Kathrin LaFaver, MD; Meredith Wicklund, MDDISCLOSURES
This transcript has been edited for clarity.
Kathrin LaFaver, MD: Hi. My name is Kathrin LaFaver. I’m a neurologist in Saratoga Springs, New York. I’ll be talking on behalf of Medscape today with Dr Meredith Wicklund, who is a senior associate consultant and behavioral neurologist specialist at Mayo Clinic in Arizona. Welcome, Meredith.
Meredith Wicklund, MD: Thank you.
Lecanemab Data
LaFaver: I’m very excited about our topic today. We’ll be talking about monoclonal antibody therapy against amyloid in Alzheimer’s disease — which has really been a hot topic, especially this year with the FDA approval of lecanemab — and associated questions. Could you give us a brief overview of why there has been so much research interest in this topic of anti-amyloid antibodies?
Wicklund: The pathologic component of what defines something as Alzheimer’s disease is, by definition, presence of amyloid plaques and tau tangles. When it was first discovered in the 1980s that the component of the plaques was actually the amyloid protein — beta amyloid specifically — interest went right from there to developing therapies to directly target the pathology that is Alzheimer’s disease.
LaFaver: Lecanemab is the first FDA-approved disease-modifying antibody in that realm. Could you review the study data, especially as it applies to both of us in daily neurology clinic?
Wicklund: The study data from a phase 3 trial did show, for the primary outcome, that there was a 27% slowing of decline compared with individuals on placebo. It’s important to point out that this was slowing of decline. It was not stabilizing decline. It was not improving decline.
I think it’s important that we inform our patients that really, even with this therapy, there’s no prospect of stabilizing or restoring cognition or function. We do progress at a slower rate compared with individuals not on this treatment, which, given that this medication is for individuals in mild disease who have relatively preserved functional status, that can be potentially very meaningful to families.
The overall benefit was small. It essentially amounts to half a point on an 18-point scale, which is statistically significant. How much clinical meaningfulness that actually leads to is unclear. Finding clinical meaningfulness cannot be defined by a particular test. It really can only be defined on the individual level, what is meaningful to them.
Recommended Tests
LaFaver: It is my understanding that, to qualify for lecanemab use, one needs to have a biomarker-supported diagnosis of Alzheimer’s disease, either via an amyloid PET scan or CSF biomarkers. What would your recommendation be for a neurologist in practice to go about these requirements?
Wicklund: Since this medication is directly targeting the amyloid pathology, and it does convey a potential risk, we want to make sure that the actual pathology is present in the individuals before we treat them and potentially expose them to risk. The best way of doing that is through either an amyloid PET scan or spinal fluid testing of beta amyloid and tau.
There are several plasma-based biomarkers in development. However, I would avoid using those currently. There are still many unknowns in terms of what exactly is the right species of tau that we should be looking at, the right mechanism of the lab test, how minority status may influence it, and how different comorbidities may influence it.
I would recommend, at this time, sticking with amyloid PET or CSF testing. Given that amyloid PET is not widely available in many community practices, generally only available at academic centers, and is quite costly, many insurances do not cover it — although Medicare has a proposal to potentially start covering it — I generally go with spinal fluid testing, which is more widely available. There are several labs across the country that can process that testing in a reliable way.
Amyloid-Related Imaging Abnormalities
LaFaver: That’s very helpful to know. There’s been a large amount of buzz just these past couple of weeks about the blood biomarker coming up. I think, as you point out, this wasn’t the marker used in the clinical studies and there are still unknowns. Maybe it’s not quite time for clinical use, unfortunately.
We also have learned that there are significant potential risks involved. One issue that’s really been a focus is ARIA — amyloid-related imaging abnormalities. Could you speak a bit about that and requirements for monitoring?
Wicklund: ARIA essentially amounts to either vasogenic edema, microhemorrhages, or superficial siderosis that develops as a result of treatment. It relates to activation of the immune system with these passive monoclonal antibodies that’s going to occur with targeting against the plaques. In the parenchyma, it will cause edema. If you have amyloid in the walls of the blood vessels, it can cause microhemorrhages.
While the term “ARIA” implies an imaging-related abnormality, and it largely is purely an imaging finding, it’s not solely an imaging-related finding. It can cause symptoms, including very serious symptoms.
Overall, with lecanemab, the incidence of ARIA within the treatment group in the phase 3 study, combined between both ARIA-E (edema/effusion) and ARIA-H (hemorrhage), was 21.5%, with about 17% being ARIA-H and about 12.5% being ARIA-E. Of course, they can occur at the same time.
Overall, in terms of people in the clinical trials, for most it was purely an imaging-related finding. About 3% developed symptomatic ARIA. Some of those were very serious symptoms, including things like seizures and need to be hospitalized. A couple of deaths have been attributed to ARIA as well.
Patients on Anticoagulation
LaFaver: Along those lines, any additional words to say for people who might be on anticoagulation or might require medications for a stroke, for example?
Wicklund: While individuals on anticoagulation were allowed in the clinical trials, the current, published appropriate-use guideline is recommending against its use, as several of the serious adverse effects, including the deaths, were for the most part attributed to anticoagulation use.
When it comes to acute stroke treatment, one must carefully consider use of tPA, as two of the three deaths were tPA associated in the clinical trials. It shouldn’t necessarily be an absolute contraindication, but it can make the clinical picture very muddy. If an individual is on lecanemab and comes to the ER with acute stroke-like symptoms, it’s more likely that they’re going to be having an ARIA side effect rather than an acute stroke.
A general recommendation would be to obtain an acute head CT with a CTA, and if there is a large vessel occlusion, proceed to thrombectomy. However, if there isn’t a large vessel occlusion, if you have the ability to get a rapid MRI with diffusion-weighted imaging to screen for acute stroke changes or tissue flair with acute edema changes suggestive of ARIA, that would be preferred before proceeding with thrombolysis. These are all relative contraindications and are going to depend on what’s available near you.
Donanemab Approval Pending
LaFaver: This will be an issue because the population we’re talking about is definitely at risk for stroke as well as Alzheimer’s disease. Where do you see this field going as far as amyloid antibody therapy is concerned, with another agent, donanemab, possibly getting FDA approval later this year as well?
Wicklund: We’re anticipating that donanemab will get FDA approval in the next coming months. Donanemab also targets the amyloid in the brain, although lecanemab and donanemab target different aspects of the production of the amyloid plaque. They were both shown to have roughly equal efficacy in their phase 3 clinical trials. Donanemab has the benefit of being a once-monthly infusion as opposed to twice-monthly infusions with lecanemab. It does have a slightly higher risk for ARIA compared with lecanemab.
Those are just some things to take into consideration when talking with your patients. In terms of where we’re going from here, we’re moving even earlier in terms of disease state. The lecanemab and donanemab phase 3 trials were done in individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease. They should not be used in individuals with moderate or more advanced Alzheimer’s disease.
There are ongoing, large, national, multicenter clinical trials of both lecanemab and donanemab in a preclinical state of Alzheimer’s disease. These individuals have evidence of amyloidosis, either through PET imaging or through CSF, but are clinically asymptomatic and do not yet have any signs of cognitive impairment or functional decline. We look forward to those results in the next few years. Hopefully, they’ll be able to show even greater benefit when moving into these early disease states in terms of delaying or even preventing cognitive decline.
LaFaver: That’s definitely very interesting to hear about. Where can people go for more information?
Wicklund: There’s a guideline on the use of lecanemab through the American Academy of Neurology. I encourage you to look at that. Also, look at the appropriate-use recommendations that were published this year in The Journal of Prevention of Alzheimer’s Disease.
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