The Bumpy Road To Approving New Alzheimer’s Drugs

16:41 minutes

Silver Spring, MD, USA - June 25, 2022: The FDA White Oak Campus, headquarters of the United States Food and Drug Administration, a federal agency of the Department of Health and Human Services (HHS).
At the beginning of March, the FDA delayed approval of another Alzheimer’s drug, an anti-amyloid called donanemab. Credit: Shutterstock

In the past few years pharmaceutical companies have developed a string of new Alzheimer’s drugs called anti-amyloids, which target amyloid plaques in patients’ brains. These plaques are one of the key biomarkers of the disease.

The first of these drugs, Aduhelm, was approved by the FDA in 2021 amid enormous controversy. The FDA approved the drug despite little evidence that it actually slowed cognitive decline in patients. Biogen, the maker of Aduhelm, pulled the plug on further research or sales of the drug last month.

In January 2023 The FDA approved another anti-amyloid medication from Biogen, lecanemab, sold under the brand name Leqembi. This time, there was much stronger evidence. Clinical trial results showed that the drug showed a modest improvement in cognitive decline in the early phases of the disease. But the drug comes with risks, including brain swelling and bleeding.

Most recently, at the beginning of March, the FDA delayed approval of another anti-amyloid drug, donanemab, created by Eli Lilly. The FDA said it will be conducting an additional review to further scrutinize the study design and efficacy data.

From the outside looking in, these Alzheimer’s drugs appear to be mired in controversy. How well do they actually work? And why has there been so much back and forth with the FDA?

To answer those questions and more, guest host Arielle Duhaime-Ross talks with Dr. Jason Karlawish, professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine, and co-director of the Penn Memory Center.

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Segment Guests

Jason Karlawish

Dr. Jason Karlawish is a Professor of Medicine, Medical Ethics & Health Policy, Neurology in the University of Pennsylvania’s Perelman School of Medicine and Co-Director of the Penn Memory Center in Philadelphia, Pennsylvania.

Segment Transcript

ARIELLE DUHAIME-ROSS: This is Science Friday. I’m Arielle Duhaime-Ross. In the past few years, we’ve seen a string of new Alzheimer’s medications enter development. They’re called antiamyloids. They target amyloid plaques in the brains of Alzheimer’s patients. Amyloid plaques are one of the key biomarkers of the disease.

The first of these drugs to reach the approval state was aducanumab, brand name, Aduhelm, in 2021. Maybe you remember it? It caused some controversy, because the FDA approved it despite there not being much evidence that it actually slowed cognitive decline in patients. The sale of that drug ended just last month when the company that makes it, Biogen, pulled the plug and stopped all research related to it.

Following that controversy, another medication of this type made it through the FDA approval process in early 2023. The medication, named lecanemab, brand name Leqembi, is also made by Biogen. This time, clinical trials showed that it could help. It was linked to a modest slowdown effect in the cognitive decline associated with the early phases of Alzheimer’s. Though trial data also showed that the drug, when given to certain patients, could increase the risk of side effects, including brain swelling and bleeding.

Now the FDA has delayed the approval of another one of these medications, donanemab, this one from Eli Lilly. Here to talk about what’s going on with these medications and what it all means for Alzheimer’s patients is my next guest, Dr. Jason Karlawish, Professor of Medical Ethics and Neurology at The University of Pennsylvania and the co-director of The Penn Memory Center. He’s based in Philadelphia, Pennsylvania. Dr. Karlawish, welcome to Science Friday.

JASON KARLAWISH: It’s a pleasure to be here. Thank you for having me, Arielle.

ARIELLE DUHAIME-ROSS: Yeah. Thank you so much for coming on the show.

So the medications I just mentioned are antiamyloids. Does that mean they do the same thing?

JASON KARLAWISH: In principle, they all target amyloid. But amyloid is a complicated protein. That’s what it is, it’s a misfolded protein, and they target different bits of the protein. The net effect is there’s less amyloid in your brain, but they go about it, as I say, by hitting different parts of it.

ARIELLE DUHAIME-ROSS: OK. So they don’t quite all work the same way exactly, but they target the same thing.

JASON KARLAWISH: Exactly. The result is a reduction in amyloid in the brain, and some of these medicines, what I think is clear and convincing evidence that translates into benefits to patients.

ARIELLE DUHAIME-ROSS: So approval was delayed for one of these medications last month, donanemab. What’s going on there?

JASON KARLAWISH: Well, we don’t quite know, because FDA hasn’t yet held the advisory board hearing that it wants to have. Once they have that hearing, we’ll hear what the FDA’S questions are. That’s what they use an advisory board for. They ask it a question that they want to see, what is your expert views on this.

My hunch is their questions are around some of the very particular aspects of the design of the trial. Patients had to have not just evidence of amyloid, which of course makes sense. The drug targets amyloid. But they also had to have evidence of another pathology seen in Alzheimer’s disease, namely, tau protein.

Now my guess is FDA might be thinking about how the label for the drug should address that issue. There’s also a possibility that they sort of have safety data they want to have reviewed in greater detail because the drug, as you pointed out, raises the risk of developing small bleeds and/or swelling in the brain. Again, that’s just speculation. But I think when I chat with my colleagues, those are the two topics that most that we think is most likely what FDA wants some advice on.

ARIELLE DUHAIME-ROSS: Coming back to Aduhelm, the first of these drugs to get approved, did the controversy that resulted from its approval impact how the FDA evaluates other antiamyloids? Is the news that this approval, this latest approval is delayed, is that the result of all of this? Is the FDA being more cautious than it would otherwise be, or is this all business as usual?

JASON KARLAWISH: Hard to say. Only the FDA knows the answer to that. Aduhelm was a failure of regulatory science. A congressional report, I think, sadly, thoroughly details what occurred at FDA and its interactions with Biogen.

These other two drugs are quite different. I think what’s going on now with these drugs needs to be seen in a very separate light than the controversy that surrounded Aduhelm. Stated otherwise, this is not Aduhelm Part 2.

Both donanemab, which is Eli Lilly’s drug, and lecanemab, which is Eisai’s drug, had well-designed Phase III trials done which the field knew about. They were published in the medical literature and presented, and that data has been presented to FDA. In contrast, aducanumab had two very quirkily done trials with a host of problems in them.

ARIELLE DUHAIME-ROSS: Got it. OK. So coming back to aducanumab, the first of these drugs to get approved, the one you just mentioned, the controversy surrounding this medication had to do with how efficacy was measured for that drug?

JASON KARLAWISH: Well, it had to do with a lot of things. I think it can be summed up that a series of just bad decisions on the part of both Biogen and the FDA and a willingness to take what amounted to a large public health and regulatory science risk to grant the drug not full approval, as safe and effective, but only what was known as conditional or accelerated approval. Meaning the evidence that it reduced amyloid was good enough to put the drug into practice. Further research would need to be done to prove that the drug actually benefited patients. That was the approval that was given to aducanumab.

ARIELLE DUHAIME-ROSS: All right. So just to make sure I understand here, what you’re telling me is that the researchers showed that it did, in fact, impact amyloid. It did decrease it. They never actually showed the other very important bit, which is not only does it reduce amyloid, but it also benefits patients. Right?

ARIELLE DUHAIME-ROSS: Patients benefit, exactly. Let’s step away from Alzheimer’s for a minute and go to something that’s very well-known in culture, hypertension. Blood pressure goes down because you take this medication.

That’s not why you are healthier. Why you’re healthier is because your chances of developing a stroke or heart attack are reduced. That’s the link between reducing those numbers, translating into better health. Blood sugar, bone mineral density, we can run a whole list of biological measures that we have reasonable confidence that if a drug reduces them, it can translate into benefits to a patient.

At the time that aducanumab was approved by FDA under the accelerated approval regulations, the link between reducing amyloid and a benefit to the patient was still a work in scientific and clinical progress. That’s why the field found that that decision by FDA was simply a scientific bridge too far.

ARIELLE DUHAIME-ROSS: So that’s aducanumab. Moving on to these two other drugs– so with Leqembi, they’ve shown that there’s a modest benefit to patients. There’s also a risk of brain swelling and bleeding for certain patients. Now, of course, all medications come with the risk of side effects, but I do think it’s worth asking, is the risk associated with Leqembi acceptable?

JASON KARLAWISH: The bottom line, it is. I say that because later today I’m going to put an order into Epic to get a patient going on Leqembi. The patient and his spouse decided that they wanted to start the drug after I spoke to them. The reason why I think I’m comfortable writing those prescriptions is because, sure, there are very real risks with Leqembi as well as Donanemab, namely small little bleeds in the brain, and those bleeds can lead to swelling or edema in the brain.

Number one, I can do a genetic test that lets me know the patient’s specific risk level, which helps them get a better sense of what’s my chances, doctor, and number two, I can use MRI scans to detect whether those little microscopic bleeds are developing. So I can give a patient a good, personalized idea of what their risk might be. I can do MRI scans to detect it before it becomes a real problem.

Does that mean that they might not suffer adverse events from those risks? Absolutely not, they may. But it’s given the benefits of the drug, given the severity and nature of the disease, it’s a conversation I’m comfortable having with my patients and a decision I’m comfortable with them making.

ARIELLE DUHAIME-ROSS: OK. So there are tests that can help you sort of make sure that your patient is in the lower risk category, which makes you comfortable, therefore, prescribing it?

JASON KARLAWISH: Yeah, yeah. These are exciting times in the field. I mean, I can do tests now of genetics, imaging, that tell them number one, they may be a candidate for this drug, and number two, based on the results of other tests, the likelihood that they might benefit from the drug and/or otherwise have a low chance of experiencing the risks. Then the question becomes one of an incredible existential and ethical importance, which is do you want to slow down your Alzheimer’s disease?

ARIELLE DUHAIME-ROSS: What you’ve been describing is a substantial workup for patients. Do we have enough physicians who are trained to do this kind of thing, enough resources to administer these new medications in the safest way possible?

JASON KARLAWISH: Simply put and with one word, no. That’s a real disappointment. It’s not a surprise. We’ve known for years, decades, that the workforce, the health care workforce for patients and families living with dementia caused by Alzheimer’s or Lewy body disease, that that workforce is woefully understaffed and underresourced. These drugs have simply shined a bright light on something everyone knew.

My view is these drugs are risky. They’re complicated. But the problem isn’t so much the drugs. It’s the drugs in the system, the system of care that we have.

Now, maybe, the drugs create a business model to incentivize the American healthcare system to want to pay attention to this disease. That’s oftentimes the history of disease in America. It needs a business model to move forward. Alzheimer’s has one now.

So we will see how things change. But yeah, I mean, unfortunately, in my region, we’re one of the few centers that are prescribing these drugs. We have a wait list to do it. I feel awful, but I have to work with the tools we have.

ARIELLE DUHAIME-ROSS: Right, a wait list for this kind of illness must be a really, really tough thing to have and see get longer.

JASON KARLAWISH: A wait list is awful. But the standard narrative that I heard for my two decades of practice was one of we’ve been hunting around to find an answer to my problem for the last, pick your one, two years. You don’t go to a cancer center and find people walking in and saying, I’ve been hunting around to find out a cause for my weight loss, bleeding, and anemia for a workup that’s over two years old with being bounced from doctor to doctor.

We’re pretty quick with getting answers to chest pain, weight loss, breathlessness. But when it comes to forgetfulness, the average American struggles for a year or two to figure out what’s going on and what’s the disease. That’s been the case for decades.

ARIELLE DUHAIME-ROSS: I understand that you’ve also started to test cerebrospinal fluid just in the past few months. Can you tell me about that?

JASON KARLAWISH: The biological entry to get an antiamyloid drug is to show that you have elevated amyloid. That, I think, makes sense. That was a key criteria to be eligible to receive the drugs.

The standard in the clinical trials was to either measure amyloid using a PET scan or using spinal fluid sampling. In our practice, we order both. I will say it’s a hassle to get the PET scans because of issues largely related to insurance and some other resource issues. But spinal fluid, we can get a little bit easier. So more and more we’re ordering that and analyzing that.

The advantage of that as well is that I can then tell a patient not just that whether they have elevated amyloid and so are a candidate for the drug, but I also can measure tau protein, which is another marker of Alzheimer’s disease. So I’m now able to tell a patient fairly definitively that the cognitive problems they’re having, those troubles with managing money, medications, the difficulties finding words are caused by at least one disease, which is Alzheimer’s disease, because I can see it in their spinal fluid. We weren’t doing that a year ago, routinely. That’s a big change.

Sometimes the word “revolution” is overused in medicine. You know, everything’s a revolution because everyone wants to be in the front, behind the vanguard. But this is a revolution.

ARIELLE DUHAIME-ROSS: I mean, you interact with these patients all the time. I have family members who have had Alzheimer’s. It’s a devastating illness. Which is why I want to ask, based on what we know about these medications, would a patient in the early phases of their illness, you know, out in the real world, notice that their decline is slowing?

JASON KARLAWISH: Yeah, so who are these patients that I’m prescribing the drug for? They’re persons who have either what we call mild cognitive impairment or mild stage dementia. Simply put, they’re either experiencing inefficiencies or even disabilities in doing life’s daily activities. Not the stereotypical ones that people think about when they think about Alzheimer’s, bathing, dressing, grooming. That’s severe stage disease.

These are people who have trouble following a recipe to cook an elaborate meal, like, bake a pie, or using transportation to get from one place to the other. What the drugs offer is that the time it would take before they develop more problems doing those activities that we do to experience and enjoy life, that the time before those troubles get worse will be delayed. That’s not something that you notice, like, I have less pain in my wrists after I started Remicade for my arthritis. Instead, it’s a slowing down, if you will, of the natural history of the disease. So you won’t notice it, but it is happening is what we have to accept, based on the results of the clinical trial and on follow on data that certainly all of us are going to be keen to look at.

ARIELLE DUHAIME-ROSS: As I’ve mentioned, I have people in my family who’ve been impacted by Alzheimer’s, more than one. I am one of those people who is worried that one day I could get diagnosed with it, too. What would you tell someone around my age, you know, someone in their mid-30s, about the future of Alzheimer’s treatment?

JASON KARLAWISH: We may find that, at some age long before the stereotypical age we think of of Alzheimer’s, namely 70, 73, that you’ll be getting certain tests that determine that you are beginning to develop the neurodegeneration. Therefore, you should start either this monitoring and/or, ideally, this treatment that will affect the rate of that neurodegeneration.

I think we have precedents in other diseases that unfold slowly but, much like a bankruptcy, slowly, but all of a sudden all at once. Heart disease, I think, is a paradigmatic one. Osteoporosis is another where you get a test, and based on that result, it’s determined that a treatment is warranted. Of course, this engenders a host of magnificent controversies around where do you set the cutoffs, is the benefit worth the risk, you know, are we expanding disease categories into populations who shouldn’t be labeled.

ARIELLE DUHAIME-ROSS: All right. So I feel like I have a sense for what you might say to my next question, but I still want to ask you. Given everything that’s happened, you know, given the delays and the pulling of a drug in this category, given all of that, do you think that antiamyloids still show promise? Are they still worth pursuing?

JASON KARLAWISH: They show promise, they’re worth pursuing, but they are not a cure. They are not halting the disease. Any reasonable patient who looks at the data will say, well, you know, I’d like an even better drug. The answer is yeah, this is what we’ve got for now. It’s a start.

What do I mean by that? After 18 months of treatment, your chances of progression to the next stage of the disease are about 30%. These are slowly progressive diseases. So 70% of the patients are just staying the way they are after 18 months.

If you take the drug, you reduce your chance of progression to the next stage by about 10%. So only about 20% of patients on the drug progress. That’s a decent reduction in risk of progression to the next stage.

But obviously what we’d like to see is the reduction go from 30 to 0, right? That will either take different, better drugs that target amyloid, or drugs that target tao, or drugs that target inflammation, or drugs that target other mechanisms that are under study. Again, these drugs are a start, they’re not an end. But for now, they’re what we have, and that’s what we’ll work with.

ARIELLE DUHAIME-ROSS: Dr. Jason Karlawish, that’s all the time we have for now. Thank you so much. I really appreciate your time.

JASON KARLAWISH: You’re very welcome, Arielle. It was a lot of fun talking, great topic.

ARIELLE DUHAIME-ROSS: Dr. Jason Karlawish is a Professor of Medical Ethics and Neurology at The University of Pennsylvania and the Co-Director of The Penn Memory Center. He’s based in Philadelphia, Pennsylvania.

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