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On January 6, 2023, the FDA approved lecanemab (Leqembi), a new Alzheimer’s treatment. Lecanemab slightly slowed cognitive decline in clinical trials, but the drug also comes with side effects.
On Thursday, January 12, 2023, SciLine interviewed: Dr. Madhav Thambisetty, a neurologist and a senior investigator in the Clinical & Translational Neuroscience Section at the National Institute on Aging, National Institutes of Health. He discussed topics including: the risks and benefits of lecanemab; the symptoms of Alzheimer’s; how Alzheimer’s is diagnosed and treated currently; and what researchers have learned from decades of research into Alzheimer’s drugs.
Dr. Madhav Thambisetty served on the FDA PCNS advisory committee on aducanumab in 2021.
MADHAV THAMBISETTY: I’m Madhav Thambisetty. I’m a neurologist and a senior investigator at the National Institute on Aging at the National Institutes of Health.
Interview with SciLine
What risks and benefits of lecanemab should Alzheimer’s patients consider?
MADHAV THAMBISETTY: The benefit that we saw in the phase three clinical trial is a small slowing of disease progression in patients who got the drug compared to those who got a placebo. This benefit appears to be quite small, but it’s statistically significant, so it looks like a real result. And there’s some question and debate about the true meaningfulness of this benefit; whether it’s robust enough to be noticeable by patients and physicians on a day to day basis. But that benefit is also accompanied by risks, and these risks include a greater chance of brain swelling, a greater chance of small bleeds in the brain, and while in most patients these might resolve on their own, and even not cause any symptoms, there’s some patients who do run into problems. And they can have symptoms such as confusion, headaches, visual disturbances, and in patients who seem to get blood thinners for other medical conditions, the risks of significant brain bleeds appears to be even higher. So, there is a small clinical benefit, but it comes with an additional concern about risks as well.
Who are the best candidates for lecanemab?
MADHAV THAMBISETTY: The prescribing label for lecanemab emphasizes that these patients should be those at the early stages of the disease, so patients who show mild symptoms. And so as a physician, I would pay close attention to making sure that any potential patients getting this medication resemble those who were enrolled in the phase three clinical trial as closely as possible. So these would be patients who have very mild symptoms, and these would be patients in whom we confirm a diagnosis of Alzheimer’s disease by a PET scan to show greater levels of brain amyloids. These would be the typical patients who might be eligible to receive this medication.
What does the lecanemab treatment plan look like?
MADHAV THAMBISETTY: The first step in the treatment plan is a confirmation that a patient’s symptoms are in fact due to the pathology of Alzheimer’s disease. And after confirming that, the guidance typically says a brain MRI scan should be obtained to make sure that there aren’t warning signs that this patient might be at risk for adverse effects or complications that we just talked about. One such complication is micro bleeds, so we want to be sure that the first MRI scan before treatment doesn’t already indicate micro-bleeds, which would put these patients at greater risk if they went on the treatment. So, these are some of the things that we first want to do before considering administering this drug: confirm the diagnosis of Alzheimer’s disease, establish their brain MRI scan does not put them at greater risk for side effects, and once the treatment has started, the guidance is that frequent monitoring by MRI scans is going to be important. Because physicians should be able to detect a brain swelling and risk of brain bleeds as they happen, so that they can make decisions about whether to hold the treatment, to stop it for some time, and then continue it, or whether the patient might need additional monitoring. So, the clinical trials had repeated MRI scans, about five to six MRI scans during the one and a half year treatment period. And a similar monitoring might be essential in patients who do get on this drug, if they’re eligible to receive it.
What symptoms do Alzheimer’s patients experience, and at what ages?
MADHAV THAMBISETTY: Typically, late-onset Alzheimer’s disease, which is the most common type of Alzheimer’s disease, begins in patients in their mid-60s, so typically after age 65. The most common symptom of Alzheimer’s disease is of course difficulties in memory. But Alzheimer’s disease can also produce difficulties in other areas of cognition, such as attention, orientation, multi-tasking and problem solving, visual-spatial problems, and so on. So, while it’s typically a disease that robs patients of memory, there are multiple other symptoms as well. It can also present with significant changes in personality and behavior. So, there’s a whole range of symptoms that can signal the onset of the disease and its progression.
How common is Alzheimer’s, and are any populations more affected than others?
MADHAV THAMBISETTY: The current estimates for Alzheimer’s disease is about five million individuals in the United States, and this number is many times higher when you look at the global burden of the disease. We’ve understood a lot about what potential risk factors might be responsible for triggering the disease, or enhancing somebody’s risk of progression. We know that other medical conditions such as diabetes, high blood pressure, high levels of blood cholesterol, obesity—these are all risk factors for Alzheimer’s disease. We also know that, as I mentioned before, there’s also genetic predisposition in certain individuals for the disease. So, patients with one copy of the APOE4 variant of the APOE gene are two to three times higher risk for developing Alzheimer’s disease. Those with two copies are at even greater risk. So we think that a mixture of lifestyle, medical conditions, and genetic predisposition, all increase an individual’s risk for Alzheimer’s disease.
What treatment options exist for Alzheimer’s currently?
MADHAV THAMBISETTY: All of the treatment options we currently have for Alzheimer’s disease are called symptomatic treatments, which means that they really do not halt the progression of the disease but they might impact symptoms in patients. The last of these symptomatic treatments was approved in 2003, and it was a drug called memantine or Namenda. The first class of these drugs were called cholinesterase inhibitors. Now both the cholinesterase inhibitors and memantine act on the symptoms of Alzheimer’s disease by regulating levels of neurotransmitters, or chemicals in the brain. The excitement about the recent anti-amyloid drugs is because of the potential that rather than working on the symptoms of the disease, like these older drugs, they might actually halt or slow down the disease progression itself. That’s a question that everybody’s excited about. It’s far from settled, but the possibility that we might be entering an era where we can look beyond symptoms and potentially target the progression of the disease is very exciting. But that’s a question that still has to be resolved and proof actively demonstrated.
What have researchers learned from decades of research into Alzheimer’s treatements?
MADHAV THAMBISETTY: We’ve learned a great deal about what might potentially cause the disease. We’ve learned a lot about the biology of the disease. When I did a literature search some months back about how much is published about the disease, I think we average, as a field, about a thousand publications a month. So, we’ve learned a great deal about the potential biological mechanisms of the disease. We’ve learned about risk factors associated with the disease. We seem to be making a lot of progress about various genetic variants that might increase the risk for Alzheimer’s disease. So, in terms of what we’ve understood about basic biology underlying Alzheimer’s disease, there’s been a lot of progress. The disconnect, or the frustration, is that this knowledge hasn’t really translated itself into effective treatment. So, there’s been a lot of progress on understanding the biology, but perhaps not so much in terms of translating that understanding into effective treatments.
Is there anything else you’d like to add?
MADHAV THAMBISETTY: The National Institute on Aging is actively involved in supporting clinical trials of medications targeting many other mechanisms besides brain amyloid. There are clinical trials supported at early stages of drugs that might affect inflammation in the brain. That might correct metabolic abnormalities. That might increase how nerve cells communicate with each other. So, the National Institute on Aging is at the forefront of supporting such research that is aiming to uncover drugs that might work by targeting several other mechanisms than brain amyloid. And I think that’s an important point that I’d like to stress as well.
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