Expert Nikhil Palekar, MD, said that although the treatment is far from a cure, it is a vital first step toward other treatments for Alzheimer Disease.
In an interview with Pharmacy Times, Nikhil Palekar, MD, director of the Stony Brook Center of Excellence for Alzheimer Disease, director of the Stony Brook Division for Geriatric Psychiatry, and director of the Stony Brook Alzheimer Disease clinical trials program, discussed the FDA approval of lecanemab-irmb (Leqembi, Eisai). Although the treatment is not a cure and cannot reverse early Alzheimer disease, Palekar said it could give patients crucial more time to join other clinical trials investigating potential treatments.
Q: What did the pathway to this approval look like for lecanemab?
Nikhil Palekar, MD: Well firstly, thank you for having me today. I really appreciate it, and this is definitely a moment in history. It’s the first medication that has been approved by FDA that has shown some meaningful clinical benefit to patients with Alzheimer's. So the pathway was not a straightforward pathway, it went through several steps. And as pharmaceutical industries or companies are developing medications, they go through various phases of clinical trials.The pivotal phase was phase 3, and the name of the trial was Clarity AD. And in that trial,what was seen was that this particular medication Leqembi, or lecanemab, showed a slowing of cognitive symptoms by about 27% in the group of participants who received the drug as opposed to placebo. And they also saw a stabilization of functioning by a similar amount, about 27% to 30%. And this is pretty significant, as this is the first medication to show this clinical benefit. Current medications for Alzheimer's do notshow much improvements or slowing of symptoms, unfortunately, so this is a big win. It's a big first step, but it's a big win for the field, for our patients and families struggling with Alzheimer's.
Q: Can you review the mechanism of action of lecanemab-irmb and why it’s effective?
Nikhil Palekar, MD:Yeah, so this medication belongs to a class of drugs called monoclonal antibodies that target amyloid-beta plaques in the brain. So it's almost like a sci-fi movie, if you will; a drug is injected intravenously, it goes and binds to these amyloid plaques, that are known to beor core pathological feature of Alzheimer's. And they start to absorb these plaques out of the brain through the bloodstream, and to the extent that they are capable of removing all plaques from the brain.The studies have shown this when they did repeat PET scans, looking for plaques in patients who were on this medication, a majority of them showed that they had no plaque detection at all in the brain when they were taking this medication. So that's really remarkable.So this is a whole group of class of medications that we're going to see coming out in the next year or two. That would be kind of the main, I guess, line of therapy or treatment for mild Alzheimer's disease.
Q: What data support this approval?
Nikhil Palekar, MD: The data actually for this particular approval is pretty robust. There were two phase 3 clinical trials. They had a total of combined about 3000 patients with mild Alzheimer's, which is defined as mild cognitive impairment with Alzheimer's disease or mild Alzheimer's disease. Half of the group received the medication Leqembi and half of them received placebo. The drug was administered for 18 months, and at the end of 18 months, it was found that the participants who received a drug, as I mentioned before, showed not only benefit in clearing the amyloid plaques in the brain, which was the primary endpoint, but also all of the secondary endpoints for the study, which was is this drug clinically meaningful, and it is, which means that it basically shows that it slowed the progression, you know, of the symptoms by about 27%. So what does that really mean in terms of time? For example, the group that was receiving the drug for 18 months, you can look at it as the symptoms were slowed down, or were stabilized to some extent, for about 5.6 months out of those 18 months. That's what the 27% slowing comes down to. And people can stay on this drug for much longer than 18 months, so you don't have to stop at the 18-month point. Trials often have a defined endpoint, but people can stay on this drug for many more years to come, if they choose to.
Q: Importantly, this is not a cure. The drug does not improve patient’s memories or cognitive abilities and does not stop the disease from worsening. What are the real impacts of this treatment for patients in practice?
Nikhil Palekar, MD: So, as you rightly said, this is not a cure. It's not going to halt the progression of symptoms, it’s not going to reverse the illness. Unfortunately, we do not have any medication at this point that can do that. But this will slow the progression down in quite a significant way, which will allow patients to remain functional for a longer period of time. And this is really important because this will also allow them to be able to have the opportunity to participate in other clinical trials that are coming up targeting other molecules or proteins that are also implicated in Alzheimer's, such as tau, as well as some new clinical trials on brain inflammation, which also seems to be quite an important piece of this disease process. So not only just for functional stability and being able to do things that they enjoy doing to the same extent that they were able to do, but also advantages in participating in newer treatments and hopefully a cure in the future.
Q: Can you review which patients are eligible for this treatment?
Nikhil Palekar, MD: It's very, very specific, and this is really important, because this drug was only tested in patients who had either mild cognitive impairment--which is a precursor stage of Alzheimer's--or mild Alzheimer's disease. This is based on clinical testing that we do with every patient that comes to our clinic. And based on their scores on the clinical assessments, cognitive assessments, as well as the clinical information received from them and their caregiver, that's how we are able to figure out if they are in the mild stage of the disease. Unfortunately, people who have progressed with a moderate stage or a severe stage would not be eligible to receive this medication. This medication has not been tested in patients with moderate or severe disease, so we really do not even know if it would be beneficial to them, and what potential side effects they would experience, since we don't know that information at this point.
Q: Are there any plans for that research?
Nikhil Palekar, MD: Not to my knowledge at this point, but as with medications that get approved, often patients seeking them who are in a more severe stage might receive them through a non-FDA-labeled indication. In that process we might learn some more information about it, but for right now, it's strictly for people with early stage disease.
Q: Significant safety concerns have been raised, including brain swelling and bleeding. How do you see these concerns and the balance of safety versus efficacy?
Nikhil Palekar, MD: The FDA did approve Leqembi, but also it did have a blackbox warning along with the approval. That blackbox warning clearly states the increased risk of a potentially dangerous side effect called ARIA, which basically causes brain swelling, and in some cases some minor bleeding in the brain. In most cases, it resolves spontaneously, but it is, of course, a worrisome side effect and needs to be monitored with frequent MRIs. It happens most often in the early stages of treatment in the first couple of months, and it also is much more frequent, we’ve seen, in those patients who test positive for the APOE4 gene. The FDA in their approval has recommended that every patient receive genetic testing for the APOE4 gene so we can evaluate the risks appropriately, as well as to be cautious in using this medication in those patients who are on blood thinners for any medical condition that they might need it, as well as for patients who might have a history of strokes, or those who have a disease called cerebral amyloid angiopathy, which is basically the accumulation of amyloid in the blood vessels of your brain, which increases your risk for bleeding. So it has to be monitored very carefully. And ultimately, a clear discussion about the potential benefits and risks has to be discussed with the patients and their caregivers. It will be an individual decision that will be based on this particular discussion that the physician, clinician will have with their patient and families.
Q: Medicare has announced that it will cover much of the cost for patients—what does that mean for patient access to this drug?
Nikhil Palekar, MD: I think that's a great first step. So Medicare has released a statement that it would cover 80% of the cost for the drug. The cost of the drug for a year is $26,500, so 80% of that will be covered by Medicare. However, at least to my knowledge, I haven't heard Medicare release a statement regarding costs or other procedures associated with the drug. For example, the testing of the presence of amyloid. So one of the things that you have to test in patients who received this drug is if they have amyloid accumulation of the brain, because the drug works on removing the amyloid plaques. This can be done in two ways either through an amyloid PET scan, or through a lumbar puncture that detects amyloid levels. This has to be done in every patient before they are qualified to receive the medication. Many patients need to get repeated MRIs at frequent intervals along the course of the treatment to look for potential side effects of brain swelling or brain bleeding. The drug is given as an infusion every two weeks, so the costs of receiving the infusion itself. And of course, the costs of clinician’s time for the assessment, the prescribing and the monitoring of these medications, which is quite a lot of office hours. And Medicare has not yet come up with a clear statement if they are going to cover for any of these. The average cost when you include all of these various aspects to a standard drug comes up to about $90,000 a year. So we still have to wait to see how things develop over the course of the next couple of weeks and wait to hear from Medicare in terms of their coverage determination for the complete prescription and monitoring and assessments that are needed for this drug.
Q: What role will pharmacists play in this treatment and how can they educate patients and their families about the risks, benefits, and costs?
Nikhil Palekar, MD: This is a great question. It's a really, really important question because we need all hands on deck and pharmacists will play a crucial role in this. This is a brand new medication, a new indication, first of its kind. And there's got to be a need for significant education. One of the most important things that I see in terms of the pharmacists role is to obviously get to know as much as possible about not only the medication, but also the specific guidelines as to what are the types of patients that would benefit from this drug in terms of patient selection that has to be done in the right way? What are the specific monitoring guidelines that need to be in place to make sure that the drug is safely administered? And then other details in terms of storing the medication and administering it. Pharmacists have been extremely well-trained and have been practicing the prescription of various infusion drugs, for example, those that are used in chemotherapy, for cancer treatments as well as certain immunological drugs, for example, rheumatoid arthritis or multiple sclerosis. So this is not something completely new for them, but I think the application of this particular drug in this patient population that we're discussing--and the associated risks involved--need to be carefully monitored by everybody, including pharmacists that are involved in managing patients.
Q: Is there anything you’d like to add?
Nikhil Palekar, MD: What I would just say is that this is definitely a huge, positive step in the right direction. And I say that because we have had multiple failures in the last two decades, and this is the first drug that has shown to slow the progression of symptoms. Yes, it is not a a wonder drug by any means. It hasn't, you know, stopped the disease in its track or reversed symptoms. But it's, I think, the first step in the right direction, and there'll be many more drugs that will come back will be coming out in this particular class of medications, so they're here to stay. But I would also say that this is not the only class of drugs that we see coming out. You will also see drugs that retarget, a protein called tau, so anti-tau drugs, as well as medications that will target neuro inflammation. So the way I see the future would be probably a multi-drug approach for Alzheimer's, a drug that targets amyloid, one that targets tau, and one that targets brain inflammation would probably be most reasonable. Unless we find a magic bullet that really is able to cure this illness, which of course, is what we all want at this point. But this is, again, an important step in the right direction for patients and families who have been struggling with this illness for a very long time. I am hopeful that this will lead to better drugs with lesser side effects and more significant effectiveness or efficacy going forward.