Advantages and Drawbacks of Lecanemab in Alzheimer Disease Treatment

Since lecanemab-IRMB (Leqembi™) was granted full approval from the Food and Drug Administration (FDA) in July for treatment of early Alzheimer disease, and gained Accelerated Approval in January, some health care professionals may be wondering what comes next. Is lecanemab-IRMB now ready to be integrated into treatment plans? Paul Schulz, MD, a neurologist at the University of Texas Health Science Center, Houston, Texas, says that there are still a few remaining steps before lecanemab treatment can begin.

Psych Congress Network caught up with Dr Schulz to get the full picture on what makes lecanemab different, possible adverse events, and what to expect going forward. 

Catch up on part 2: Patient Considerations When Prescribing Lecanemab for Alzheimer Disease

Watch part 3: Lecanemab Considerations and Efficacy

Read the Transcript: 

Paul Schulz, MD: My name is Dr Paul Schulz. I'm a neurologist at the University of Texas Health Science Center in Houston, and I specialize in dementia. So all day long I see people either evaluating them for dementia or I put them in various experimental therapeutic trials trying to find new medications to improve the outcome of people with Alzheimer's and hopefully someday cure it.

Psych Congress Network (PCN): Can you discuss some of the notable benefits of lecanemab compared to other available treatments on the market?

Dr Schulz: Lecanemab is very special because it's the first drug in that category that completed phase 3 trials and then got FDA approval. Phase 3 trials means a large study in the United States, usually 500 to 1,000 people getting the drug and about that number, not getting it. That comes after other smaller trials, of course. But a large phase 3 is the one where we as scientists and then the FDA as a regulatory agency says, “okay, let me see all of the data for efficacy, meaning did it improve people's outcome, and let us see all the data for safety, what were the problems that came up in that large of a group of people.” And this is the first Alzheimer's drug ever that has affected the course of the disease successfully in phase 3, had a low side effect profile and then got full FDA approval for us to be able to prescribe it.

Of course, the next phase is for insurance to decide to cover it. So there's still one hurdle left before people will be able to go out and prescribe it as a physician or as a patient to be able to receive it.

For perspective, there's 3 drugs in this category and the category is anti-amyloid antibodies. So antibodies designed and made in the lab to attach to amyloid in the brain and pull it out of the brain. Aducanumab was the first one that finished phase 2 years ago, but has not yet received full FDA approval. So it's a little behind lecanemab now. And the third drug in this same category is donanemab that's owned by Lilly. And that drug successfully completed phase 3 trials about 2 months ago and had a publication in JAMA 2 days ago outlining the results of it. And they will be going to the FDA later this year for approval.

But again, the special thing about lecanemab of the 3, it's the first one that finished phase 3 trials and that got FDA approval, which makes it that much closer to being available for us as prescribers and our patients to receive it.

PCN: The study mentioned that a higher percentage of lecanemab-treated patients discontinued the study due to adverse reactions when compared to the placebo group study. Could you elaborate on the nature and severity of these reactions, how they were managed, and what clinicians need to know about these adverse effects?

Dr Schulz: There's 3 main side effects that we see with all of the antibodies that we give. The first one, not surprisingly, is that when a foreign substance enter my body, whether it's a bacteria or a virus, my immune system attacks it like a foreign invader, goes nuts over it so to speak. And not surprisingly, if I get an antibody made by some other person in their body and it's infused into my body, my immune system may recognize it as not being from me and may tackle it.

So the first thing we see is infusion reactions. So we're giving antibodies, they aren't literally from another person, but they were made from another person and cloned up in the lab, sterile and all that, but they are different than the antibodies I make and different from the antibodies that you make. And so not surprising when we receive them, sometimes our immune system reacts against them. In the lecanemab trial, about 35% of people eventually had an allergic reaction. Now, thank goodness very few of them are significant and giving people steroids for a day or two before the injection or Benadryl a day or two before in, my experience, took care of preventing an allergic reaction. We do occasionally though, have someone with a more serious allergic reaction and we just don't give the drug to them again because obviously the downside of a severe allergic reaction is much more serious than what we're accomplishing with the medication.

The second major side effect that we see with all of the anti-amyloid antibodies, including lecanemab, is called ARIA-E. ARIA stands for amyloid related imaging abnormality, and we called it that before we knew what it was because we weren't very innovative. And we saw it in people who had amyloid in the brain and in whom we were trying to get rid of the amyloid, so we call it amyloid related imaging abnormality. And then we put an E after it eventually when we figured out that when we see a certain look on the MRIs of people who have it's due to edema, it's due to swelling. So we call that ARIA-E.

Not surprisingly, antibodies that we give people do exactly what antibodies you make do to people, which is I get a flu shot and my arm swells up and it's a little painful because there's a big immune response going on. Well, we see the same kind of swelling in the brain when we give anti-amyloid antibodies to people who have a lot of amyloid in the brain. And so you'll literally see swelling in different parts of the brain in people. About a third to a half of people who get the antibodies will have swelling. Three quarters of the time there's no symptoms. So we pick that up on things like MRIs and that's why we do MRIs regularly when someone's receiving these meds.

So the good news is that generally speaking, not many symptoms, we see it on the MRI, we stop the infusions and people get better. And so 99.5% of people don't have any lasting effect from it, and they get over it and then you start infusing them again. And three quarters of people don't have a second swelling response. They don't develop ARIA-E again. One quarter do and so you just stop the infusion again, wait till it goes away, start it again and so forth.

Very rarely do you have a serious side effect, but I have seen people get seizures and of course people with Alzheimer's can get them anyway, but in the setting of the swelling, we have to assume they're related. And sometimes we have to give steroids to reduce the swelling if it's particularly aggressive. With that caveat, the ARIA-E tends to be generally very manageable. But obviously, in each of our trials, there's been one or two or three people that have had a more lasting effect, which is unfortunate, but a very small percentage of people.

The third major side effect is called ARIA-H, amyloid related imaging abnormality type H. The H stands for micro hemorrhage, H is hemorrhage. And so at the beginning of all of our anti-amyloid trials, about 10% of Alzheimer's patients or MCI patients due to Alzheimer's pathology, will have particular hemorrhages on the baseline MRI before they get any treatment. It's a part of the disease and it's related to the fact that we have amyloid not only in the brain causing problems in the outer part of the brain where we think, but there's also amyloid in the blood vessels of the brain. It makes the blood vessels leaky. It sort of makes the wall stiff and irregular. And sometimes they have these micro hemorrhages. The hemorrhages are like one or two millimeters in size, very small, but you can see them on an MRI.

And what we've learned is that during treatment, a certain number of people will get more. Now in the control group for example, it might go from 10%, have them to 14% have them, but in the treated group, like with lecanemab, it goes from 10% to 17 or 18%. So more people have hemorrhages in the treated group than the untreated group. But both groups have them. What we've learned is to be very circumspect about it and say, well, if you get more than a certain number of hemorrhages, you know what, we're just going to stop because we don't want the 15th hemorrhage to be a large one. So if people have more than four hemorrhages to start with we don't start them on any of the anti-amyloid therapies. If they develop more and get over 10 little guys, we stop the treatments and don't go on from there.

So to summarize the answer to your question, infusion reactions, ARIA-E and ARIA-H are 3 things that we see. They're generally very manageable, but part of it is that we've learned through experience how to treat them and how to avoid them.
 

Paul Schulz, MD, is a professor of neurology at McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth). He received his combined BA-MD degrees from Boston University in 1984. He did a medical internship there, and moved to Baylor College of Medicine for his residency in Neurology. He stayed for a laboratory fellowship in cellular neurophysiology after which he became an assistant professor. Later, he was an associate professor of neurology, neuroscience, and translational biology and molecular medicine. Dr. Schulz was also the vice chair of education for neurology, the deputy chair of the Methodist neurology service, and directed the Cognitive Disorders Clinics at Baylor and the Houston Veterans Administration Hospital.