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Anti Amyloid Antibodies to Slow Alzheimer's Disease · Confronting Dementia

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The views and comments expressed in this podcast are those of the
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speakers and do not reflect the official stance, endorsement or
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opinions of Sutter Health or California Pacific Medical
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Center. Welcome to this week's episode
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of Confronting Dementia, a podcast by the Ray Dolby Brain
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Health Center, part of Sutter Health.
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I'm Doctor Travis Urban, associate medical director of
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the Dolby Brain Health Center. So far in this podcast series,
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we've focused really on the early stages of Alzheimer's
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disease, both the science behind how to get to a diagnosis of
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Alzheimer's disease and also the lived experience of getting that
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initial diagnosis. But after getting a diagnosis of
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dementia or Alzheimer's disease, the next logical question is,
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well, what can I do about it? For the longest time, the major
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recommendations that we were giving to patients were only
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lifestyle changes, things with your diet, exercise, increasing
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engagement and some pills, namely a drug called Donepezil
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or Aricept, which could help optimize functioning and are
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important but couldn't stop or slow the disease process.
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But this all changed in 2023 when the FDA approved a drug
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called lecanumab, which is also called Lecanbi, followed shortly
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by another drug called donanemab, also called Kisunla,
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which for the first time in the history of Alzheimer's disease,
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showed they could slow down the progression of Alzheimer's
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disease by removing amyloid plaque from the brain.
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And the release of these novel drugs completely changed how
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neurologists practice, both in terms of the tools we have
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available to diagnose Alzheimer's disease and how we
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think about our approach to testing patients.
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But these new therapies aren't for all Alzheimer's patients,
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and they carry potentially serious side effects, namely
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brain swelling or brain bleeding.
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They're also not the easiest to give and to monitor over time.
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Here to help me break down everything related to these
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promising new therapies, I have the pleasure of welcoming back
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our medical director at the Ray Dolby Brain Health Center, Dr.
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Armin Mugamian. Armin, welcome back to the show.
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Oh great to be here as always. Before we jump in, it's January
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2026. How are the holidays for you?
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They were good, you know, as always, a little chaotic in laws
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in town, kids off school for 2 1/2 weeks.
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Yeah, yeah. Keeping them busy and uninfected
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when we're all indoors, which is impossible as we are both
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possibly a little bit under with a slightly nasal voice from our
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from our mild colds. But no, we had a good time.
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We had we did a little traveling, went to Joshua Tree,
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kids climbed on rocks. No one, no one fell and injured
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their head. How was your your holiday?
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Oh, same. It's good to see people, but
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chaotic. We went to Texas, that's where
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my family's from, and we took our three small kids on the
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plane down there, which getting there was fine.
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But you know, in the travel day, we picked up probably at least
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two different bugs, which slowly made us sicker and sicker.
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So by the time we were flying back, you know, two of my kids
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were febrile and it was it was a mess, but it's good to see
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family. I saw all the family and like my
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kids played with their third cousins.
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It was wild. So it was it was it was good.
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It's a lot. It's always good.
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All right, so jumping in, starting with the basics.
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So how do these new therapies work, lecanemab and donanemab,
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and how are they given and what can they do for patients?
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Yeah. So I think it's a great topic to
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talk about and an exciting time for Alzheimer's disease as we
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have this new treatment to offer to patients.
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But as you mentioned in your intro, they are complex and
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require more testing and more monitoring.
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And, and the way that these medications work is they, they
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clear the underlying pathology of Alzheimer's disease.
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So as we've talked about in the prior podcast episodes, you
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know, Alzheimer's disease is not just the clinical symptoms of
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losing your memory and the clinical declines that come with
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dementia where patients require more care and and lose some
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function. But it is it's due to this
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underlying pathology of amyloid and Tau.
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But these medications are addressing that first pathology
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of Alzheimer's disease, the pathology of amyloid.
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And what they do is they stimulate the immune system to
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remove this amyloid from the brain and slow the progression
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of Alzheimer's disease. So they are antibodies that we
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infuse into patients. And I think that's the first
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complicating factor or potentially complicating factor
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is that these aren't oral medications, aren't something
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you're going to take as a pill, but they're actually infusions
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that are given IV at this point. And and developing injectable
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versions of these is definitely coming down the pipeline.
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But they're they're they're IV infusions of an antibody that
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stimulates your immune system to remove the pathology of
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Alzheimer's disease and slow the progression down.
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And so now we're calling these disease modifying therapies,
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meaning we are changing the underlying course of the
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disease. We're bending the curve, slowing
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the slope of progression, which is super exciting to be able to
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offer patients. Right.
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Yeah. So.
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Finally, being able to take out and address some of those
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underlying pathologies. Why then if you are taking out
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amyloid, I mean, what, what can these drugs achieve?
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Like what do they what do they help patients?
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How do they help patients at the?
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End of the day, no, I think that that's the that is the question.
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Because I think when patients are faced with this idea of or
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fairly daunting idea of, of infusions and MRI monitoring,
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which we'll talk about in a little bit, they have to think
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about, OK, what are they, what is the, the goal of treatment
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and the goal of treatment in this case is to slow the
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progression of the disease. What does that mean?
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You know, I think it, it, what it doesn't mean is that we're
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not curing the disease, we're not stopping the progression of
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the disease. What we are doing is slowing the
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rate of progression and what the the efficacy that comes out in
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the clinical trials. If we kind of look at the
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totality of it, I sort of think of this as about a 30% slowing
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of cognition over time for patients in the early stages of
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the disease. We'll define what early stage
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means in a little bit, but we're slowing the progression of the
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disease for me. And I think what resonates the
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most to patients is the looking at the conversion from one stage
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to the next. So as we've talked about in
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prior episodes, if patients come to you with a mild cognitive
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impairment, meaning symptoms of cognitive change that they're
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adapting around the next stage of the disease is a mild
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dementia stage, meaning that they now need some assistance
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with some activities like managing their medications or
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finances. And if you, if you look at the
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conversion from one stat stage to the next stage, the we reduce
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the risk of conversion by about 35%, thirty, 35% depending on
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the medication. So we're keeping patients in
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these earlier stages for a longer period of time and we are
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reducing the risk of progressive cognitive and functional
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declines. Right.
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So the idea being the treatments to help slow decline, they help
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delay the advancement of the disease to the next stage.
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And I think another way that is sometimes helpful to talk about
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what how these drugs help patients, these infusions last a
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year and a half. That's sort of the initial
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period of treatment is a year and a half or 18 months.
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Like you were saying, Armin, the degree of slowing we see is
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around 30%. And so if we think about 30% of
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18 months or 1/3 of 18 months, it's, it's, it's around six
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months. And so it's a little bit hard to
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explain sometimes, but there's this idea that by slowing the
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rate of change, by slowing down the progression of the disease,
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you are buying yourself back more time.
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And over that at least initial year and 1/2, which was how it
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was studied in the trial over that year and a half time
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period, the expectation is that you are sort of buying yourself
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back six months of time. It's another way of taking that
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30% number and making it something a bit more tangible in
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terms of the lived experience of of doing these infusions.
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And it gets confusing, like we were just talking about this six
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month number, the six months of time bought back over a year and
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a half. It's it's not a, a fixed number,
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right? You know, you're on this a
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shallower slope, a slower rate of change.
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And over a year and a half, you've bought yourself back six
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months. But the expectation is that, you
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know, over time, as your disease is slower than it otherwise
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would have been, you keep adding to that time bought back.
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So maybe it's six months at a year and a half, and then maybe
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it's, you know, nine months to 12 months at three years.
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But it's this sort of additive time bought back as the disease
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process goes on. And that's what's sort of panned
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out in the studies, right. So the initial studies, which we
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call the randomized placebo-controlled time was 18
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months, as you said. But as it happens with these
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trials is that there's a continuation phase.
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And So what was done in this open label extension was
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extending the data out for four years for lecanemab, 3 years now
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for donanemab data. And we see this progressive
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widening over time and the amount of time saved for a
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patient is increasing. And so now at four years for
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lecanemab, the patients that were treated at four years or
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where the patients untreated were at three years.
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So that is exciting to see that we are buying more time for
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patients, keeping them in this earlier stage for a longer
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period of time. Yeah.
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Right, so the benefit right is slowing time bought back and and
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who were these treatments really for?
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Who was the ideal Canada? So as we've talked about the,
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the pathology of Alzheimer's disease is the accumulation of
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amyloid and Tau in the brain. And amyloid is the first protein
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that accumulates and then you get to Tau.
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And the further along patients are in the progression of the
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disease, the more Tau there is in the brain and the less
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dependent they the progression is on amyloid removal.
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So I like to explain that. So I think it kind of explains
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why we're treating early stage patients.
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We're treating early stage patients because that is when
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the disease is more dependent on amyloid for progressing.
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So if we're going to clear amyloid, we better do it when it
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matters. And so we're treating patients
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in in what has become defined now is early stage Alzheimer's
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disease, which is the clinical stages of mild cognitive
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impairment symptoms that we're adapting around to early stage
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mild dementia where patients may have some functional declines
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due to their Alzheimer's disease, but are living largely
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independent lives. They're not needing help with
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activities of daily living like bathing and dressing and going
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to the bathroom. Etcetera, right, Yeah.
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And even right. So early stage is really the
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key. But even in that word, early
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stage, I mean it's a wide it's. A huge window.
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Window right from someone who's just on the cusp of MCI versus
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someone who's sort of on the cusp of more of a moderate
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dementia. So even within early stage, it's
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a wide range of pathology of levels of impairment that are
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considered candidates for the therapy, which also what we've
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seen additionally in the trials is that when we treat the
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earlier and earlier we treat people, the greater the efficacy
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appears to be the greater degree of slowing.
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So when we talked about that 30% slowing that you know, six
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months of time bought back over that at least initial year and a
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half therapy, but that's the average number, but that's
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average of people who are much less impaired and people who are
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much more impaired. So it is our expectation that
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someone who is at an earlier stage probably has a bit more
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slowing, a bit more than 30%, a bit more than six months, maybe
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it's more like 7 to 8 or a bit even a bit more than that over
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that initial period. Someone who's a bit later in the
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disease process, who's a bit more well into a mild dementia
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phase, that slowing is is likely less than six months or less
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than that 30%. So it it really all kind of
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comes early stages important, but even within that it's the
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earlier the better with these the.
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Earlier we intervene the more likely we are to see benefit
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with these medications. Absolutely.
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The the statistic that I like to think about is it's a subgroup
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analysis. So you know you have to look at
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these with a little bit of of caution, but I think are
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exciting to see that in the donanemab trial when we look at
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patients with mild cognitive impairment that had low levels
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of Tau that secondary pathology in their brain, we're seeing a
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60% slowing. If we look at patients with in
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lecanemab trial with low to no amounts of Tau in their brain at
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four years, 69% of those patients did not decline at all
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on the Cdr Summa boxes, which is super exciting.
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So more data to come there. I think that we're learning when
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we get new medications, it's not just about using it in the
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patients that were trialed, but we will learn more about these
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medications over time and refine who we give it to.
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And some of the trials that we're doing at the Dolby Center
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are going to be studying a patient population before they
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even have symptoms. And I think that that's a super
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exciting time, potentially exciting indication, but early
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times to treat those patients. Yet, you know, the point of a
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clinical trial is not just to determine efficacy, but also
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safety in that specific patient population.
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But I I'm very optimistic about that.
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Potential for these medications to have even greater impact in
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patients before they even have symptoms may even delay or
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prevent the onset of cognitive symptoms due to Alzheimer's
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disease. Right.
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Yeah, you brought it up. I think it's a it's an area that
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we as providers are all waiting to see the results of these
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trials that are ongoing because we've been talking about, you
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know, people who have symptoms of Alzheimer's disease and
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treating those people. And I want to just you make that
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point. I want to call that out a bit.
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You know, there are people who have the pathology in their
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brain, amyloid plaque deposition, Tau tangled
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deposition, but who do not show symptoms.
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And it is our belief mine that these are pre symptomatic people
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that likely at some point they will start to show symptoms but
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do not show symptoms yet. And we haven't seen results in
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treating those patients yet. Does treating those patients
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actually prevent the disease altogether?
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And those trials are ongoing. That's the ahead trial.
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And then you're going to have to remind me of the.
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One Trailblazer 3. Yeah.
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Too many trailblazers, yeah. Right.
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So with Donanemab, with Donanemab, thank you.
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So hopefully we'll see results from those soon, but those just
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to take this treating early approach to that full extension
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of going to people who have pathology before symptoms, you
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know, maybe we could prevent Alzheimer's disease altogether.
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And that's sort of the most exciting potential promise that
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these drugs hold. And if that turns out to be the
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case, I mean, it would totally change how we approach, you
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know, then we start screening people early.
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It changes every. Changes everything.
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I mean, it's it's fun to have that optimism for the future.
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I think we're still waiting for the results of those trials.
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But I think you and I are both equally optimistic about it.
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But early days yet, yeah. And I don't, right?
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I don't want to get too rosy here.
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So I mean these drugs have very significant potentially side
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effects. So can you talk a little bit
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about some of the side effects that are common in this class of
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medications, these anti amyloid antibodies and how we go about
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monitoring them, how we understand them?
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Yeah, and so on. Absolutely, you know it.
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So it comes down to thinking about how they work.
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So again, they're stimulating the immune system to remove
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amyloid from the brain. And sometimes you can over
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stimulate the immune system and that can lead to a bleeding or
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swelling that happens in the brain.
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The other thing that's interesting is that amyloid can
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accumulate in the brain itself, but it can also accumulate in
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the blood vessels. And so patients that have this
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amyloid in the blood vessels, as you're removing it out, that can
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lead to some bleeding that happens.
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And so the main side effects are bleeding and swelling that
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happens in the brain. It sounds incredibly scary.
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It goes by the name of Aria. Aria which stands for Amyloid
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Related Imaging abnormalities. Beautiful Acronym.
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Terrible. Yeah, terrible name.
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Yeah, exactly it. Yeah, exactly.
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Beautiful acronym, terrible name.
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It's why we all call it Aria. And I, I like to highlight the
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point of imaging abnormalities because I think that's a really
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important point to bring up. But in itself it is 2 forms.
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You can get a, a swelling form, that's the Aria E or edema form,
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that's the brain swelling or an Aria H form, which is a bleeding
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form. And this is a a side effect that
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occurs. So we can actually stratify
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patients for the risk of developing Aria and we do that
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in two ways. One, we get a baseline MRI which
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helps us understand and if they have any features that make them
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higher risk for the development of of this Aria side effect.
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And the other way is through a gene test called the APOE gene,
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patients can have one or two copies of the APOE 4 gene and
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the more copies of that APOE 4 gene, the higher the risk of
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developing this Aria side effect.
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The other thing I think that's very important to hear about
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Aria is that the rates of Aria seem very high when we just look
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at the top line from the clinical trials where you're
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looking at 2525% plus of development of Aria.
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But as we talked about the acronym, it stands for Amyloid
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related imaging abnormalities. So the majority of patients
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actually feel nothing when they are have Aria.
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So it is an asymptomatic side effect and around 75% of
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patients, the 25% of patients that feel the symptoms of Aria
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tend to be transient symptoms of headache, nausea, dizziness,
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walking changes, vision changes, they get a little more confused.
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That will resolve typically over the course of a couple of weeks,
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but there is the risk of a little bleed.
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Typically the bleeds of Aria are very tiny, but sometimes they
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can be larger and this is causing a stroke and this can
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lead to more permanent neurologic problems.
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That risk is around a half a percent of patients that are
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treated. So again, we want to
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appropriately contextualize this because if you just say there's
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a 25% risk of bleeding and swelling in the brain, no one
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would sign up for this. But on the other side, this is a
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manageable side effect and the risk of having a permanent
20:11
neurologic disability or a permanent problem because of a
20:14
side effect from these medications is relatively low.
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So there is this appropriate counseling that we have to do
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and risk stratification before we initiate treatment so that
20:23
patients understand the risk as well as the benefit.
20:26
Right, right. Yeah.
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So you're saying Aria is really most of the time just an imaging
20:32
abnormality, something we see on the imaging, but isn't
20:35
necessarily correlating into any kind of clinical symptom that
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patients have? Exactly.
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And then we can because we can see it on imaging that that
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really leads to monitoring people for it.
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So that we're not just going to start you on it and hope for the
20:48
best. We're we're going to monitor
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you, especially when you initiate treatment because
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that's when the risk of this is the highest in the first six
20:54
months of treatment is typically when we see 90 plus percent of
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the Aria occurring after six months.
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It's really uncommon. And so we monitor people after
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the first, second and third month, six month of treatment to
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look for that asymptomatic Aria before it becomes a problem so
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that we can intervene typically by just holding the medication
21:13
and letting the yeah, stopping the medication temporarily.
21:16
Sometimes, often patients can go back on so that we can then
21:20
adjust and make sure that they don't become symptomatic from
21:23
the treatment. Right.
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So yes, brain swelling, brain bleeding at the surface sound
21:28
awful, but they, you know, we can really understand which
21:32
patients are likely to have it, you know, by getting that
21:35
baseline MRI, like you said, there's very clear, often clear
21:39
features on there to suggest someone would be at higher risk
21:41
for these side effects. That gene.
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You talked about APOE, which like it's really just in our
21:48
experience, you know, you talked about APOE 4.
21:51
If it's really people who have the 2 copies of E4 where that
21:55
risk is really, really high. I mean, it goes up to, you know,
21:58
40 to 50% likelihood that something's going to happen.
22:03
And I would say just speaking experientially, I think most of
22:06
our patients are probably, you know, 3334 we have, we have
22:12
fewer. I think this overall having 2
22:15
copies of the four is rarer. But we do have people that we're
22:20
treating who are E4E4. Some of those have had
22:24
significant Aria, others have had none at all and it totally
22:30
tolerated the treatment fine. So I mean, it's really, I mean
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every patient is is unique with this, but we do everything that
22:37
we can do to assess someone's risk before we start.
22:41
And then once we are going, like you said, we're following people
22:45
with these regular MRI scans for in the first six months that
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early time when it's it's likely to occur.
22:53
So again, yes, serious, but it is an understandable risk and a
22:59
monitorable. Risk, yeah.
23:01
And the interesting thing is that when these medications were
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trialled in clinical trials, the rates of Aria were pretty high.
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But in our experience, both yours and eyes and at the Dolby
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Center, but also nationwide and some newly published studies,
23:16
the rates of Aria and clinical practice are lower than what was
23:19
seen in the clinical trials, which I think many of us were
23:21
surprised cause typically you see more side effects in
23:24
practice than you do in trials. I don't think we quite
23:26
understand that, but it's an exciting thing to see.
23:30
Yeah, agreed. Agreed.
23:31
Right. So the side effects that we're
23:33
monitoring for is the Aria, but just in a little bit, just tell
23:37
me a bit about the other. There's one other side effect
23:40
that can happen with these drugs that can happen right at this
23:43
start. Yeah.
23:44
So the other thing that can happen is an infusion related
23:47
reaction. Again, these are antibodies that
23:49
stimulate the immune system. And sometimes when you get those
23:52
infusions right away, typically in the 1st 4 hours or so of
23:57
treatment if if it's going to happen, you'll get some flu like
24:00
symptoms. I I liken this to when people
24:01
get a vaccine stimulates the immune system.
24:04
You feel a little feverish, a little fluish, muscle ache,
24:10
pretty typically it goes away with a Tylenol.
24:13
More rarely the people can have more significant allergic
24:17
reactions, potentially even like an anaphylactic reaction where
24:21
you get like a blood, blood pressure drops or you get like a
24:26
rash. That's pretty uncommon.
24:28
But it's important to note that is the other side effect.
24:30
And that's why when we first start these treatments, we
24:33
usually keep people in the infusion Centers for a couple of
24:36
hours after their treatment just to make sure you're tolerating
24:38
it. We don't want you having one of
24:40
those reactions on the drive home.
24:42
The other thing everyone always asks is how long do these
24:44
treatments last? You know, they last about 30 to
24:47
60 minutes per treatment. And it's not something like
24:51
chemotherapy where people get wiped out.
24:53
Sometimes people report a little bit of tiredness when they first
24:55
start. But typically this is you get a
24:57
treatment over an hour, let's say, and then you're you're off
25:00
doing whatever you need to do for the rest of the day.
25:03
Yeah, right. And like you were saying, this
25:05
sort of fluish reaction, I mean, essentially what we're doing
25:09
when we give people these infusions, they're antibodies,
25:12
right, that are targeted against the amyloid plaque, which is
25:15
what your body makes when it's fighting off any kind of
25:17
infection or antibodies and you're pumping the body with all
25:21
these antibodies. We have to do that right now
25:24
because only a, a tiny fraction of those antibodies can cross
25:27
from the blood into the brain, getting across what's called the
25:30
blood brain barrier. So we give you a whole bunch to
25:33
just get the little bit that we can in there to have an effect.
25:37
But that's sort of why these reactions can happen.
25:40
And again, it's on the order of 20.
25:43
On the mild side and I think the more severe ones are, are a few
25:47
percentage of total. Yeah, small but sort of trying
25:51
to explain mechanistically why these things can can happen.
25:54
But right, So there's just the sort of potentially fluish kind
25:59
of reaction from getting the like while you're getting the
26:01
infusion and then the risk of Aria.
26:04
But the another thing that I think comes up a lot is, you
26:07
know, people here in Fusion and then place people's minds go is,
26:12
you know, chemotherapy. That's what they are used to
26:14
thinking about, thinking about infusions.
26:17
And other than the things we talked about, I mean, these
26:20
these drugs are and what we've seen generally well tolerated.
26:24
It's not a toxic thing. It's a very targeted substance
26:28
that we're giving to people. Like you said, it's maybe a
26:30
little bit of fatigue the day of your infusion, but it it's not
26:34
like you're going to be home vomiting for weeks on end.
26:37
And, and I think one of the things that I found most
26:40
encouraging now we nearly have, we have treated almost probably
26:43
about 400 or less than 400 patients at this point.
26:47
And you know the, it sounds really daunting when patients
26:51
hear about this, OK, every two week or every four week
26:53
infusions, Lecanemab every two weeks, donanemab every four
26:56
weeks, 4 Mris in the first six months of treatment.
27:00
We haven't seen a lot of patients give up on it, right.
27:03
Most patients tolerate this really well.
27:05
Sometimes we've had to stop because of Aria, but rarely
27:08
patients have just said, oh, this is too overwhelming, I'm
27:11
not going to do it. And I think that I'd like to
27:14
think part of that is that we've counseled people appropriately
27:16
about the expectations so that we're not starting patients that
27:19
are not wanting to do it. But it also shows that these
27:22
medications are tolerable and that although it sounds like a
27:25
lot, it is, it's doable for the vast majority of our patients.
27:29
I would say 95% have been able to, plus have been able to
27:33
continue on in treatment and not found it overwhelming.
27:36
Yeah, great. And I wanted to also address if
27:42
you've a listener has been listening to the news at all
27:46
about these medications. Yes, these most recent
27:51
medications are FDA approved, but there there was a lot of
27:54
controversy surrounding this class of medications before
27:58
these recent approvals. There is a history there.
28:01
Is a history a history? I mean, I can you talk a bit
28:05
about what this controversy was? And I think also just we've been
28:10
targeting amyloid for a long time, long time.
28:13
And I think there's a lot of it has led to a lot of skepticism
28:18
about whether treating amyloid is a viable path.
28:21
And maybe we can talk a little bit about that too.
28:24
But I think let's just start with the controversy around
28:28
these drugs. Yeah, well, I mean, I may start
28:30
with the history. And it symbolizes the iterative
28:34
process of science. Sure.
28:36
And that can be really frustrating for patients.
28:39
It can be frustrating for us as doctors because we get our hopes
28:42
up and there's failures. And, and the other thing is that
28:46
Alzheimer's disease, although a scary disease, moves really
28:48
slowly. So it actually is kind of hard
28:50
to study because each trial takes 5 + 8 years to to do.
28:56
And so you have this iterative process.
28:58
So pretty soon 3 iterations of trials just took three decades,
29:02
you know, or two decades. So there have been a lot of
29:05
failures in Alzheimer's disease, specifically targeting amyloid.
29:10
And I think that was a variety of different factors.
29:13
It was not targeting the right species of amyloid.
29:16
You know, we talk about amyloid as a single thing, but it's
29:18
actually a cascade of progressive aggregation and we
29:22
targeted the wrong thing. That didn't work.
29:24
When you target more soluble species, it's targeting the
29:28
right stage of the disease, getting the right dose into
29:31
people. So all of these things are
29:33
unfortunately learned over time and it took a long time.
29:36
Where there was more controversy was with this drug called
29:39
aducanumab or Aduhelm, which released data in 2019 the and
29:44
then actually got a conditional approval in 2020-2021.
29:49
And the problem with aducanumab was that the company stopped the
29:54
trial early because they didn't think the medication was going
29:56
to work. But what had happened when they
29:59
were doing the trial is they actually started to increase the
30:02
dose over time, but they didn't do the analysis on the entirety
30:07
of that pop. They did the analysis on the
30:09
entirety of the population and not looking at those that got
30:11
the highest doses. And then after they stopped the
30:14
trial, they went back and looked at the data and they realized
30:17
that those patients that got the highest doses, that cleared the
30:20
most amount of amyloid actually had efficacy of the medication.
30:24
Now, the controversy came because the company Biogen sort
30:28
of pushed the drug to get approval.
30:30
The right thing would have been to put your head down and just
30:33
do the third trial and prove the efficacy in a completed trial
30:37
instead of pushing it through. And it led to people having a
30:40
really bad taste in their mouth. It ultimately did get approved.
30:43
Under this conditional approval. It didn't really have a lot of
30:45
uptake because Medicare didn't pay for it.
30:49
But now we have these two medications, lecanemab and
30:52
donanemab that have been fully approved by the FDA, that have
30:56
completed their full trials and have shown the efficacy that was
30:59
pretty similar actually to the efficacy of the aducanumab
31:02
drugs. The other everyone always asks
31:05
about which medication to pick, and we can talk about that in a
31:08
minute. But the other thing that I think
31:10
that's really important to note about having two medications is
31:14
that these medications work pretty similarly, but it proves
31:19
the mechanism, right, because you now have two different
31:22
medications to run by two different companies to an
31:25
independent trials that do very similar things that show the
31:28
efficacy that's pretty consistent between the two
31:30
medications. And I think that's really
31:32
important to note because it shows that this works.
31:36
Right. And I and with you on that 100%
31:40
I it's a lot of interesting things.
31:42
I think, you know, one other thing, just when you were
31:44
talking about the iterative process of getting to these
31:48
treatments that show efficacy against amyloid, it was also
31:52
this, the advent of being able to image amyloid in the brain
31:56
also. And we had this technology
32:00
called amyloid PET scanning. So now we can like make sure
32:03
that these people that we're treating do actually have
32:06
Alzheimer's. Disease, I know it's amazing
32:07
because if you look back at some of the original clinical trials,
32:10
we did it before we used amyloid PET as a entry criteria and like
32:14
30% of the people in the trial didn't actually have Alzheimer's
32:17
disease. So is we did not, we just
32:20
weren't able, we didn't have the right tools also and then right
32:24
targeting the right stage, being able to these things because
32:27
Alzheimer's move so slowly, right?
32:29
They just take time. And and that's my stance.
32:32
I and with aducanumab a bit too, it was the FDA approved it
32:38
purely based on the fact that it removed amyloid solely.
32:42
Not, I don't know if Biogen pushed it through, but the FDA
32:46
just to be fair to Biogen a bit, I mean the FDA was the one who
32:49
ultimately said, well, we think just based on amyloid clearance
32:53
alone and not the efficacy that this could benefit patients.
32:57
I think that was the major sticking point of controversy.
33:00
But I. Do think the FDA got it right?
33:02
I just think the process didn't leave people with a lot of
33:05
confidence, with a lot of confidence.
33:06
And ultimately I think the FDA is right, but I don't think it
33:10
we didn't need to make that leap for biomarker.
33:12
The the the outcome being the biomarker right away.
33:14
We should have started with the more robust clinical advocacy.
33:17
Yeah. And like, I think people are
33:19
sort of picking up on, I mean, we do have treated a lot of
33:23
people with anti amyloid therapy at the Ray Dolby Brain Health
33:27
Center. I mean, I, but ours is not, I
33:30
think a universal perspective across all of neurology.
33:33
I think some still have some skepticism around the efficacy
33:37
here. But and I but, and I tend and I
33:40
side with your thoughts that, you know, in those clinical
33:44
trials where amyloid plaque in the brain was substantially
33:48
reduced, those trials showed efficacy.
33:52
And there are other trials like another antibody even called
33:55
gantanerimab where there was not substantial plaque reduction
33:59
over the course of the trial. We didn't see any efficacy in
34:04
that trial. So it, the clinical trials that
34:06
have been done, namely lecanemab, donanemab and these
34:09
these other ones, aducanumab, gantanerimab, it's, it's those
34:11
trials where the plaque has gone down, where we've seen
34:14
efficacies. So that that to me is suggesting
34:17
that these this approach to treatment is having an effect.
34:21
It's not, we're not stopping it. You know, it is slowing and and
34:24
and better earlier, but it is something and and I think that's
34:29
really important to patients to be able to participate in
34:34
something finally that can. And it's the first step.
34:37
I mean, rarely in medicine have we hit it out of the park on the
34:40
1st, on the first swing. And so it's the first step.
34:43
And we will learn from here. We're going to get better from
34:45
here. But the other exciting aspect of
34:48
this is that this is the first time we're able to slow the
34:50
progression of Alzheimer's disease.
34:52
And I think this will be the spark that ignites more and more
34:55
trials because for so many years it was thought of as a
34:59
inevitable process that couldn't be modified.
35:02
So now we can modify the disease, and we're going to get
35:04
better at it from here. And when you say better at it,
35:07
what are some of the ways coming down the pipeline that we're
35:11
sort of hoping to get? Better, we've talked a little
35:13
bit about it already. 1 is like earlier intervention, so maybe
35:17
in that pre symptomatic time before patients have major
35:21
symptoms. The other, The thing is to a
35:23
multimodal approach, so we've talked about Alzheimer's disease
35:27
is the combination of two pathologies, amyloid and Tau.
35:30
Clearly the next step will be targeting Tau and seeing if in
35:33
addition to amyloid removal, Tau reduction also slows the
35:37
progression of the disease. And then maybe other avenues
35:40
around addressing inflammatory components, whatever that really
35:44
means. But there's a lot of other
35:46
secondary factors that Dr. progression of the disease that
35:49
ultimately maybe we could target, reduce and reduce the
35:52
progression of the disease. Absolutely.
35:54
Yeah, yeah, very, very exciting. Tau therapies.
35:56
If we can finally have a Tau therapy, I think we'll really be
36:00
able to really bend back the course of the disease.
36:03
And and I think people think of neurology is different than
36:08
anything else. But if you, this is so parallel
36:10
to almost every other aspect of medicine, you know, we don't
36:14
have one cancer treatment. It's it's a combination of
36:16
cocktail. We don't have one HIV
36:18
medication. We have a cocktail.
36:19
We don't have one blood pressure or diabetes medications.
36:22
And this is where we're heading is is it will be multimodal.
36:26
Earlier intervening is better. We don't wait for people to have
36:29
symptoms of cancer and a lump coming out of their neck to
36:31
treat their cancer. This is where we have to go.
36:34
Yeah. No matter of a disease process,
36:36
you know, and if you can head it off before it starts, right?
36:39
Prevention is the goal and and other things too.
36:42
If I mean right now patients have to go to an infusion center
36:48
by and large, you know, to get their infusion.
36:50
And I think what we're seeing over time is hopefully in terms
36:54
of improving patient access, we'll be able to have versions
36:58
of these drugs that we can give people at home under the skin
37:01
subcutaneously. I think that is coming and
37:04
hopefully happening soon. And other ways of just getting
37:07
the drugs into the brain, you know, we're getting better at
37:10
that all. So attaching drugs to these
37:13
little carriers that help it get across the blood brain barrier
37:17
so we don't have to use these huge doses that can reduce the
37:21
rates hopefully of Aria. So you know, the technology even
37:25
around anti amyloid itself is also getting better.
37:28
So, I mean, so there's a lot of, you know, hopeful things
37:31
happening there. It's exciting.
37:33
Yeah. Yeah.
37:34
When we were talking about amyloid PET, I realized I'm
37:36
going to backtrack just for a minute.
37:38
You know, we're talking about eligibility, it's about clinical
37:41
stage, but it's also about confirming pathology, right?
37:44
We have to make sure before patients, you know, we want to
37:47
look for those patients in early stage disease, ideally mild
37:50
cognitive impairment more than mild dementia, but we also have
37:52
to really make sure they have that underlying Alzheimer's
37:55
disease pathology of amyloid. So doing an amyloid PET, which
37:58
is the most common way we do it these days, there are a few
38:01
other technologies like spinal fluid or bloods kind of coming
38:05
along, but really amyloid pets, the main workhorse to confirm
38:08
they have those aggregates because that's what we're
38:10
targeting. Right, exactly.
38:13
And I think that sort of bring it all back when you talk to
38:17
patients about these infusions, you know who and we talked early
38:22
stage is important, but I think lots of other factors are
38:25
important also, right? Like is this infusion the right
38:29
approach for me in my situation? And what are some of the other
38:34
considerations that come into play for you when you're talking
38:37
to people about these new therapies?
38:39
I mean, I talk about it very much as we've talked about it
38:41
today kind of setting up what is Alzheimer's disease, what is the
38:45
efficacy, These are inconvenient.
38:47
They require the Mris. They're they're IV, you have to
38:50
go to the infusion centre, maybe subcutaneous is coming in the
38:53
future and you are getting this 30% slowing of cognitive
38:57
impairment for all that effort. And it's modest, but it's real.
39:03
And I think it is in, you know, it is something that is is
39:07
meaningful to patients to stay in these early stages longer.
39:11
I think that now you would never approve a medication for hope,
39:16
but I do think that having a pathway of treatment that can
39:20
slow the progression of the disease does give patients hope.
39:23
And I think that that is very powerful for patients when they
39:27
get the diagnosis that there is something that they can do to
39:29
slow this disease down. So I think that that is a very
39:32
positive benefit. Again, not improving your
39:35
medication because of hope, but I think that there's a lot of
39:38
power in, in enabling patients to, to, to with these
39:42
medications and, and giving them hope.
39:44
The other thing to think about is that this isn't done in
39:46
isolation. You know, this is an additive
39:49
therapy. You started by talking about
39:52
Donepezil and lifestyle factors and those are certainly
39:56
beneficial and and patients need to go on those medications when
40:00
appropriate. They need to live healthy
40:02
lifestyles and this is really the third new bucket of
40:06
treatment in the armamentarium of dealing with this disease.
40:09
Right. Agree.
40:10
And when I talk about it too, I mean, I think every patient is
40:14
different, obviously, and it comes at this with a different
40:17
approach. And I think about it differently
40:20
when someone's in their mid 60s versus late 80s, right?
40:25
And how much are you trying to, how much medical intervention do
40:29
you want for, you know, this six months of time saved over a year
40:33
and a half, right? And what are your other medical
40:35
comorbidities? You know, it's not like it's
40:38
every patient who's going to really be the ideal fit for
40:41
these infusions. We, I think we tend to emphasize
40:45
these treatments more in people who are a bit younger.
40:49
Depends though. I mean, it's very, very healthy.
40:52
80 year olds of mine have also done it.
40:54
I mean, I think the oldest person I've treated is 87.
40:57
They did very well. They're very mildly affected.
40:59
They were very happy with it and they did just fine.
41:02
But you know, there's a lot of different factors that come in
41:05
to play when deciding like who is a a good.
41:07
Candidate I I completely agree. And I think our job as
41:12
clinicians, our job at the the brain health, the Dolby Brain
41:15
Health Center is to open the door and talk about what these
41:20
medications are. And I think opening the door is
41:22
doing the evaluation to understand, are they candidates,
41:26
what is their diagnosis and then opening the door towards
41:29
understanding the safety, the efficacy and the downsides to
41:33
doing the medication as well as the potential benefits,
41:35
benefits. So our job is not to get people
41:37
onto these therapies. It's they get them to the point
41:39
where they can make the decision for themselves and enabling
41:43
their their that decision making.
41:45
Agreed. I think that's all I've got.
41:47
Arman, thanks so much for coming back today.
41:50
Yeah, it's always a pleasure and thanks for having me.
41:55
Thanks for listening to this weeks episode.
41:57
We'd love to hear from you. You can e-mail us at
41:59
confrontingdementia@sutterhealth.org. Tell us if you like our content
42:04
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42:06
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