Lecanemab and the state of Alzheimer’s treatment research

“The data we have from the New England Journal study and from a presentation in an international meeting shows that lecanemab slows down the decline seen in persons with mild-stage dementia caused by Alzheimer’s disease or mild cognitive impairment. They show a slower rate of decline in their cognition and loss of functional abilities, and they show changes in their markers of the disease that suggest that this is the result of affecting the disease process.

“The risks of the drug are very measurable risks, specifically risks to the brain. The drug can cause small bleeds in the brain—microhemorrhages—and can also cause areas of swelling, or edema—microedema. Depending on the severity of those problems they can become quite symptomatic, causing people to even have to stop taking the drug. They’re detectable using an MRI scan, and so use of the drug is going to require very careful MRI imaging, especially early on.” (Posted January 6, 2023 | Download Video)

Jason Karlawish, M.D.
Professor of medicine; co-director, Penn Memory Center, Perelman School of Medicine, University of Pennsylvania Grab This Quote

“This is an exciting drug because it showed a benefit in terms of reducing cognitive and functional decline. In terms of cognitive decline, it showed a slowing down of about 25%, and in terms of functional decline, 37%, which translates perhaps into getting a benefit of 3 to 5 months longer of better cognition and function, which we’ve never had before. So that’s very exciting.

“In terms of risks, it shares the similar risks to other drugs in its class—there have been other drugs that have not necessarily made it to approval, or Aduhelm or aducanumab, which did. And they share the same risks, which are that there are a risk of brain bleeding and brain swelling, although the risk in this drug is a little bit lower than what we saw in aducanumab. And there’s also risks that you would typically find—perhaps an increased risk of bleeding if somebody is taking a blood thinner already. So these are things that we have to look out for.” (Posted January 6, 2023 | Download Video)

Sarah Kremen, M.D.
Associate professor of neurology; director, neurobehavior program; director, Alzheimer's disease clinical trials program, The Jona Goldrich Center for Alzheimer's and Memory Disorders, Cedars-Sinai Grab This Quote

“Well, that’s the million-dollar question. We want drugs, obviously, where the benefits outweigh the risks. And I think that answer always rests with the physician and the patient to come to an individual decision for that individual. In this case we know, on a population level, lecanemab slows the progression of the disease over time. That’s clearly the major benefit. So, while the disease is going to gradually get worse over one to two years, those treated with this drug, the progression is about 30 percent slower. So that’s the major benefit. That’s really the game changing event that we haven’t had so clearly with other medications.

The risks are mostly innocuous, like some infusion reactions—the medicine is given by vein twice a month. And over the first few exposures people sometimes have an infusion reaction. They can develop fever or things like that. But the major health risk is: Occasionally there are some changes in the brain that look like they’re little bleeding or little spots of swelling that are called amyloid-related imaging abnormalities. So those are the major risks. They’re rarely symptomatic, but when they are symptomatic, they can be really important, and they have to be monitored. And so those are the risks we look for.” (Posted January 6, 2023 | Download Video)

Allan Levey, M.D., Ph.D.
Professor of neurology, Emory University School of Medicine; director of the Emory Goizueta Alzheimer's Disease Research Center Grab This Quote

“Patients treated with lecanemab in the clinical trial had a 27% slowing in their rate of decline. They didn’t get better. All the patients continued to get worse, but they got worse at a slower rate. And so one would hope that over the course of years that this would amount to a significant change for the better in their quality of life.

“There are risks associated with lecanemab. It can cause swelling and bleeding in the brain, particularly in patients that have blood vessel abnormalities to begin with or that are on blood thinners. And taking lecanemab requires a lot of safety monitoring, including multiple MRIs that are done several, every few months, as well as visits to your doctor. So it’s a fairly involved process, potentially getting this drug.” (Posted January 6, 2023 | Download Video)

Erik Musiek, M.D., Ph.D.
Professor of neurology, Washington University School of Medicine in St. Louis Grab This Quote

“The only candidates for the drug, you have to have mild cognitive impairment or mild-stage dementia. The former describing someone who has cognitive impairment causing inefficiencies in their daily life. The latter term, mild-stage dementia, describing someone with mild disabilities in their daily life. And you have to have evidence of elevated amyloid. Those are necessities in order to receive the drug.

“An additional finding from the studies that’s I think is very important is how the drug works in individuals who have evidence of the apoE4 gene. The apoE4 gene has been well described for a number of years as increasing one’s risk of developing Alzheimer’s disease. In this study, and as well other studies of drugs like lecanemab, individuals who have an apoE4 gene were more likely to experience those risks of microscopic bleeds in their brain and microscopic hemorrhages. Another finding, which was an exploratory finding, was that they were less likely to have as much benefit as individuals who don’t have that gene. I’m not saying it doesn’t benefit someone with the apoE4 gene, but it’s very interesting that there was this lesser degree of benefit in them.

“I think that what this all sums up to is: For individuals making the decision whether to take this drug, I believe, I think, many clinicians like myself feel that apoE4 testing needs to be one of the options to consider whether this the right drug for me—and what are the chances of me benefitting as well as suffering risks.” (Posted January 6, 2023 | Download Video)

Jason Karlawish, M.D.
Professor of medicine; co-director, Penn Memory Center, Perelman School of Medicine, University of Pennsylvania Grab This Quote

“We can only answer that based upon who we know are people who are actually participating in the study. So what we know is that people who were admitted into this study were between the ages of 50 and 90. So we can say, if you’re between the ages of 50 and 90, you might be a candidate. People who have a particular genetic makeup may do better with this drug than others. For example, there is a gene risk factor called the apoE4 gene. People who have one copy of this gene have an increased risk of bleeding and swelling, and if you have two copies you have a greater risk of brain bleeding and brain swelling. And this is a class effect, not just for lecanemab but also for aducanumab or Aduhelm.” (Posted January 6, 2023 | Download Video)

Sarah Kremen, M.D.
Associate professor of neurology; director, neurobehavior program; director, Alzheimer's disease clinical trials program, The Jona Goldrich Center for Alzheimer's and Memory Disorders, Cedars-Sinai Grab This Quote

“We know in medicine that all of us are different individuals, and so some people almost always respond better to certain medications than others. And I think we’re going to need to see some additional information to know for sure who are the best responders. The analyses that were done in the initial study did look at a number of factors, and the drug seems to be effective across many different types of individuals. We still don’t have enough diversity. So we know from the study—better than others—that there were more Asians and Hispanics than typically. There were more African-Americans, but still less than 50 African-Americans in the study. So we really have to worry about genetic background, and whether the genetic risks are going to play a role.

“We do know that the brain-swelling abnormalities—the amyloid-related imaging abnormalities—are more likely in those with a genetically prone form of Alzheimer’s disease, due to a certain gene called the apolipoprotein E gene. So we know there are going to be different groups at higher risk, and very likely certain groups are more likely to benefit than others. But we’re going to need to see that over a broader experience and time.” (Posted January 6, 2023 | Download Video)

Allan Levey, M.D., Ph.D.
Professor of neurology, Emory University School of Medicine; director of the Emory Goizueta Alzheimer's Disease Research Center Grab This Quote

“This is not a drug for all patients with Alzheimer’s disease, in fact this is a drug really for a small subset of patients. So patients in the trial all had very mild Alzheimer’s disease, so they were really at the beginning of the disease. People that have more advanced disease, the data suggest that this drug and others drugs have not been successful in helping them. Also, people that have memory loss have to have biomarker evidence that they have Alzheimer’s disease. So not everyone with memory loss or with dementia has Alzheimer’s disease, but it can be proven that you have it by looking at certain biomarkers, either by imaging or looking at your spinal fluid or your blood to make sure you have these amyloid plaques in the brain that are a constituent of the disease and, therefore, would respond to this drug. The drug removes the amyloid plaques from the brain, so if you don’t have them, the drug is not going to be effective. So not all people that come to their doctor with a memory problem—or even that have a diagnosis of Alzheimer’s disease—are going to be appropriate candidates for this drug.” (Posted January 6, 2023 | Download Video)

Erik Musiek, M.D., Ph.D.
Professor of neurology, Washington University School of Medicine in St. Louis Grab This Quote

“In the early days when anti-amyloid therapies were being tried in people with Alzheimer’s disease, we actually didn’t require them to have evidence of elevated amyloid. And when we looked at those studies what we found after we were able to test for amyloid more robustly—that about a third to as many as even half of the patients didn’t have enough amyloid in their brains. So the trials have matured such that you only enroll someone in an anti-amyloid trial if they have evidence of having amyloid.

“In addition there has been, I think, greater attention paid to the dosing of the drug, with evidence that you’re beginning to really clear amyloid from the brain—as well as attention to the effect on other markers of the disease like tau protein, which is the other pathologic marker. So greater attention to having amyloid, greater attention to the dosing of the drug to really see that you’re clearing amyloid. We’ve also learned the risks that surround these anti-amyloid drugs, namely the microscopic brain bleeds and swelling that really require vigilance early on, especially in dosing the drug, to make sure those aren’t occurring.” (Posted January 6, 2023 | Download Video)

Jason Karlawish, M.D.
Professor of medicine; co-director, Penn Memory Center, Perelman School of Medicine, University of Pennsylvania Grab This Quote

“In recent years, there has been a lot of discussion about whether taking amyloid out of the brain was the right way to go. Originally, of course, the studies of looking at brains under the microscope from people who had Alzheimer’s disease identified amyloid as one of the main proteins that accumulates in the brain and may be harmful. And that has generated a lot of study and research looking at how could we reduce amyloid levels in the brain. And while we’ve been very successful at pulling amyloid out of the brain with the development of many drugs, it isn’t until really lecanemab that we’ve been able to see that pulling amyloid out of the brain might actually be helpful. And because of that there’s been a lot of doubt about whether amyloid was even the right target or where we should go. Are there other proteins, are there other processes that we should be looking at. What we know is that Alzheimer’s is a very complicated disease. And while there are these proteins that we see, like amyloid and tau, we also know that there’s a lot of other things going on that contribute.” (Posted January 6, 2023 | Download Video)

Sarah Kremen, M.D.
Associate professor of neurology; director, neurobehavior program; director, Alzheimer's disease clinical trials program, The Jona Goldrich Center for Alzheimer's and Memory Disorders, Cedars-Sinai Grab This Quote

“I think we’ve learned several things from clinical trials which are very important. Number one, we know that the disease starts in the brain decades before symptoms begin. So the timing of initiating a medicine is really important. ‘The earlier the better’ is clearly something that’s come out of trials so far. Two, we need to know for sure that people have Alzheimer’s disease pathology. Drugs like lecanemab that target a certain pathology—we only know if that pathology is present because there are certain biomarker studies that are done to clarify and confirm that. And then thirdly, we know that there are other changes that are happening in the brain beyond the amyloid plaques and neurofibrillary tangles. And so we know that the results are likely to be less than perfect. We’re not going to be able to reverse the disease, we’re not going to be able to slow it down totally until we target additional changes in the brain in addition to the amyloid plaques.” (Posted January 6, 2023 | Download Video)

Allan Levey, M.D., Ph.D.
Professor of neurology, Emory University School of Medicine; director of the Emory Goizueta Alzheimer's Disease Research Center Grab This Quote

“One of the main lessons is that earlier seems to be better. So treating people with these drugs seems to work better in people that have milder disease and are earlier in the course of the disease. So far none of our therapies have worked in people that have more severe, more advanced disease. We’ve also learned a lot about the biology of Alzheimer’s disease, that it’s very complicated. It’s more than just amyloid plaques. We know that amyloid plaques are part of the story, and that this drug shows us that removing them early in the course of the disease may help, but I think we’re going to need to target other kinds of pathology in the brain besides amyloid plaques if we want to see really big improvements—or even a cure to Alzheimer’s disease. These type of things could include other kinds of pathology like proteins like tau, things like inflammation in the brain, blood vessel abnormalities, problems with the blood-brain barrier. There’s really a large variety of things that go awry in patients as their brain ages and when they have Alzheimer’s disease. And it’s probably going to take multiple targets and multiple drugs in combination to ultimately achieve really good results.” (Posted January 6, 2023 | Download Video)

Erik Musiek, M.D., Ph.D.
Professor of neurology, Washington University School of Medicine in St. Louis Grab This Quote

“So far what we’re seeing in the interaction between the drug, a drug like lecanemab, and the disease, Alzheimer’s, is this apoE effect—is something that I think we need to learn more about. These almost two sort of types of Alzheimer’s—one a person with a4 gene, and one a person without it—in terms of the course to their disease and how they respond to therapies.

“Even more interesting is emerging data that in individuals who are 70, 80 plus, the co-pathologies often present in their brain. By co-pathology, what I’m describing are pathologies like TDP-43 and alpha-synuclein, as well as vascular disease. And it’s the collection of these pathologies that drive the decline in cognitive function and loss of functional abilities, such that we’re beginning to more think of this disease as a heterogeneous problem caused by multiple misfolded proteins, amyloid and tau being one of them. And a perspective on the disease more and more is recognizing a need for multi-faceted approaches to going after those pathologies, or at least being respectful of the fact that there’s not potentially just one way and only one way that we’re going to successfully treat the disease.” (Posted January 6, 2023 | Download Video)

Jason Karlawish, M.D.
Professor of medicine; co-director, Penn Memory Center, Perelman School of Medicine, University of Pennsylvania Grab This Quote

“The body of research thus far for Alzheimer’s disease has really demonstrated that it’s a very complicated disease. And while amyloid is certainly important in the pathophysiology and the development of Alzheimer’s disease—as is the accumulation of tau, which we know is accumulating in the neurons, the cells of the brain, and causing the neurons to die—that’s not the whole picture. And that, really, this is a multi-faceted disease, which again probably also is affected by metabolism, by inflammation. And so we are going to have to attack this disease from many different ways, not just looking at amyloid and tau, but also how can we reduce inflammation in the brain, whether that’s by exercise or by some other medication that you take. How can we improve cellular function? There’s a lot of different cells operating in the brain. How can we boost them by different mechanisms? So it’s not going to be a single drug. We know now that our approach will be very similar to how people have treated HIV and AIDS, that it takes multiple medications that work in multiple different ways in order to improve brain function.” (Posted January 6, 2023 | Download Video)

Sarah Kremen, M.D.
Associate professor of neurology; director, neurobehavior program; director, Alzheimer's disease clinical trials program, The Jona Goldrich Center for Alzheimer's and Memory Disorders, Cedars-Sinai Grab This Quote

“I think the results of lecanemab trial do a few things to inform us about mechanisms. There’s obviously been great debate over the years about the role of amyloid, whether it plays a key causal role in disease, and I think we can say confidently that reducing amyloid—as has been done successfully now—can lead to a slowing of disease progression. So I think it helps us confirm that amyloid plays a role.

“But also, we can be very, I think, confident in the results of all types of science, including the clinical trial results, that there is far more complex changes in the brain that go on in addition to the amyloid plaques. So there’s a whole cascade of events, from amyloid plaques, to neurofibrillary tangles, to inflammation, changes in the energetics, the metabolism of the brain, the way brain cells communicate, the synaptic function. There are all sorts of things that happen in addition to the amyloid plaques. And we know that these mechanisms are all likely to be contributing now.” (Posted January 6, 2023 | Download Video)

Allan Levey, M.D., Ph.D.
Professor of neurology, Emory University School of Medicine; director of the Emory Goizueta Alzheimer's Disease Research Center Grab This Quote

“We’ve had some long-going studies of Alzheimer’s disease that have been going, some of them for 30  years. And now we understand that these amyloid plaques, which this new drug targets, accumulate in the brain years before people have any symptoms. So as much as 20 years before people have symptoms, they’re already getting these plaques in the brain. And we think the plaques may be an initiator of the disease. They may not be the entire story. So they set things in motion that later lead to degeneration in the brain and memory loss. And so it seems as though the earlier we can get rid of these plaques probably better. But there are other targets like tau and inflammation and other things that happen later in the course of the disease that maybe we can target with future therapies. Some of those trials are going on right now.

“We also—there has been a lot of interest in inflammation in the brain, and now we’re starting to understand that inflammation is not just a bystander to this disease, that it may actually be part of the cause of the disease. And so that opens up a whole new world of potential therapies, which are still in their infancy but hopefully can be added to lecanemab or other amyloid-related targets in the future to really help people with the disease.” (Posted January 6, 2023 | Download Video)

Erik Musiek, M.D., Ph.D.
Professor of neurology, Washington University School of Medicine in St. Louis Grab This Quote