Treatment can lessen severity of early Alzheimer's disease

Host Amber Smith: Upstate Medical University in Syracuse, New York, invites you to be The Informed Patient, with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith.

A new drug that can reduce cognitive and functional decline in people living with early Alzheimer's disease is available for infusion at Upstate University Hospital. The drug is lecanemab, and here to tell us more about it is neurologist Dr. Tinatin Chabrashvili, a professor of neurology and the director of Upstate's Neurodegenerative Disorders Center.

Welcome back to "The Informed Patient," Dr. Chabrashvili.

Tinatin Chabrasvili, MD, PhD: Thank you for inviting me back, Amber.

Host Amber Smith: Is this new medicine, lecanemab, or Leqembi, is this considered a potential cure for Alzheimer's?

Tinatin Chabrasvili, MD, PhD: Lecanemab, or Leqembi, is not a cure for Alzheimer's disease. But this is the traditionally approved treatment that addresses the underlying biology of Alzheimer's disease and that changes the course in a meaningful way for people in the early stages of the disease.

In the clinical trial known as Clarity AD trial, starting approximately at six months across all time points, lecanemab demonstrated statistically significant slowing of cognitive and functional decline with continued treatment. So this is not the cure, it just slows down the decline in terms of the cognitive and functional aspects.

Host Amber Smith: So is this designed for someone who's been diagnosed with mild cognitive impairment, or do they have to have been diagnosed with Alzheimer's?

Tinatin Chabrasvili, MD, PhD: This is a very good point, Amber, because not every type of mild cognitive impairment is caused by Alzheimer's disease.

So, this drug is indicated in those patients who have underlying Alzheimer's disease pathology, either mild cognitive impairment due to Alzheimer's disease or early dementia due to Alzheimer's disease.

Host Amber Smith: So how would a person know that they might benefit from this medication?

Tinatin Chabrasvili, MD, PhD: They require, obviously, some cognitive, symptoms. That's the first thing.

And assessing the patient clinically, it's the very first step for the assessment. And then ruling out other causes of dementia, including Alzheimer's disease. This is a sequential process and involves clinical assessments, assessments from the brain structural standpoint and also assessment of Alzheimer's disease biological biomarkers.

Host Amber Smith: Do the doctors look at beta-amyloid levels to determine whether somebody should try this?

Tinatin Chabrasvili, MD, PhD: Yes, absolutely. That's a mandatory step before we initiate treatment with lecanemab. It requires biological proof that the individual has Alzheimer's disease, and Alzheimer's disease is the one causing the symptoms.

And the next question is how we identify whether someone has Alzheimer's disease or not. And we usually use two diagnostic tools at this moment. One is the amyloid PET scan, and the second is biofluid biomarkers. Currently, we're required to do Alzheimer's disease biomarker assessment in spinal fluid. However, Alzheimer's disease blood-based biomarkers are in development, and we hope that they will be implemented in the clinic soon.

Host Amber Smith: So you have that testing that has to be done to determine whether this might be something that would be of benefit for a patient.

Tinatin Chabrasvili, MD, PhD: That is correct. Because the individual has to have underlying Alzheimer's disease pathology causing the symptoms to benefit from this medication.

Host Amber Smith: Can you describe what beta-amyloid is?

Tinatin Chabrasvili, MD, PhD: Amyloid-beta is a protein fragment that is closely associated with Alzheimer's disease. And this is actually a peptide composed of 36 to 43 amino acids, and it's derived from the large protein known as amyloid precursor protein. It requires two enzymes to cleave sequentially.

Amyloid-beta exists in different forms and normal biological functions such as in synaptic plasticity (how nerve cells communicate), neurogenesis (growth of nerve tissues), even possibly immune response. However, there are toxic species that are associated with development of Alzheimer's disease pathology, and particularly amyloid-beta 42 has been shown to be toxic and associated with the formation of amyloid plaques in the brain.

So accumulation of amyloid-beta in the form of plaques has been a hallmark of Alzheimer's disease and has been very closely related to development of Alzheimer's disease pathology. It has been thought that accumulation and aggregation of this amyloid-beta in the brain can disrupt the cell function, induce inflammation and, ultimately, lead to neuronal (nerve cell) death.

It is really important to recognize that the balance between the production and clearance of amyloid-beta is crucial for brain health. In Alzheimer's disease, the balance is disrupted, leading to accumulation of this peptide. And we also have to remember, however, that disruption can be influenced by multiple factors, such as genetic factors, mutations in amyloid precursor genes and in other genes, like those involved in cleavage of amyloid precursor protein.

I also want to emphasize that Alzheimer's disease is an ongoing neurotoxic process that begins before and continues after plaque deposition. Amyloid-beta converts into larger and smaller species, including oligomers and protofibrils. And this is really important when we are talking about designing appropriate monoclonal antibodies to scavenge these toxic species. Continuous accumulation of these profibrils contributes to neurodegeneration and eventually to neuronal death.

It's also important to highlight that the amyloid-beta cascade also triggers the downstream molecular pathways, including tau (a protein) pathology, which further contributes to neurodegeneration.

So, this is a very complex process, and recognizing the pathophysiology will help us to design proper treatments.

Host Amber Smith: Do I understand correctly, though, in dementia, or Alzheimer's, there's an increase of the amyloid in the brain, and then this new medication, lecanemab, helps lower those levels? Is that how it works?

Tinatin Chabrasvili, MD, PhD: Yes. That is absolutely correct about lecanemab, which is a humanized immunoglobulin monoclonal antibody, directed specifically against soluble and insoluble forms of amyloid-beta, and clears these toxic species. I also want to emphasize that, specifically, lecanemab is the only anti-amyloid antibody that preferentially binds to neurotoxic protofibrils, approximately 10 to 15 times higher sensitivity versus fibrils and more than 1,000-fold versus monomers.

So, it's a complex biology, and as I indicated earlier, there are different toxic species' efficiency, and there are other monoclonal antibodies similar to lecanemab. And efficacy depends on which species are cleared, and how efficiently they are cleared, from the brain.

Host Amber Smith: You're listening to Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith.

I'm talking with neurologist Dr. Tinatin Chabrashvili about a new Alzheimer's drug called lecanemab, or Leqembi, that Upstate is now offering.

Let's go over the benefits and the risks of this medication, which I know may be different depending on the individual. But in general, what are the benefits?

Tinatin Chabrasvili, MD, PhD: The clinical trial, (called) the Clarity Trial, showed that it slows down the cognitive decline and functional decline approximately by 27%. So this is not the cure, but it's really slowing down of the process, and this slowdown of the cognitive decline was associated with clearing of amyloid-beta in the brain.

Host Amber Smith: And then what are the risks?

Tinatin Chabrasvili, MD, PhD: All drugs, lecanemab and other monoclonal antibodies similar to lecanemab, are associated with side effects. One of the most important side effects isx amyloid-related imaging abnormality, known as ARIA. Other side effects, include allergic reactions, headaches, infusion-related side effects. However, the most common reported side effects are infusion-related reaction, amyloid-related imaging abnormalities and headaches.

Host Amber Smith: How concerned should a patient be about amyloid-related imaging abnormalities?

Tinatin Chabrasvili, MD, PhD: Well, lecanemab has a boxed warning for amyloid-related imaging abnormalities, also called ARIA. And this refers to abnormalities seen on MRI scans that are associated with certain treatments for Alzheimer's disease, particularly those involving immunotherapy approaches like monoclonal antibodies in general, targeting amyloid-beta in the brain. These antibodies are designed to help clear amyloid plaques, which are characteristic for Alzheimer's disease.

However, the process can sometimes lead to unintended effects on brain tissue surrounding the plaques. Sometimes this could be seen only on the MRI of the brain and can be just incidental findings. However, sometimes they can manifest symptomatically, so monitoring of these patients who are receiving lecanemab is very important.

And to add one more thing, ARIAs are two different types. One is ARIA E, which is ARIA with edema (fluid buildup). And the second type is ARIA H, which is, area with hemosiderin deposition (a condition resulting from hemorrhaging). There is one particular group of patients who are especially susceptible for this type of side effects, and these are the APOE4 homozygous. So we have to be especially careful with those patients. And that's another black-box warning for this particular medication, that patients who are APOE4 homozygous, have to be counseled very carefully about these particular side effects.

Host Amber Smith: And you're saying APOE4, that's a particular gene.

Tinatin Chabrasvili, MD, PhD: That is correct.

The full name is apolipoprotein E, epsilon 4.

Host Amber Smith: So let me ask you, before we get some basics on how this drug is infused, are there any medical conditions that would disqualify a person from having lecanemab?

Tinatin Chabrasvili, MD, PhD: Yes. There are certain conditions that disqualify the patients, and more importantly, if someone has dementia not related to underlying Alzheimer's disease pathology. So that's one of the most important.

Another important contraindication (reason not to use the drug) is if someone has more than four microhemorrhages in their brain. So obtaining an MRI of their brain and evaluating for the risk in the development of ARIA is also important.

Any psychiatric disorders with psychotic symptoms, such as hallucinations, delusions or major depressive disorders, they are also contraindications. Any autoimmune disorders that are not well controlled. And also TIA (transient ischemic attack, or "mini-stroke") or stroke or seizures within the past 12 months of screening. And obviously, someone allergic to this drug should not be infused.

Host Amber Smith: Once you have patients who are qualified, it's a drug that has to be infused into their body.

How long does that take, and how often do they come for infusions?

Tinatin Chabrasvili, MD, PhD: Usually it takes one hour to infuse, and it's administered every two weeks. We try to have a consistent schedule, but if it's delayed one day or so, we can accommodate the patient, adjust the schedule.

But we try to be very structured in terms of scheduling, because besides these biweekly infusions, we need to also monitor these patients that we have to order their scans MRI scans, between fourth and fifth, sixth and seventh, and before 13th and 14th infusions. So having that schedule, it really helps to avoid any confusion.

Host Amber Smith: From the patient's point of view, does this feel like getting intravenous fluid, or do they experience any sensations during the infusion?

Tinatin Chabrasvili, MD, PhD: Mostly the sensation is the same as during any other infusion of the drug. They may feel like that there is some slight warmth or slight fullness at the site of infusion.

After the infusion, they may experience some fatigue, maybe some emotional response as well. So we have to remember that as well. And later on they may have more of these infusion-related reactions. Overall, the experience of receiving lecanemab can vary from patient to patient, but many patients overall find the process to be manageable and relatively comfortable.

Before anyone starts this infusion, any patient should really have a very honest and frank conversation with their health care providers. Discuss all: side effect profile, what to expect during the infusion, what temperature to expect at the infusion site, and that helps to make the experience more comfortable.

Host Amber Smith: How soon might patients or their loved ones notice a difference?

Tinatin Chabrasvili, MD, PhD: Well, that's a very good question. And that can vary, again, from patient to patient. Obviously it depends on the individual disease state, and it can be either short-, medium- or more long-term observed effects. But again, this can vary.

And we will probably learn more when we have more real world data.

Host Amber Smith: The Alzheimer's Association says the manufacturers of lecanemab have set the price at $26,500 a year. Is it covered by Medicare or Medicaid and private health insurers at this point?

Tinatin Chabrasvili, MD, PhD: The Centers for Medicare and Medicaid Services, known as CMS, announced that they will cover lecanemab, as long as any patient enrolls in a CMS-approved registry. So my experience has been that we can work with Medicare, Medicaid, and we can work with the private insurance companies, but it really varies from state to state, as I understand, and it also depends on the specific private insurances as well.

Host Amber Smith: Do you think that lecanemab -- I know it's designed for people in the early stages -- could potentially be used in people with more advanced Alzheimer's in the future?

Tinatin Chabrasvili, MD, PhD: Well, the clinical trial was conducted on patients with MCI (mild cognitive impairment), diagnosed with MCI or mild dementia due to Alzheimer's disease. So right now we cannot prescribe this medication for those patients with either moderate- or advanced-stage (Alzhemer's). And more importantly, we don't know whether this medication will be beneficial for this patient population or not, but there is a very considerable interest to explore the efficacy and safety of these treatments, and we will see, in the future, if the evidence will sway towards the treatment with these monoclonal antibodies.

Host Amber Smith: I'm curious how you feel, as a provider, having a medication like this to offer. Are you optimistic that it will have an impact?

Tinatin Chabrasvili, MD, PhD: I think that this is a very important step forward, because this is a new hope for Alzheimer's disease patients and for the entire Alzheimer's disease community.

Of course, by current evidence, this was only by 27% a slowing down. however, this is a very important step forward. We are learning a lot. So I am optimistic, Amber, I am optimistic. I am very cautious, but I'm very optimistic as well.

Host Amber Smith: Well, I appreciate you making time for this interview, Dr. Chabrashvili.

Tinatin Chabrasvili, MD, PhD: Thank you so much for having me and allowing me to participate in this very important topic discussion.

Host Amber Smith: My guest has been Dr. Tinatin Chabrashvili, the director of Upstate's Neurodegenerative Disorders Center.

"The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe.

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