If you haven’t heard, there’s been big news recently about Alzheimer’s disease. Over the past year, the Food and Drug Administration has approved two new treatments that may slow the cognitive decline in people with dementia, and studies are under way to see if these treatments possibly delay or prevent the onset of Alzheimer’s.
One of the drugs, lecanemab, is the first to show in clinical trials evidence of slowing cognitive decline. The other drug, known as aducanumab, was shown to remove beta amyloid plaques, the hallmark brain lesions seen as the leading cause of Alzheimer’s.
Critics claim that two drugs have dangerous side effects that offset whatever modest benefits patients may receive. Other experts feel the two drugs are effective and poised to bring about a productive new era in Alzheimer’s research and drug development that may lead one day to treatments that keep a person from suffering from the debilitating late stages of disease.
To help us understand these developments, Dr. Joshua Grill is joining the UCI Podcast. Dr. Grill is the director of the Institute for Memory Impairments and Neurological Disorders at UCI, better known as UCI MIND. For more than 30 years, UCI MIND has been at the forefront of Alzheimer’s disease research. The mission of UCI MIND is to enhance the quality of life for older adults by researching genetic, clinical and lifestyle factors that promote successful brain aging.
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Thank you for joining the UCI Podcast, Dr. Grill.
Thank you very much for having me.
What are your thoughts about the FDA’s approval of lecanemab and aducanumab?
Well, I have several thoughts. First and foremost, I think it’s important to note what an incredible accomplishment this is for the field of Alzheimer’s disease research. It had been more than 15 years since we had had a new drug approved. These approvals represent important progress that the field is making toward our ultimate goal of having, you know, meaningful therapies and solutions for people living with these diseases. I admit, I have mixed feelings because both approvals to this point, the two drugs you mentioned were approved through something called the accelerated pathway. So, they were approved based on the biological activity of the drug rather than the clinical benefit of the drug. I personally don’t agree that the field has come far enough to be able to approve drugs based on the biological activity, which is unquestioned for both of these medications. But I don’t think we should be approving drugs based on the biological activity.
I think we need to demonstrate the clinical benefit of these drugs. What I was saying is that these two approvals have come via this accelerated pathway, right? Which basically the approval is based on the demonstration that both of these drugs can lower the levels of a protein in the brain called amyloid. And we know that amyloid accumulates in the brain of every person with Alzheimer’s disease, and we’re excited to have drugs that can do that. But full approval requires demonstrating a drug actually has a clinical benefit for patients more than just a biological activity. And I think it’s important to also say, I expect that lecanemab will get full approval in the next year or so, because the data are very convincing that lecanemab does have a clinical benefit, namely slowing the progression of Alzheimer’s disease. So people who take lecanemab compared to people who take placebo in a clinical trial get worse more slowly. They don’t get better. They still get worse, but they get worse more slowly. That’s meaningful. We’ve never had a drug that could do that. And I think the demonstration of that clinical benefit will be adequate for the F.D.A. to fully approve lecanemab. But it also shows that we still have a lot of work left to do because we want drugs that stop the disease or bring people back to where they were five or 10 years ago. And that’s going to take more research
In comparison, what does aducanumab do?
So aducanumab like lecanemab has been convincingly shown to lower amyloid levels in the brain, but it has not been convincingly shown to actually slow the course of the disease. In fact, there were very mixed data in two very large, multi-site multinational clinical trials of aducanumab. And there was a lot of controversy around whether the drug should be approved. And then, ultimately controversy around its approval through the accelerated pathway, which was the first time that pathway had been used in Alzheimer’s disease.
Who would be eligible to take these drugs?
At this very moment, it’s difficult for anyone to gain access to these drugs. Aducanumab was approved but ultimately the company really stopped marketing the drug. And the main way someone could gain access to aducanumab right now is to participate in their phase four clinical trial. Lecanemab is very recently approved, and so there’s a timeline associated with that and some important milestones that lie ahead, including, as I mentioned, hopefully full approval of aducanumab and then key decisions by Medicare and insurers about whether it will be covered to what extent it’s covered. And that’ll launch numerous steps toward a clinical practice that includes routine access to lecanemab when the right steps are in place, meaning that the right doctor can make the diagnosis, can order the tests that are necessary to determine if a person is appropriate for lecanemab and has the steps in place to ensure that someone is safe while they’re taking it.
One of the important decisions people need to make about taking a drug are the dangerous side effects of these drugs. And I’ve read that that’s there are some pretty severe ones, specifically for lecanemab. So how should, how should a clinician and a patient weigh these issues?
Right. Well, I think you hit the nail on the head when it’s a clinician and their patient who will have to weigh these issues. And every drug has side effects. And as you point out, lecanemab has potentially risky side effects that include what we call amyloid related imaging abnormalities. And this is leakage across the blood vessels in the brain, or even bleeding in rare cases. Lecanemab actually has a pretty good safety profile. There’s been a lot of news about safety issues. And I’m not trying to minimize that news. I think that this drug does have very real safety issues in the double-blind placebo-controlled trials, the safety was quite good. Um, and the rates of those amyloid-related imaging abnormalities were much lower than we’ve seen for some other drugs like lecanemab. Now, there’s been a lot of headlines around some cases from people who were participating in what’s called an open-label extension study.
And I, like many, want to see more data about this overall safety profile. And ultimately, you know, the real understanding of safety will come after this drug is in clinical practice with things like patient registries, which will be absolutely critical. But I do think that this drug is safe enough for clinical practice, and I think it does, look pretty good compared to some of the other compounds that are still in development, for example, or compared to aducanumab. We have to be careful making comparisons across clinical trials. But the rates in the phase three clinical trial of lecanemab were only around 12% and only about 3% had symptoms. And so I think expert neurologists, expert geriatricians and geriatric psychiatrists who understand these data, understand how these drugs work and have the tools necessary to determine if a person is appropriate for lecanemab and doing well while on it. That’s a recipe for some people to gain access to a treatment that may slow the course of their disease.
Okay. And reading about these two treatments, I noticed that both of these drugs are based upon monoclonal antibodies, which are lab created proteins. How does this differ than previous dementia drugs?
This differs from previous dementia drugs in a number of important ways. The drugs have been shown and were developed because they directly target the biology of this disease, which we have increasingly understood because of decades of outstanding research. And that’s why the drugs got this accelerated approval pathway as well. They convincingly were shown to lower the plaques in the brain that accumulate in a person with Alzheimer’s disease. Previous drugs were, if you will, targeting downstream effects of the disease rather than the underpinning biology of the disease. So they helped keep chemical levels in the brain, artificially raised chemical levels that we know go down in a person with Alzheimer’s disease. So they helped masked mask the symptoms a bit, but they didn’t slow the disease in any way, shape or form. We sometimes refer to those drugs, which include the majority of drugs or all the drugs that people with Alzheimer’s disease in their family know now, Aricept, Exelon, Razadyne and Namenda, all those drugs we think of as symptomatic.
When a person is taking those drugs, they perform a little better on memory tests or other thinking tests, but the rate at which their memory worsens over time isn’t changed by the fact that they’re taking those drugs with these new medications, beginning with these monoclonal antibodies against the amyloid protein. What we hope and what the data for Namenda suggests is that we’re actually slowing the progression of the disease. And that’ll mean that hopefully the longer a person takes these drugs, the more they benefit. And the earlier we start these medications, the bigger the impact because we’re slowing the disease when a person is functioning at their, at their highest possible level. And that’s even now being tested in a new clinical trial that we’re a part of called the head study, where instead of giving lecanemab to people who already have mild cognitive impairment or mild dementia, we’re targeting people who have normal memory, but in whom the amyloid protein does seem to be accumulating in the brain, putting them at increased risk to someday get those memory problems. But we’re testing whether lecanemab can actually delay or even prevent the onset of memory problems in people who are at risk to have that in their future.
How do you determine that, say my brain in, for instance, is accumulating plaque?
So there are a couple of ways we can do that. Now. The tried intrude method is with a brain scan and specifically something called an amyloid PET scan with PET, meaning positron emission tomography. So we inject a tracer, a dye into the blood, and what that tracer does is if the plaques are present in the brain, it grabs a hold of it and the scanner can measure the tracer and whether it’s present or absent in the brain. Um, that’s the way we’ve been doing these studies for the last decade. People who are older, they may have a family history or even concerns about their memory but they perform normally on standardized tests. They have this brain scan, and if the plaques are found to be accumulating in their brain, they’re eligible to participate in these studies of these promising therapies. The technology is coming fast and furious, and now we have blood tests that can give us similar information, and we’re beginning to incorporate the blood test as an easier way to identify people who are right for the study. And, and, and to this point for the, for the ahead study, more so to rule out people who are unlikely to qualify. So we do a blood test. If it doesn’t say you shouldn’t be in the study, then we do the PET scan to see if you should be in this study.
The estimated costs of lecanemab and aducanumab are more than $25,000 a year, which is out of the price range for most people out of pocket. What it would take, what will it take for Medicare and other major health insurers to approve it?
Yeah. This was part of the controversy around aducanumab as well. They originally priced it in the high $50,000 range for a year’s worth of treatment. And before the Centers for Medicare and Medicaid Services rendered a decision about coverage, they cut the cost in half. That cut was not sufficient to get CMS to cover the cost of the drug, though they issued what was known as a coverage with evidence determination, meaning that Medicare would only cover the cost of aducanumab for people who were enrolled in a CMS approved clinical trial of that drug. And they indicated with that decision that a similar approach would be in place for any anti-amyloid drug, particularly one that was approved through this accelerated pathway. CMS has since suggested that they will take new data and revisit the decision. And in particular, if lecanemab achieves full FDA approval, which I hope it will, I hope too that CMS would be open to covering the cost of lecanemab because, as you point out, few families can afford more than $25,000 per year for a new medication.
What other promising dementia treatments are in the clinical trial pipeline?
Well, we’ve been doing drug development for Alzheimer’s disease for decades now, and I think many of us believe we’re hopefully at an exciting inflection point where we’re going to see more and more progress coming faster and faster. It’s important to say that there were numerous anti-amyloid drugs, monoclonal antibodies against the amyloid protein, that that didn’t achieve clinical efficacy or approval. In order for us to get where we are now with the first handful of these drugs getting approval, and seeming to have clinical benefit. Similarly, we’re at the early days of drugs that target tau, the other hallmark pathology of the brain in Alzheimer’s disease, what we call neurofibrillary tangles. And we sometimes refer to those as anti-tau drugs, tau being the protein that accumulates in the, in the tangles themselves. And so hopefully we’ll see greater progress in the anti-tau space.
And in particular with approved anti-amyloid drugs, we may have the opportunity to do combination trials targeting these two fundamental changes in the brain associated with Alzheimer’s disease, plaques and tangles. And of course, we’re here at UCI, where some of the world’s foremost researchers studying the inflammatory effects of Alzheimer’s disease have long held and certainly convinced me that we should also be thinking about drugs that target the inflammation in the brain, associated with this disease. And so ultimately, we may someday be looking at not just combination therapies, but even cocktail approaches. And those will certainly be difficult clinical trials to do, but that’s a challenge we will welcome, if we can find combinations of treatments that can actually stop this disease in its tracks.
You recently published an article in a peer reviewed journal in which you discussed the need to have greater representation in Alzheimer’s disease clinical trials. Could you tell us a little bit more about that?
Alzheimer’s disease is a disease that affects every community. There are no populations of people who are spared from this disease. It affects rich people and poor people, Democrats and Republicans, Blacks, Hispanics, whites, Asians, Pacific Islanders. The list goes on, and we are committed to doing research that discover solutions that work for everyone. But historically, research has not been inclusive of everyone, and no studies are worse in this regard than our clinical trials of new medications. This is something we have to change. We need to know whether these drugs are equally safe and equally efficacious in, in everyone, and not just the affluent, well-educated white people who generally make up more than 90% of our clinical trials. Now we know that this will take tremendous effort. We know that there are barriers to doing better at recruiting diverse populations into clinical trials.
There are historical sources, good reasons for distrust among some communities of medical research. There are issues around access to our, to our studies. Um, and recently we’ve even been scientifically studying whether the criteria we use for clinical trials may differently exclude people from trials who want to be in them. And we need to understand all these things more fully. And we’re committed to doing that work. And then systematically lower the barriers to inclusion in our clinical trials so that we can recruit populations that are representative of our diverse nation.
How can people learn more about UCI MIND and participate in either clinical trials or other studies?
We are Orange County’s only NIA-funded Alzheimer’s Disease Research Center. And the majority of that means that our mission is to do research that that changes our understanding ability to diagnose and treat Alzheimer’s disease and related dementias. But I’ve always felt that another thing that comes with that mission is sharing what we’re learning with the community at large and involving them in our research. So we actually put a lot of energy into reaching out into the community, delivering community education talks and a lot of energy into our website, which is mind.uci.edu. We have multimodal approaches to educating the community. Some of our supporters were instrumental in helping us start something called UCI MINDcast. So we now have our own podcast. We have video content on our website, and we work hard to maintain a very timely blog.
When things like the FDA approval of lecanemab happened, people can turn to our website to get an immediate reaction to those types of events and other things that they’re seeing in the news. And as far as getting involved, aside from looking at our website and seeing what’s happening, we built something here at UCI several years ago called the Consent to Contact Registry or C2C. People can visit, C2C.uci.edu and they can enroll in a recruitment registry by spending 15 or 20 minutes telling us a little bit about themselves so that we can match those people up to studies happening at UCI MIND or elsewhere at UCI, in particular in the clinical research domain. And that’s something that we’ve been working hard to grow. It’s been a very effective tool at accelerating research at UCI. And like we discussed earlier, we’ve also put a lot of energy and effort into making sure that the registry itself is as diverse as Orange County. So people can enroll in Spanish, Korean, Vietnamese and Mandarin Chinese, in addition to English.
That’s pretty comprehensive.
Okay. Well, we’re going to close here by going through some rapid fire questions about Alzheimer’s disease. So, you’re ready?
All right. What’s the difference between dementia and Alzheimer’s disease?
Dementia means that someone has cognitive problems that get in the way of living life the way they once did. And Alzheimer’s disease is the most common cause of dementia, but it is not the only cause of dementia. And so we have experts here at UCI who study other forms of dementia, like frontotemporal, lobar degeneration, Parkinson’s disease, Lewy body dementia and the like.
Can I inherit Alzheimer’s disease?
Alzheimer’s disease generally is not inherited. Having a family history of Alzheimer’s disease increases a person’s risk, but not every person who has a family history of Alzheimer’s disease is destined to get it themselves. And not every person who gets Alzheimer’s disease had a parent who had it. So family history is a part of the equation, but it’s just a part of the equation.
Would that family history be more maternal or paternal?
Maternal and paternal family history matter. You can find studies to suggest maternal history may matter more, but family history matters. But it’s still just a piece of the larger equation of who does and does not get Alzheimer’s disease.
So if I had a parent who passed away from Alzheimer’s disease, I don’t necessarily need to worry.
I don’t think anyone necessarily needs to worry any more than we all should be worrying, because this is a huge public health problem. And if you’ve known this disease in your own family, you know the burden it creates. People with a family history of Alzheimer’s disease who are concerned about the risk for themselves definitely populate a lot of our studies, and we understand their motivation which always includes a motivation to help us make progress in the broader sense. And without those people, we don’t make that progress. And so I’m forever grateful to the many, many hundreds of people enrolled in studies at UCI MIND.
What if any lifestyle factors can contribute to Alzheimer’s disease?
The geneticists estimate that as much of the risk, as much as 50% of the risk for Alzheimer’s disease, is due to our genes which we get from mom and dad. That leaves 50% to be due to the environment and our lifestyle. And this has been the source of tremendous research over the last few decades. In fact, I have a whole hour-long talk called “Lowering Your Risk for Alzheimer’s Disease” that emphasizes these things, but it’s relatively straightforward. Lead a healthy life, get physical exercise, eat a healthy diet, avoid foods high and fat and cholesterol, and eat adequate amounts of fish, healthy fruits and dark green leafy vegetables. Get a good night’s sleep. When we sleep, we actually clean our brain. And one of the things we clean from our brain is that amyloid protein that accumulates in the plaques of Alzheimer’s disease stay mentally and cognitively active as we age and stay socially active.
Manage stress, avoid head trauma and basically lead a good cardiovascular health lifestyle that your primary care physician recommends. And you don’t have to do much more than that. You don’t need to buy expensive books or take expensive courses. There’s little to no evidence to support things like dietary supplements as doing anything more than a healthy diet can do. And certainly you don’t need expensive gimmick interventions that cost thousands of dollars. And again, I urge people to visit the UCI MIND website to learn more about these things, and to come to a talk and ask someone before you take any steps. Or certainly to talk to your own doctor andours before you take any steps around new medications or new supplements to try to prevent dementia.
And finally, how do I know I need to be tested for cognitive decline?
This is a tricky issue, and it’s changing with time. And someday we’ll screen everyone at a particular age to see if Alzheimer’s disease has begun so that we can start a therapy that’ll prevent it from happening right now. The standard recommendations are that if you or your loved one are noticing cognitive problems in your daily life, then you should seek out a diagnostic workup from an expert clinician. If a person’s asking the same question over and over again in a single conversation, if they’re having trouble finding a way to a place that was once well known to them, then these are certainly red flags. And it’s also important to say that I’m a huge proponent of early diagnosis. I think a diagnosis is key. There are other causes of cognitive problem with age, some of which have better treatment options than Alzheimer’s disease. And so understanding what’s going on whether it’s Alzheimer’s disease, whether it’s something else, and having information to make a plan, including whether there are treatments that might be right for you, is key. And that comes from talking to a clinician who understands the brain.
And these cognitive tests are available through UCI MIND.
UCI MIND is a research organization, but UCI Health has a number of outstanding clinicians in neurology, psychiatry and family medicine in the division of geriatrics and gerontology – all of whom are extremely well-trained, excellent providers who understand the aging brain and the conditions that afflicted.
Thank you for joining us, Dr. Grill.
Thank you so much for having me, Tom.
I’m Tom Vasich thanking you for listening to our conversation. The UCI Podcast is the production of Strategic Communications and Public Affairs at the University of California Irvine. Please subscribe wherever you listen to podcasts.