Expert Insights: Lecanemab and Alzheimer Disease

In this video, Madhav Thambisetty, MD, discusses a new treatment for patients with Alzheimer disease, lecanemab, recently approved by the FDA, including the presumed mechanism of action, benefits, risks, and what is next for research on the disease. 

Additional Resources:

• Thambisetty M, Howard R. Lecanemab trial in AD brings hope but requires greater clarity. Nat Rev Neurol. Published online January 6, 2023. doi:10.1038/s41582-022-00768-w
• van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948

Madhav Thambisetty, MD, is a neurologist and a senior investigator in the Clinical & Translational Neuroscience Section at the National Institute on Aging, National Institutes of Health.

TRANSCRIPTION:

Dr Madhav Thambissetty: So lecanemab, like other anti-amyloid antibodies, targets a sticky fragment of the beta-amyloid peptide, and it is believed that the buildup of beta-amyloid in the brain triggers the disease and might cause the disease to progress. Lecanemab is a little different to other anti-amyloid antibodies because it targets a specific type of beta-amyloid called protofibrils. And scientists believe that the early buildup of these protofibrils, as well as their toxic properties, makes this type of beta-amyloid an attractive target. So this was the scientific basis on which lecanemab was developed. It binds to protofibrils in the brain, and this binding of lecanemab to the protofibrils enhances its clearance across the brain, and that's its presumed mechanism of action in Alzheimer's disease.

Like other anti-amyloid antibodies, lecanemab is associated with risks for microbleeds in the brain, risk of brain swelling. In most patients, these may not cause any symptoms, but there are some patients in whom these manifest as difficulties with vision, headache, and confusion. There are some patients, especially those who might be taking other medications like blood thinners, in whom the risks of significant brain bleeds appears to be especially high. We also know that patients who have two copies of a gene variant called APOE4 may be at particularly high risk of brain bleeds, and they might not derive as much of a clinical benefit from the drug as those who do not carry this particular gene variant. So there are specific groups in which the risk-versus-benefit profile might be different.

Both patients who got lecanemab and those who got placebo during the clinical trial declined in terms of their memory and function. But comparing the rates of decline, it looks as if patients who got lecanemab declined a little slower than patients who got placebo. Now to put this in a relative context, patients on the lecanemab arm of the trial slowed their disease by less than a half a point on an 18-point scale compared to those on placebo. So this seems to be a small effect. It's unclear how meaningful this effect is going to be. It's also unlikely that patients or their physicians will see dramatic differences on a day-to-day basis when they get this drug. So while the clinical significance still remains to be clarified, the benefit appears to be small or modest at best, and that benefit has to be taken in context with the side effects that we've just discussed.

One piece of information that we know right now is how much the drug is going to cost. It's going to cost $26,500 a year, and that's the price for the drug alone. The next big decision that we are all going to be looking out for is what the Centers for Medicare Services are going to decide in terms of covering the drug. And so that is going to be a key part of understanding how accessible this drug is going to be, how much it's going to cost in terms of other investigations that are going to be required, like MRI scans, PET scans, the cost of administering this drug by intravenous infusions every other week. So all of these are going to be factors that are going to determine what the true cost of the drug is, how accessible it's going to be, and how much is going to be covered by CMS. I think these are all questions that are not settled yet.

I think the scientist in me takes hope that there's a lot of research on multiple mechanisms related to Alzheimer's disease, and I believe that the wider the net we cast is in terms of potential mechanisms, the better our chances are of developing truly effective treatments for Alzheimer's disease. The National Institute on Aging (NIA) is at the forefront of supporting research on a variety of different disease mechanisms. So anti-amyloid treatments are just one of several. There are many other mechanisms that are actively being studied, both in early stages in preclinical research as well as in clinical trials in humans. And these include drugs that target inflammation in the brain, drugs that correct metabolic abnormalities, drugs that increase communication effectively between nerve cells in the brain, as well as drugs that potentially target other toxic proteins in the brain like tau.

My own group at the NIA works on a strategy called drug repurposing, and we are especially interested to see if there might be safe effective drugs for other conditions in common use that might also have a protective benefit in patients with Alzheimer's disease. So that's one of the important areas of research that I lead in the NIA. So there are a variety of approaches, and I think the more we study these diverse approaches, the better our chances of impacting this disease in a meaningful way.

It's important to emphasize that we really need to be targeting and studying a diverse variety of approaches, and I think a predominant focus on one approach is not going to be as effective as trying to study multiple different approaches. It might be that different patients might benefit from distinct drugs, and so unless we study a wide variety of mechanisms, we are unlikely to be able to find truly effective treatments.

Very nice talking to you.