Consistent statistical evidence from clinical trials slows the course of Alzheimer’s disease before the Food and Drug Administration this month agreed to lecanemab, which clears the brain of a toxic amyloid protein that has been a key target of Alzheimer’s disease No drug has ever been discovered with Pharmaceutical developer.
Lecanemab, marketed as Recambi by Eisai and Biogen, is not a treatment for Alzheimer’s disease. It has sometimes serious side effects, modest benefits, and a price tag of $26,500 a year (not yet covered by Medicare) is more than enough to put both patients and doctors on hold. The approval of the is a milestone for a field that has seen many failures over the years.
Patients with early-stage Alzheimer’s disease or mild cognitive impairment will quickly find that lecanemab is not a sedative, stimulant, or pain-relieving nerve drug. No. Their memory is not suddenly improved. This drug only slightly slows the constant progression of Alzheimer’s disease.
Patient expectations also need to be tempered in other ways. Lecanemab works by clearing out certain forms of amyloid, but clearing the amyloid alone is not enough to keep Alzheimer’s disease at bay to maintain full cognition. You may also need to take drugs in development to reduce blood pressure or remove other abnormal proteins.
Samuel Gandhi, a leading expert on Alzheimer’s disease and a researcher at the Icahn School of Medicine in Mount Sinai, has already started answering patient questions about lecanemab. Gandy understands the unique molecular target of lecanemab. He collaborates with his colleague Michelle Ehrlich, a physician and researcher at the Icahn School of Medicine, to create transgenic his mice and learn more about Alzheimer’s disease-associated proteins. how the drug works.
Scientific American We spoke to Gandy about what patients taking iecanemab can expect in the clinic and the future research needed to make Alzheimer’s disease a manageable disease.
[An edited transcript of the interview follows.]
As both a researcher and a clinician, how would you explain the results of a drug trial of lecanemab to one of your patients?
The trial showed that over 18 months, patients who received the drug declined at a slower rate than those who received a placebo. The slowing of decline was statistically significant at her five different prespecified endpoints (study objectives). This does not guarantee that the changes will be noticeable in the patient’s daily life. As a way of managing expectations, I remind patients that the benefit is to slow decline and that patients and families should not expect improvement. I keep saying it’s highly unlikely.
Did you have any side effects?
In one clinical study, about 15% of patients had brain swelling.And there are patients who have genetic risk factors for Alzheimer’s disease appointmentFour They also tend to be less responsive to medications that tend to have a higher chance of side effects.
Brain swelling can usually be detected on a brain scan before symptoms appear, but not always. In some patients, this swelling may also include small amounts of bleeding that usually do not cause problems. There are concerns that three of her patients who received lecanemab died from cerebral hemorrhages. At least two of her patients were taking some form of blood thinner., Also, blood thinners can cause bleeding even without lecanemab. When evaluating patients with lecanemab, I will mention these side effects, but clarify that I cannot confirm what role lecanemab played in the bleeding. situation.
Will swelling and bleeding in the brain limit the number of patients to whom the drug can be administered?
Yes, my estimate is that about 20% of the population with MCI (mild cognitive impairment) may be eligible for this drug. Patients with a history of stroke or taking blood thinners were warned that side effects were more likely than those who had never had a stroke and were not taking blood thinners. increase.
what do the drugs do?
What makes this drug unique is not only the amyloid plaques characteristic of Alzheimer’s disease, but also protofibrils, which share the properties of both oligomers and plaques, as well as clumps of amyloid called oligomers that float within and between brain cells. to target. We believe that some oligomers may form within or around plaques. Oligomers are not visible on amyloid brain scans, so we still don’t know when they removed them. This is important because oligomers are even more toxic to brain cells than plaque.
For years, reports of drug failures for Alzheimer’s disease have been reported one after another. What is the significance of this drug approval?
This is the first amyloid-targeted drug to provide a statistically significant benefit for patients. This provides strong evidence that amyloid is part of the story, but it is also clear that it is not the whole story. , involving tangles of aggregates of another protein called tau that accumulate within cells. And many experts believe it takes multiple drugs to get a stronger effect. This is noteworthy because the presence of Alzheimer’s disease pathology can now be detected before any symptoms appear. If we can stop the progression of the condition in that group, we may be able to prevent the decline from beginning.
Given your statement that this drug has limited immediate effects and side effects, do you think it would make a big difference in patient care?
There is some evidence from studies that the difference in disease progression between those taking placebo and those taking lecanemab increases over time. there is people take drugs This is not necessarily because the drug is more effective, but because many untreated patients continue to decline, the difference between the drug and placebo may be widening.
Skepticism has increased in recent years due to the disappointment of many drug trials linked to amyloid as a leading cause of Alzheimer’s disease.
Lecanemab trial We show that amyloid molecules are involved in disease progression or initiation.Alzheimer’s disease involves so many molecules and cells that I think the controversy in this area is understandable. Magnitude of effect of lecanemab on cognitive decline is rather small, but I believe that combining anti-amyloid therapy with other approaches may have the potential to produce more potent effects. If that approach proves effective, it will be very “robust”.
With the recent failure of plaque-targeting drugs, could lecanemab be a test of whether future drugs should target oligomers instead?
What this study shows is that it may be best to target both oligomers and plaques. However, it is also worth continuing to develop blood tests, spinal fluid tests, or brain scans to measure oligomers that are undetectable in currently living patients.
You mentioned earlier about the need for drug cocktails. What goes in?
I think the first two ingredients are anti-amyloid drugs like lecanemab and anti-inflammatory molecules that target microglia, the inflammatory cells in the brain. cause activation. This is the cell that cleans up the trash in your brain. This is both good and bad. Microglia ingest amyloid and attempt to clear it, but once activated, dozens of microglial molecules cause inflammation and damage nerve cells and synapses, actually exacerbating the problem. We know that inflammation is the cause of arthritis pain, but inflammation is also involved in brain damage in Alzheimer’s disease.
Could tau and the tangles it creates be another target?
I think once we see what the anti-amyloid and anti-inflammatory combination looks like, we’ll know if we need to target tangles, which also affect neuronal function. Anti-tangle antibodies tested so far does not seem very promising.
How long do you think it will be before patients see these cocktails?
first clinical trial of Microglial inflammatory regulators are in their infancy. None of them have produced results yet, so it’s really impossible to predict. We don’t know whether we want it up or down, or what stage of the disease we want to treat.
Do you think lecanemab itself could be further optimized?
Even people without symptoms of Alzheimer’s disease have detectable chemical changes in their spinal fluid and blood, and there is evidence that predicts the onset of Alzheimer’s disease. It may be possible to treat those people with drugs such as lecanemab. Avoid developing symptoms at all. As I said before, this is what we are aiming for. This is not where we are now.
Do you think it will be possible to have a drug that works for people in the later stages of Alzheimer’s disease?
The problem is that late-stage dementia patients have lost so many neurons and synapses and there is no way to rebuild them. However, new neurons are born in the right place in the brain and must interact with certain other neurons to be effective. Stimulates neurogenesis in the hub of the hippocampus. It can prevent memory loss in oligomer-only mice, plaque-bearing mice, and tangle-bearing mice. The complexity of pathology makes neurogenesis approaches particularly attractive. About half of people with dementia have multiple medical conditions, so targeting a single protein is unlikely to be ideal. I am skeptical that targeting a single molecule will suffice.
Given the strenuous progress in this field, what do you think is the overall significance of lecanemab in Alzheimer’s disease research?
I think that means that at least part of our understanding of disease is correct.And now I need to focus on other targets and optimizations [the drug’s] advantage. The science behind the development of lecanemab suggests that it should target both plaques and oligomers. The current state of Alzheimer’s disease Oncology was in the 1960s and 1970s, small effect. More research has made it possible to improve gains through multiple generations of optimization.
