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--:-- Sean Rameswaram: About two weeks ago, the Food and Drug Administration did something it hadn't done in nearly two decades. It approved a new treatment for Alzheimer's disease. It was like a ray of sun coming through the horizon. Until now, there has been no hope for folks who've gotten the diagnosis of Alzheimer's. With this new drug, the hope begins. Huge news. Just the kind of thing the six million Americans living with Alzheimer's today want to hear. But there's a catch. It's a hotly contested decision by the FDA.
--:-- Sean Rameswaram: Adam Feuerstein is a senior writer at STAT. A good number of people in the scientific community are kind of enraged about because they doubt that the drug is actually effective. The jury is still out on whether it works. And in this instance, I think that the evidence is still quite murky as to the effectiveness of this product.
--:-- Adam Feuerstein: Before we talk about this new product, how is Alzheimer's currently treated?
--:-- Sean Rameswaram: Right now, the medicines that are currently approved to treat Alzheimer's really only treat the symptoms, and they only treat the symptoms for a short period of time. And so that's kind of why this medicine is so important and has gotten so much attention, because it really treats the underlying cause of the disease.
--:-- Adam Feuerstein: For decades, scientists who study Alzheimer's have focused a lot of the research on something called amyloid. And what it is, is essentially it's a protein. And when these proteins collect, They clump together in the brain. They become toxic to the neurons in your brain, and they essentially destroy the neurons in your brain. So there is this theory called the beta amyloid hypothesis, which basically says that these clumps of amyloid are what causes Alzheimer's. It causes the memory loss, the loss of cognition. And so if you can remove these amyloid plaques from the brain, you may be able to treat Alzheimer's effectively.
--:-- Adam Feuerstein: So for decades now, drug makers have tried to come up with drugs that can clear amyloid from the brain. The problem is, is that we've, over the years, there's a long list of drugs that have successfully cleared those plaques or to some degree. But the problem is they've never really been able to show that doing that actually slows the progression of the disease, improves cognition, improves memory.
--:-- Sean Rameswaram: Okay, so let's talk about this new drug. What is it called? What exactly does it do? Where did it come from?
--:-- Adam Feuerstein: The scientific name of the drug is aducanumab, the brand name. Aducanumab? Aducanumab, yes. If and when you ever see commercials for aducanumab on TV, the brand name is Aduhelm. The company that's developed the drug is called Biogen. It's a Cambridge, Massachusetts-based biotech company that does a lot of work in neuroscience. So they actually didn't invent the drug. The drug was actually invented by a small Swiss drug maker. Biogen licensed the drug back in kind of the mid 2000s.
--:-- Adam Feuerstein: And what the drug does is it's an antibody. So it's given by infusion. Patients have to sit through an intravenous infusion once a month to get this drug. And basically what the drug is, the antibody goes out and it seeks out these amyloid plaques and it essentially uses the immune system to clear those plaques from the brain.
--:-- Sean Rameswaram: Okay. And where do we get into trouble with this drug? We get into trouble with this drug because like a lot of these Alzheimer's drugs, It's gone through a lot of ups and downs. I would say the first real kind of excitement over aducanumab or aduhelm was back in 2015. And that's when Biogen ran a smaller clinical trial in which they were basically testing different doses of the drug in patients with Alzheimer's.
--:-- Adam Feuerstein: There was also a placebo group in the trial. So some patients received the placebo. And from that study, they saw both a reduction in the amount of amyloid plaques that were in the brain of these patients. And they connected that. They also showed that that correlated with a slowing of the progression of the disease.
--:-- Sean Rameswaram: The important distinction here is, and for a lot of people, when you hear about a drug with Alzheimer's, they say, oh, is this a cure? This is not a cure for Alzheimer's. This does not do anything to improve your memory. Basically what this drug does, it slows the progression of the disease. So if you think of Alzheimer's over time, slowly over the years, patients get worse and worse. Their memory loss gets worse. They lose the ability to function, to take care of themselves over time. What this drug does is slows that down.
--:-- Adam Feuerstein: Okay, new drug slows down Alzheimer's in trials. What happens next? They ran two large phase three studies. They ran those at the same time. Some patients received the drug and some patients received placebo. And while they were conducting the study, the company, they had independent data monitors who looked at the studies. They basically unblinded the study results while the study was ongoing. This was back in March of 2019. These independent data monitors who looked at the data from the study said, you know what? This drug doesn't work. It's not going to work. And so we should stop the studies. And that's what they did.
--:-- Sean Rameswaram: So back in March in 2019, Biogen announced to the world that these two large phase three studies that they were running of aducanumab failed, essentially, that they were the drug was futile and that they were stopping the studies. Biogen shares are tumbling this morning. This is very bad news, not just for shareholders in this, not just for the company, but also for anybody who was really hoping on this as a new way to try and treat Alzheimer's.
--:-- Adam Feuerstein: What do we mean when we say this drug doesn't work? Does it not remove these amyloid plaques?
--:-- Sean Rameswaram: There was no doubt that the drug was actually clearing these amyloid plaques from the brain to some extent. But that wasn't translating into a benefit for the patient. Right. The patient wasn't really there was no change in the cognition of the patient. So the drug is certainly doing something, but it isn't necessarily helping anyone's Alzheimer's.
--:-- Adam Feuerstein: Right. Exactly. So back in March of 2019, these studies are stopped. Biogen is obviously disappointed. And that's where we think that's where basically we think the drug is dead. But then in October of 2019 so just you know a few months later Biogen announced that they did a new analysis of previously unavailable data from those halted studies
--:-- Sean Rameswaram: What it demonstrates again is that the road to breakthrough innovation is full of twist and turn And what they found in that analysis was that one of the studies was actually positive. One of the studies showed a slowing of cognitive decline. They showed a benefit for patients in one study. The other study was still negative. And so basically, the company concluded that we shouldn't have stopped the study when we did. We've done a new analysis. It was based on treating patients at a higher dose of the drug for a longer period of time.
--:-- Adam Feuerstein: The persistence and the passion and the specialization of the company in that space basically demonstrates that it leads to success eventually. Based on those data, they said they were going to go seek FDA approval.
--:-- Sean Rameswaram: How is Biogen measuring effectiveness here? The scale that physicians use to sort of measure the benefit for an Alzheimer's drug, it's an 18 point scale. So it's like zero to 18 that you measure an improvement in cognition. So this drug, the difference between aduhelm and placebo was literally a fraction of one point on an 18 point scale. It was actually, I think, 0.39. So that's how small the benefit was over placebo on this 18 point scale.
--:-- Adam Feuerstein: But at the same time, you have to understand that in the world of Alzheimer's, where literally there are no good drugs to treat patients. To some people, that's enough, that that is clinically meaningful and that benefit is large enough to justify treating patients with.
--:-- Sean Rameswaram: Just kind of decide that your drug works? It was a very controversial decision, Sean, what they decided to do. There were a lot of people who thought that, no, these data were not strong enough to justify the drug's approval, that they should actually just go and run an entirely new clinical trial.
--:-- Adam Feuerstein: But the company was very aggressive. They believed that the drug worked. They believed that the data that they had from this sort of reanalysis of the clinical trials supported the drug's approval. And so they went to the FDA with it. And what does the FDA say?
--:-- Sean Rameswaram: More twists and turns here. As part of the FDA review process, the FDA takes the drug and it invites a panel of independent experts. And this panel of independent experts were basically asked by the FDA to review all the data. We have zero yeses, 10 noes, 1 uncertain. This panel of independent experts, nearly unanimously, they said the data were insufficient, They weren't strong enough to support approval and that they recommended that the FDA not approve the drug.
--:-- Adam Feuerstein: So essentially they said, FDA, you should reject this drug. And the FDA still approved it. And the FDA still approves it. And you want to know why? I would love to know why.
--:-- Sean Rameswaram: Right. The FDA ignored the recommendation of this independent panel of experts. And what the FDA decided to do was basically they granted the drug what is called an accelerated approval. You can think of an accelerated approval as a conditional approval. The drug is on the market just like any other drug. But the basis for that approval was, remember we talked about those amyloid plaques and what these drugs are designed to do, a drug like adecanumab is designed to do, is to remove those amyloid plaques from the brain.
--:-- Adam Feuerstein: So what the FDA said was under the accelerated approval guidelines, they said, we believe that simply having a drug that removes these plaques from the brain is suggestive of a clinical benefit for patients. And we're going to let the drug get on the market. We're going to approve the drug now. And we're going to make Biogen conduct another clinical trial to confirm that benefit. And that's what they're doing.
--:-- Sean Rameswaram: And that's what they're doing. More controversy surrounding the FDA approval of Biogen's Alzheimer's drug. A third scientist resigning from the independent committee that advised the agency on the treatment. Dr. Aaron Kesselhelm, a professor at Harvard Medical School, quit Thursday, saying, quote, this might be the worst approval decision that the FDA has made that I can remember.
--:-- Adam Feuerstein: So FDA approved it after its own scientists are nearly universally against it. The scientists on this independent panel are furious. How do patients feel about all this drama?
--:-- Sean Rameswaram: You know, the debate over this has been intense. I mean, I joke, you know, like Alzheimer's Twitter right now is going crazy. You should see it. It's better than like crypto Twitter right now. If you've known anybody with dementia, you know, with Alzheimer's, you know, the cost to the healthcare system, the personal cost, the pain, the suffering that's involved here is intense. And so there are people who are desperate for treatment. And so, you know, for a lot of those people, they see this as a hopeful sign that, you know, that even if we don't necessarily know whether or not this drug actually works, having a drug in the market that might help them, you know, is being hailed from that side.
--:-- Adam Feuerstein: But then there are others, and there's another side, like scientists, people who like FDA observers, FDA critics who say that what this represents is a lowering of the approval standards, that the FDA was too flexible. The clinical data for this drug should be stronger before it's allowed on the market. Because, you know, on the other side, you don't want to give a drug to a patient that doesn't work.
--:-- Sean Rameswaram: My name is Phil Guttes, and I am a participant in the aducanumab trials for most of the last five years. I'm also on the board of the Delaware Valley Chapter of the Alzheimer's Association. I was first diagnosed with Alzheimer's about five years ago as part of the Biogen aducanumab trial. I had been complaining, apparently annoyingly complaining, that there was something wrong in my brain. I just didn't feel like I was remembering things anymore and that it just something felt off.
--:-- Phil Guttes: So my sister saw an ad on Facebook for a trial for people who were concerned about their memory and suggested I look into it. I did. And after a bunch of testing, an MRI and a PET scan, I was accepted into the, I believe it was the N-Gage trial for aducanumab. And the trial is pretty straightforward. Once a month, you would travel to a facility and you'd offer up your arm and they'd jab you and stick an IV in and you'd sit there for about an hour. And that was that.
--:-- Sean Rameswaram: There was no, you know, aha, I feel better moment. And a matter of fact, you know, some period of time after I began infusions, I sought social security disability because I felt I could work anymore. And Biogen canceled the aducanumab trials about probably two years into my experience. They announced that the drug had failed a futility analysis and they canceled it. And then seven, eight months later, they announced, they said, oh, we found later data and the drug is effective and we are applying to the FDA for approval.
--:-- Phil Guttes: They said that anybody who had been in an aducanumab trial would be eligible for this EMBARC trial and that we would receive the highest dose of the medicine. And I think I've now been through a year's worth of treatment of EMBARC. I feel better. So my head feels clearer. I feel more capable of engaging with longer projects. I've actually started doing a little bit of work. I edit proofread court transcripts. And, you know, I think two years ago, a year ago, I wouldn't have been able to do it.
--:-- Sean Rameswaram: You know, for me, that is such a mental relief because I've been a worker. My career was, you know, everything to me. And people don't know this, but Alzheimer's steals more than your memories. It steals your ability to work. It steals your identity. And, you know, to be able to have some form of identity back. That question that we're always asking or asked, what do you do? Well, you know, now I don't have to say I sit in my room and I read on my iPad all day. I can say, you know, I edit, proofread, court transcripts. And, you know, I feel like I'm doing a little bit to help again.
--:-- Phil Guttes: I guess I wish the scientists could understand that this is the first ray of hope that those of us living with Alzheimer's have had. And I also believe that this approval, I think it's going to reinvigorate interest in this field. And I think we're going to see, you know, a steady flow of potential treatments now coming to the FDA and hopefully to market in coming years. And if Adjuhelm helps give us more time to wait for those additional, possibly stronger treatments, then that's a win-win.
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--:-- Sean Rameswaram: Okay, we're back. In the first half of the show, you heard about a new Alzheimer's drug called Adjahelm that doesn't actually cure Alzheimer's. Instead, it slows it down, fractionally. When it went to the FDA, experts were nearly unanimous in their opposition, and then it got approved anyway. We wanted to find out how that happened, so we reached out to Natalie Shore. She's a columnist with the New Republic who knows a thing or two about how the FDA approved Adjahelm.
--:-- Natalie Shore: It's an abbreviated regulatory pathway that began in the early 1990s, in the context that there were a lot of HIV patients who were dying very quickly, and they were very desperate to stem that any way they could. And so they were willing to take a lower standard of evidence to get these drugs into patients' bodies. Now, that's something that has been abused a lot since. Drug companies are using these abbreviated pathways so much more often than they used to. And there's a lot of suspicion that they're doing it because they're worried that their drugs wouldn't meet the standard of evidence for ordinary approval.
--:-- Sean Rameswaram: Why was this drug fast-tracked?
--:-- Natalie Shore: So the story with this drug is less typical and more galling than a lot of others. This drug began its clinical trials and then was stopped in 2019 because they just weren't seeing any positive effect and they just decided to throw in the towel. And then, basically, Biogen and the FDA, some people have accused them of colluding together to re-examine the data and decide, hey, let's start this back up again, because they found something in the high-dosage arm of the trial showing that maybe there was a tiny bit of effectiveness.
--:-- Sean Rameswaram: And instead of running another clinical trial, they basically made a case to the FDA that it should be approved and they can do another clinical trial after it's already been approved, which is now due hypothetically by 2029.
--:-- Natalie Shore: Of course, by then, several years will have gone by and several billions of dollars may have been made off of this drug.
--:-- Sean Rameswaram: How much does this Adjahelm cost?
--:-- Natalie Shore: Adjahelm is being priced for about $55,000 per year per patient. There are about $55,000 a year? $55,000 a year for one patient. That's like a salary. And there are about 6 million Alzheimer's patients in the United States alone.
--:-- Sean Rameswaram: I do not agree with their price tag. That I feel is ridiculous.
--:-- Natalie Shore: Dare I ask how they're justifying that price tag?
--:-- Sean Rameswaram: Well, I mean, they don't really have to justify the price tag in our system. A lot of other countries negotiate drug prices based on value, and we don't have a system that does that. And because it's all going to come through, or most of it's going to come through, presumably Medicare Part B, which charges patients a 20% copay, a lot of individual patients that take this are going to be on the hook for 20% of $55,000, which is $11,000.
--:-- Natalie Shore: I mean pharmaceutical companies have been under scrutiny for a long time especially when it comes to drug costs. But fast tracking Adjahelm to market against the advice of independent scientists and this sort of long vetting process it sort of makes you question the FDA more than it makes you question Biogen who is clearly in it to make boatloads of money right
--:-- Sean Rameswaram: Yeah, I mean, I think that that's true. In a system like ours, when you have drug manufacturing governed by for-profit entities, of course they're going to pull things like that. Now, I think that that's a problem to begin with, but the fact that we have that system means that we at least want very strong public advocates at the FDA. We need regulators to step in and say we will only accept drugs that have very strong evidence for their efficacy. That was simply not the case here with Atahome.
--:-- Natalie Shore: And why do we think that is? So it's hard to ascribe any given regulatory decision to any given thing. But in general, there are a lot of reasons to be concerned about the FDA's relationship with the pharmaceutical industry.
--:-- Sean Rameswaram: For one thing, in this specific case, as groups like Public Citizen have pointed out, the FDA and Biogen may well have had a very inappropriately close relationship as Biogen was looking back over the data from its aborted clinical trials and preparing it for FDA approval.
--:-- Natalie Shore: A lot of people have said that the regulators at the FDA very consistently seemed biased throughout the process. There's been a very well-documented revolving door between pharmaceutical companies and the FDA going in both directions.
--:-- Sean Rameswaram: The FDA's approval infrastructure is itself financed by user fees paid by pharmaceutical companies. To a lot of people, that puts them in a very fraught relationship wherein the pharmaceutical companies are essentially the client of the FDA.
--:-- Natalie Shore: In this case, you also can't underestimate the role played by patient advocacy groups. I don't blame any individual patient for desperately wanting this drug. But patient advocacy groups in a lot of cases, including this one, groups like the Alzheimer's Association and Us Against Alzheimer's, are partially funded by Biogen and definitely play a significant role in applying public pressure that basically pushes the FDA to do this.
--:-- Sean Rameswaram: And I think Phil who we heard from earlier is one such patient. I suppose I am in step with big pharma here but I've also been part of a drug trial for the last five years. Biogen sends a car to pick me up to bring me to my treatment facility and to take me home. The amount of money that is spent testing these drugs is extraordinary. I'm also very well aware that they could make billions of dollars off this drug. And I'm not saying that I think that patients or patient advocates who want to use Atahelm have ulterior motives. I think that they're going through something really difficult, and I don't judge them for that. But I do think that Biogen and other drug manufacturers have very clear ulterior motives when they fund these groups because they know that they are the more morally powerful messengers than actual drug manufacturers.
--:-- Sean Rameswaram: It's a really unfortunate time to feel skeptical of how the FDA approves drugs, considering tens of millions of Americans are walking around with brand new vaccinations in their bodies, right?
--:-- Natalie Shore: Yeah, and I think that we can all be very, very thankful for these vaccines and have a lot of faith in them. And even though those vaccines were approved quickly, what they didn't do was reduce their standards of evidence. Those are two very different things and have very different clinical outcomes.
--:-- Sean Rameswaram: It's also just funny timing because it felt like for a moment the pandemic did something kind of impossible, which was it redeemed some pharmaceutical companies, right?
--:-- Natalie Shore: Yeah, I mean, the fact is pharmaceutical companies perform a socially necessary function. I don't want to live in a world in which I can't get any pharmaceutical products, but I do want to live in a world wherein pharmaceutical product research, development, manufacture and marketing isn't governed by business interests.
--:-- Sean Rameswaram: I would like to live in a world wherein pharmaceutical development is far more guided by the public interest than it currently is.
--:-- Natalie Shore: I mean, how do we get to that world when we're living in this hyper-capitalist reality where the tentacles of the pharmaceutical industry touch every sort of side of this issue?
--:-- Sean Rameswaram: Well, I'm a firm believer in Medicare for all. But beyond that, we already fund a lot of research publicly for pharmaceutical advancements. I would love also for us to publicly fund and publicly supervise clinical trials more than we do and publicly manufacture drugs so that there's a lot more democratic control over the process and that we get more drugs that are actually useful as opposed to drugs with extremely marginal, if any, benefits. That are then priced stratospherically out of reach for patients or that threaten to destabilize our healthcare system.
--:-- Sean Rameswaram: Natalie Schur is with The New Republic. Adam Feuerstein, who you heard from earlier in the show, is with Stat. He also co-hosts their weekly podcast. It's called The Readout Loud. I'm Sean Ramos from It's Today Explained. Thank you.
--:-- Adam Feuerstein: Thank you.
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