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RHITU CHATTERJEE, BYLINE: A new drug for Alzheimer's ought to be good news. But a lot of experts don't see it that way.
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JASON KARLAWISH: The data just aren't there right now to say that this is the drug to open up the new era for the treatment of Alzheimer's.
DAVID RIND: It's quite possible that it does not work.
JOY SNIDER: I don't want to give them something that is not going to help them and could possibly hurt them.
CHATTERJEE: Rhitu Chatterjee here with NPR science correspondent Jon Hamilton. Jon, who were those scientists? And what's the drug they're talking about?
JON HAMILTON, BYLINE: That was Dr. Jason Karlawish at the University of Pennsylvania, Dr. David Rind of the Institute for Clinical and Economic Review and Dr. Joy Snider of Washington University in St. Louis. The drug they were talking about is called aducanumab. It's now being marketed under the brand name Aduhelm. And it's the first drug ever approved by the Food and Drug Administration to treat the disease process underlying Alzheimer's. Aduhelm is really good at reducing those sticky plaques that tend to build up in the brains of people with the disease.
CHATTERJEE: That sounds really promising. Why the skepticism from those experts?
HAMILTON: Because it's still not clear whether reducing those plaques can slow down the loss of memory and thinking caused by Alzheimer's. Also, aducanumab has some potentially dangerous side effects, like swelling and bleeding in the brain. Oh, and then there's the cost, which looks to be about $56,000 a year.
CHATTERJEE: So today on SHORT WAVE, how a controversial Alzheimer's drug got approved by the Food and Drug Administration.
HAMILTON: And what this will mean to doctors and their Alzheimer's patients.
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CHATTERJEE: Jon, let's start at the beginning. Where did this drug come from?
HAMILTON: It's what's known as an amyloid drug. Amyloid aggregates into the sticky plaque that you see in the brains of people with Alzheimer's. And over the past couple of decades, drugmakers have churned out a whole bunch of experimental drugs that are designed to get rid of this amyloid plaque. The thinking is that amyloid is to Alzheimer's what cholesterol is to heart disease. So a drug that reduces amyloid should protect the brain the way a drug that lowers cholesterol protects the heart. And aducanumab is one of these amyloid drugs. It's made by an American company called Biogen and a Japanese company called Eisai.
CHATTERJEE: So what happened to all those other amyloid drugs?
HAMILTON: They all failed. A lot of them did, in fact, lower amyloid. But they didn't keep Alzheimer's patients from getting worse. So over time, drug companies started giving up on the approach even though they had invested billions of dollars in it. The question was whether that was going to happen with Biogen and aducanumab, too. Back in 2016, I spoke with the chief medical officer at Biogen about the drug. His name is Dr. Al Sandrock. And at the time, Biogen had just completed a small study that suggested the drug might slow down memory loss. Even so - Sandrock was really cautious.
AL SANDROCK: We think we have something important here. We hope we're right because if it's true, it would benefit millions of patients. But we don't know we're right yet. We're going to have to do a couple of large trials to confirm what we think we see.
CHATTERJEE: So those trials that he's talking about, did they ever happen?
HAMILTON: Here is where the story starts to get a little bit weird. The trials were started but never finished. After they had enrolled thousands of patients, Biogen conducted something called a futility analysis. It's designed to show whether a study is likely to produce a positive result or whether continuing it is, well, you know, futile.
CHATTERJEE: Is that because companies just don't want to invest a lot of time and money into something that might not end up producing results?
HAMILTON: Right. These studies are really expensive. And continue a trial that's not going to pan out for a company is just, to their mind, throwing money away. And Biogen's analysis showed that for these two big studies, they weren't going to probably get anything. So there was no point spending money to finish them because the drug was probably going to fail. So Biogen pulled the plug.
CHATTERJEE: Well, you know, hearing you put it that way, it sounds like the end of the story. How do we get from there to the FDA ending up approving this drug?
HAMILTON: Well, Biogen had continued gathering data on patients until it actually halted the trials. That's in March of 2019. That meant they had gathered several months of data that hadn't been considered in the futility analysis. And when the company went and crunched all the numbers in that larger group, it decided that maybe aducanumab did help some people. Specifically, they thought it was helping people in the very earliest stages of Alzheimer's who were getting a high dose of the drug. They took this information to the FDA. And by all accounts, the FDA staff encouraged the company to reevaluate its decision to give up on aducanumab. Then in October of 2019 - this is six months after halting the two studies - Biogen announced it was going to seek FDA approval after all.
CHATTERJEE: How unusual is that? And did they decide to seek approval just with whatever data they already had?
HAMILTON: I've never seen anything quite like this. And even with the extra data, the results were pretty hard to interpret. So when Biogen started talking about getting FDA approval, a lot of scientists thought it was, you know, a long shot.
CHATTERJEE: Right.
HAMILTON: After all, Biogen had formerly given up on the drug. It hadn't finished the studies. And what Biogen ended up submitting to the FDA was one unfinished study where aducanumab seemed to help a bit and another unfinished study where the drug seemed to have no benefit. That got a lot of discussion when an independent panel of experts that advises the FDA had a meeting about aducanumab. This was in late 2020. After Biogen made its online presentation, an FDA official gave a presentation of his own. And to a lot of people, it sounded like he was making a pitch for approving this drug.
CHATTERJEE: I'm guessing that doesn't happen often, right?
HAMILTON: Nope. And it really seemed to annoy some of the members of the advisory panel. Let me play you one moment from the part of the meeting in November 2020, where panel members got a chance to respond to what they'd been hearing. This is Dr. Scott Emerson, a biostatistician from the University of Washington.
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SCOTT EMERSON: This analysis seems to be subject to the Texas sharpshooter policy, a name for the joke of someone first firing a shotgun at a barn and then painting a target around the bullet holes.
CHATTERJEE: Wow.
HAMILTON: Yeah. In other words, he's suggesting that the FDA and Biogen had somehow come up with evaluation criteria that were designed to make the drug look like a success.
CHATTERJEE: Wow. How did other people on the panel feel about this?
HAMILTON: Ten of 11 members voted against approval. And a number of Alzheimer's experts also asked the FDA not to approve the drug. I spoke with Dr. Lon Schneider at USC. And I asked him, should the FDA approve this drug?
LON SCHNEIDER: No. One identical study was flat-out negative. The other one was biased and unblinded. And whatever effects it showed were truly trivial.
CHATTERJEE: Still, the drug got approved.
HAMILTON: Right? I mean, usually the FDA follows the recommendations of advisory panels. But what the FDA did in this case was find a way to approve the drug without directly disagreeing with the panel. After the advisory committee meeting, the FDA changed the basis for reviewing the drug. They decided to use something called accelerated approval, which has been used for some cancer drugs. This sort of approval allows the FDA to approve some drugs without knowing whether they will benefit patients. So for example, a cancer drug might be approved because it shrinks tumors, not because it necessarily helps people live longer. The FDA's justification for accelerated approval of aducanumab was that it reduced amyloid plaque in the brain. And it does. But that wasn't what the FDA asked its advisory panel to look at.
CHATTERJEE: So from everything that you've told us, Jon, it sounds like the FDA really wanted to approve the drug. Otherwise, why would they approve it despite such overwhelming skepticism from its own advisory panel?
HAMILTON: Well, I certainly don't know why the FDA decided to do what it did. But there are - several critics have suggested that, indeed, the approval was foreordained. And the FDA's decision really upset some members of the advisory panel. Three of them actually resigned in protest. And they say Biogen should have had to conduct another study as kind of a tiebreaker, you know, to see whether the drug actually helped patients. The FDA says Biogen is going to conduct that study after aducanumab is on the market. But that could take nearly a decade for us to see results.
CHATTERJEE: Wow. That seems like a really long time.
HAMILTON: It is.
CHATTERJEE: So we've heard from lots of people who don't want this drug on the market. What about the people who do?
HAMILTON: One group that has been a really powerful advocate for aducanumab is the Alzheimer's Association. The group says the first drugs for other diseases, like cancer, often didn't work very well either. But over time, they got better. Also, it's worth remembering there are about 6 million people in the U.S. with Alzheimer's. And until now, there has been nothing available that offered any hope of slowing down the disease. I spoke with a couple in St. Louis about this. Their names are Philip Lynn (ph) and Kurt Ray-Winkle (ph). Philip was diagnosed with Alzheimer's when he was still in his 50s. But he managed to get into one of the clinical trials of aducanumab. And Ray-Winkel says his spouse's mental function has been stable or may have even improved since he went on the drug.
KURT RAY-WINKLE: That was attitude-changing. And it confirmed that there really is hope and that there really is something to be hopeful for.
CHATTERJEE: Does this mean that the drug really is working for Philip Lynn?
HAMILTON: It's possible. Even drugs that fail in a clinical trial can be helping some people.
CHATTERJEE: Jon, you mentioned earlier that this drug is expensive, $56,000. How many people will be able to afford it, really?
HAMILTON: We actually don't even know how much it's going to cost yet because this drug has to be given intravenously in a medical setting. So there're going to be additional costs for that. And because patients will need to be monitored for potential brain swelling and bleeding, it's going to cost even more money. This could all mean billions of dollars a year, most of it probably coming from taxpayers through Medicare.
CHATTERJEE: So how will all of this affect the development of other Alzheimer's drugs?
HAMILTON: One question is whether pharmaceutical companies that developed and then gave up on other amyloid drugs will be asking the FDA to approve these drugs the same way it did aducanumab. And ironically, these companies may only have to show that their drug is as effective as aducanumab, a drug that maybe doesn't even work. But the future of Alzheimer's drugs is probably going to be about targets other than amyloid. For example, right now, there are a number of experimental drugs that target a protein called tau. So a lot of researchers think there are going to be much more effective treatments for Alzheimer's in the next few years. They just won't target amyloid.
CHATTERJEE: Well, thank you, Jon, for walking us through this very complicated and interesting story.
HAMILTON: Happy to do it.
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CHATTERJEE: This episode was produced by Thomas Lu, edited by Gisele Grayson and fact-checked by Indi Khera. The audio engineer for this episode was Josh Newell. I'm Rhitu Chatterjee. This is SHORT WAVE from NPR.
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