uh, and if the swelling is severe, it can rarely lead to stroke-like symptoms, seizures, and certainly also death. Um, but generally, the most common manifestation if people are going to have symptoms related to RAE is going to be that headache. Uh, typically the RAH, given that these are micro hemorrhages, um, typically there are no symptoms associated with that. Uh, rarely that, you know, hemorrhage can be a macro hemorrhage, and certainly that can cause uh focal symptoms depending on the location. But for the most part, uh, if it develops, it's gonna be asymptomatic.

Michael Harper:

So what do you do? You start with someone on treatment, first couple of months, you get their first MRI and they have one of these manifestations. What's what's sort of typically they're not having any symptoms? What do you typically do? How do you how do you sort of think about those folks?

Daniel Parker:

We do have a criteria, radiographic criteria to grade the aria. So mild, moderate, and severe. So if someone has mild ARIA E or ARIA H, generally we can safely treat through that. What I do is I'll reach out to the patient, I'll talk to them about it. I give them the option of pausing treatment, uh, repeating the MRI in a month or so just to assess for stability of the findings or resolution of the ARIA E. And then uh generally, you know, we can safely uh resume treatment. Um, certainly if it is moderate or severe, then we will pause treatment, repeat the MRI. And you know, this practice varies uh depending on the center. Typically, for someone with asymptomatic ARIA, I'll repeat the MRI uh after about a month to assess for either resolution of the ARIA E, stabilization of the ARIA H. As long as it's not severe aria by radiographic criteria, um, once we see resolution of the ARIA E and stabilization of the ARIA H, uh then we can safely resume treatment. Typically, if the ARIA occurs, it's gonna happen once, not happen again. Um, certainly if someone has severe ARIA E or ARIA H, regardless of whether uh, you know, they're asymptomatic, we're gonna stop treating.

Michael Harper:

Great. That sort of covered the set of the nuts and bolts of what I was hoping to talk with. I wanted to just sort of maybe you could share us now that you've been doing this for quite a while, 110 patients is probably more than anybody that I currently know of. What are some general lessons that you've learned that you think is worth sharing with our listeners?

Daniel Parker:

You know, one of the key lessons is that it's really a matter of timing. Uh, these treatments can be effective, but we really have to catch people early, diagnose people early, and start people early on treatment. Uh, so I think it's really important that we're taking uh these symptoms seriously when people are reporting memory changes, that we're doing appropriate testing. We're not delaying that diagnosis because I do really think, based on all the evidence from the clinical trials as well as some of the long-term outcomes data, that these drugs can make a difference if they're started early in appropriate patients. Also, you know, we were all very nervous when we first started using these treatments about the risk of side effects. Was it going to be higher than what we saw in the clinical trials? A similar rate to what was seen in the clinical trials. I think actually our rate of ARIA E has been a little bit lower. And my guess is that's because we're treating people generally who are earlier in the disease process. If you look at our rate of ARIA H, it's been a little bit higher. I think that's mainly because we're using uh the SWE sequence to identify microhemorrhages, which is more sensitive than the GRE sequence that was used in the clinical trials. But we've been able to manage the ARIA risk, and I think we're all a lot more comfortable than we were when we first started.

Michael Harper:

Dr. Parker, I want to thank you for being with me today, for sharing your experience and with using these medications and for not only that, just sharing the background. I think it's really helpful for folks to know sort of how we got here, how these med how these drugs potentially work. And also want to thank you for sort of being on the front lines, for being the one of the folks who is sort of on the frontier and helping us to really understand how these medications work and sharing it with the rest of us. So thanks. Great to have you today.

Daniel Parker:

My pleasure. Thanks for having me.

Michael Harper:

Before we wrap up, what are uh some things that are in the pipeline here? Is there imagine that there is more coming after Lacanamab and Donanemab?

Daniel Parker:

Yes. So um, you know, one treatment that we entering phase three clinical trials this year is a anti-amyloid antibody called Trontinemab . This is actually an older anti-amyloid antibody, gantenerumab, which has been conjugated to a transferrin receptor ligand, which allows it to cross the blood-brain barrier. And by crossing the blood brain barrier, uh we're able to get much higher concentrations of the drug into the brain, which leads to much more rapid amyloid clearance. And also by crossing the blood brain barrier, we're bypassing a lot of that vascular amyloid. So the risk of side effects is actually lower. So using this treatment in the phase two trials, most participants were amyloid negative within the course of a couple months of treatment with a much lower risk of side effects. So I'm very excited for this treatment. Certainly, we're gonna have to wait a couple years for the phase three trials to be completed. Um, but I think this is just the beginning of anti amyloid therapy, and the next generation of drugs is gonna be safer and more effective.