How well does a new Alzheimer's drug work for those most at risk?
EMILY KWONG, HOST:
You're listening to SHORT WAVE...
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KWONG: ...from NPR.
There was a big announcement in January from the FDA. They were accelerating approval for a drug called lecanemab.
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SCOTT SIMON, BYLINE: The U.S. Food and Drug Administration has approved a drug that appears to slow down the progression of Alzheimer's disease.
KWONG: Now, in clinical trials, lecanemab's effects on early Alzheimer's disease were pretty small. Among the hundreds of patients who took the drug, cognitive decline slowed by about 27%. But that was enough to trigger excitement in both patients and scientists because, well, nothing else has worked that well. The drug met two endpoints, clearing amyloid plaques in the brain and slowing the rate of cognitive decline.
JONATHAN JACKSON: That is unprecedented. We haven't been able to do that before.
KWONG: Dr. Jonathan Jackson has been following this research closely. He's an assistant professor of neurology at Harvard Medical School and the executive director of the CARE Research Center, which stands for community access, recruitment and engagement.
JACKSON: It was cause for celebration, but as with anything scientific, there are lots and lots of other questions that cropped up, even as we got this good news.
KWONG: One of those questions has come up over and over again in Alzheimer's drug trials but also across a lot of medical research, which is, did this study test the drug on a representative group of patients - meaning, does the population evaluated in the study match the population most affected by the disease? One of the companies behind this drug, Eisai Pharmaceuticals, says this clinical trial was the most racially diverse ever for an Alzheimer's treatment. And it was a big study. Among the 1,795 participants recruited, 25% identified as nonwhite. So it was a quarter POC, and that's considered diverse by clinical trial standards. But Jonathan still has questions.
JACKSON: It turns out that 22 of that 25% identify as Hispanic or Latino. Only 3% identified as Black or African American.
KWONG: So his point is that even though the trial results overall were statistically significant, they didn't reveal much about how the drug impacted Hispanic or Latino and Black or African American patients. And that matters because those populations are at a higher risk for Alzheimer's disease.
JACKSON: For women, for individuals at high genetic risk, for Hispanic individuals and for Black individuals, we did not get that level of certainty. Even in the world's most diverse Alzheimer's trial, a giant trial - 1,800 people - that lasted for a much longer time than most trials did, 18 months, we're still not sure that all of the groups that are at highest risk of Alzheimer's disease actually see any kind of benefit.
KWONG: Today on the show, we get up to speed on the fast-tracked drug lecanemab and unpack the most diverse clinical trial to date with Dr. Jonathan Jackson. I'm Emily Kwong, and you're listening to SHORT WAVE, the daily science podcast from NPR.
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KWONG: Jonathan Jackson has been studying early detections of Alzheimer's disease for years. He's the executive director of the CARE Research Center at Massachusetts General Hospital and Harvard Medical School. He's interested in how many patients in this trial are at high risk for this disease.
JACKSON: It doesn't really make sense to sort of lump Hispanic and Black people into one giant category and say that it's diverse.
KWONG: You said that there wasn't a lot of information indicating whether lecanemab was effective in these groups. Why is that when the study was so big?
JACKSON: Yeah. So I think it's not about getting more and more and more people into the trial but maybe stepping back and asking the question, do we really understand what lecanemab is doing?
JACKSON: And then the deeper question - do we really understand what Alzheimer's disease is doing?
KWONG: And I suppose what's also tricky for me about - in even talking to you about this is it's one study, so you can't have complete answers based on one study.
JACKSON: Yes, it's only one study. What's important to remember is, if you've read any articles or seen any interviews, talking to neurologists or study doctors, they will use the word modest. They will say that lecanemab has a modest effect, and that is just fancy scientific jargon for saying, we see it in our science. Are you going to see it at home? Probably not. And for the groups that didn't even see a clear effect in a tightly controlled trial, they may not see any difference at all. So we're kind of in this very messy reality where we have met a scientific endpoint, but we don't know whether it's clinically meaningful to the average person who is living with dementia. So we might just need to have another way of approaching clinical trials, other interventions that we can try, other potential treatments that we can try that may work in these groups of high risk.
KWONG: When we look at the population in the U.S. with Alzheimer's disease, it's more than 6 million people, and a disproportionate number are Black Americans. What does it mean when we don't study Alzheimer's in the populations it affects the most?
JACKSON: If we don't include individuals that are at highest risk for Alzheimer's disease in our research studies, in our clinical trials, it means that we don't understand Alzheimer's disease. It's just full stop. And so a lack of diversity in these trials, to me, indicates - it's almost a canary-in-the-coal-mine type of situation. It means that there's something off with the quality of our science. And if we can try to address that problem, if we can find a way to inclusively and representatively include individuals that are at high risk and show a benefit for that group, then it means that we probably understand the disease process a little bit better than with the data that we are currently showing for trials like lecanemab. So we might just need to have another way of approaching clinical trials, other interventions that we can try, other potential treatments that may work in these groups of high risk.
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KWONG: We at SHORT WAVE wanted to share this critique with one of the companies that made the drug, Eisai Pharmaceuticals. Shobha Dhadda is senior vice president of biostatistics and clinical development operations for neurology there. And Shobha agrees - for a disease whose burden differs across race, the clinical results should reflect that. And she said this.
SHOBHA DHADDA: Yeah, so - and I've heard from other researchers, also, similar comments about the eligibility criteria in a clinical trial. So when you're designing a study and you're putting the eligibility criteria, the patient population has to depend on the hypothesis you're studying. For example, lecanemab - the hypothesis is based on the amyloid plaque reduction, right? So we have to have, if - we have to enroll patients who have the amyloid plaque in the brain. We cannot - otherwise, the drug will not be effective. However, I agree that we do have to overenroll some of these underrepresented populations to get the more representative population. So we had more than one-third from the underrepresented population...
DHADDA: ...To get to what we actually had in the study. So you do have to overenroll and - to get to where you are, initially, at least until you understand if there is actually any difference in the disease pathology of these underrepresented population versus the other global population.
KWONG: So what kinds of thoughts are you having for subsequent trials? You know, now that it's in the FDA - things are moving on the FDA side, are there any plans or thoughts you want to share on this point of diversity?
DHADDA: Yeah. So we are actually spending a lot of strategic thinking on how do we continue to increase diversity and also to - thinking more deeply on the science aspect of it, saying, we have to screen sufficient number of patients to actually address that question. Is there really a difference in the disease pathology or the treatment effect in this patient population? And that - and this is not just us. As a community, clinical trial community, we all have to do our part to address these questions and answer questions, scientifically and operationally both.
KWONG: And to be clear, Jonathan's analysis goes beyond this Alzheimer's study right to the heart of what it means to measure the diversity of a clinical trial.
You know, the bar, the standard for a lot of studies in terms of diversity is for it to reflect the U.S. census population.
KWONG: What do you think of that in the world of medicine, specifically with Alzheimer's? Yeah.
JACKSON: Yeah. The scientific term is bad on top of bad on top of bad. No. 1, the problem with the U.S. census is that they change the definitions every decade, and so it's really impossible to have a consistent definition of any particular group. The second thing that is potentially problematic is that the U.S. census has some blind spots. So we know that there are racial and ethnic groups that are completely invisible to the way that we currently conduct the U.S. census. So Middle Eastern and North African individuals, for example - we think of Asian as one giant group, which is potentially problematic. But the more difficult problem is that it's better to reflect the population that is disproportionately burdened by the disease because that means that you have the best opportunity to understand the mechanics of what's driving something like dementia.
And so instead of trying to answer these questions after a drug is approved, it would be easier and, indeed, better for us to start to answer these questions around diversity and inclusion while we're conducting the trials, present that data to FDA and then have a much more significant return on our investment by taking care of this upstream instead of crossing our fingers and hoping that it works in a much broader population after it's approved.
KWONG: I'm wondering if you have any other examples of diseases whose very understanding has been impacted by the clinical studies on which the drugs were designed or any broader statement you want to make about it.
JACKSON: So FDA's own scientists have done a couple of analysis and shown that between 1 in 10 and 1 in 5 drugs that are approved have some sort of differential effect in ethno-racial minorities, you know, particularly in Black people. There is not currently a lot of rules or guidance or regulation around diversity and representation, but it is something that is increasingly being scrutinized.
JACKSON: So my hope is that we will have more thoughtful guidance in the next several years.
KWONG: Yeah. So the last thing I just want to ask you is what is the standard that you want to see in clinical trials in the future?
JACKSON: Yeah. So the laundry list is long.
KWONG: What are your top three?
JACKSON: Top three - this is interesting. It feels like I have to, like, rattle off my top three favorite albums or my top three movies of all time. So No. 1 would be to be really thoughtful and plan who you want to enroll ahead of time and make sure that you include a disproportionate number of individuals who are disproportionately affected by the disease. The second thing that I would try to change is rethinking the way that we design clinical trials themselves. Right now, we have a system that says that the only way for this to work is for the study drug to remain secret from everyone. Otherwise, it will ruin the science. Science should never be something that's quite so delicate. You can design really elegant research studies that are completely open. You can understand what you're taking, and you can choose, as a patient, whether you want to take this or whether you want to take something else. You can have a lot more power and consideration and contribution to the way that the science is designed and conducted and executed.
And then the third thing is, I would try to find a way to connect clinical care with clinical research. There are lots and lots of things that are escaping our notice as scientists because we have a narrow definition of who can design and benefit from research. So being a little bit more open-minded about that, really democratizing and even decolonizing scientific research, I think will be the next key driver of innovation.
KWONG: It's been so good to talk to you. Thank you for sharing all of this.
JACKSON: Yeah. Thank you, Emily. This has been great.
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KWONG: Today's episode was produced by Liz Metzger, edited by Gabriel Spitzer and fact-checked by Anil Oza. You can see more of Anil's reporting on this story at npr.org/shortwave. The audio engineer was Patrick Murray. Our senior director of programming is Beth Donovan, and the senior vice president of programming is Anya Grundmann. I'm Emily Kwong. Thanks for listening to SHORT WAVE from NPR.
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