FDA’s Approval Of Debated Alzheimer’s Treatment Raises Controversy

JOHN DANKOSKY: This is Science Friday. I’m John Dankosky in for Ira Flatow. Later this hour, a look at intellectual humility. Admitting you’re wrong can be difficult, even for scientists. And we’re going to nominate another Charismatic Creature, this one, known as a living fossil.

But first, this week the FDA gave the green light to a drug for the treatment of Alzheimer’s disease. It’s a monoclonal antibody called Aducanumab. It targets the beta amyloid that forms the amyloid plaques found in the brains of people with Alzheimer’s. The drug will be sold by the company Biogen under the trade name Aduhelm. And the price, it’s going to list for about $56,000 a year.

But the data is less clear on the efficacy of the drug. While researchers agree that it leads to less amyloid plaque, no one’s quite sure what that means in terms of real benefits for people with the disease. An outside advisory panel had recommended against the treatment’s approval. Joining me now to help sort through the approval and what happens next is Pam Belluck. She’s a science and health writer for the New York Times, and you’ll find some links to some of her recent articles on our website at ScienceFriday.com. Pam, welcome to Science Friday. Thanks so much for joining us.

PAM BELLUCK: Well, I’m happy to join you.

JOHN DANKOSKY: So first of all, walk us through this drug. What does it actually do?

PAM BELLUCK: Yeah. So Aducanumab or Aduhelm as it’s going to be branded, as you said, it is an anti amyloid drug. What it does is targets a key protein that is involved in Alzheimer’s. Amyloid is the protein that clumps into plaques in the brains of people with Alzheimer’s. Aducanumab does a pretty good job of clearing amyloid out of the brain, and the question is, does it actually produce any benefit, and the evidence has really been pretty contradictory.

There were two large phase III trials that were nearly identical that Biogen conducted of this drug. And they were both stopped early by data safety and monitoring committee because the committee said, we looked at the data, this drug doesn’t look like it’s working. And so everybody thought that this was yet another failure.

And then a few months later Biogen was sifting through some data that had come in in the three months between when the data that the data monitoring committee was looking at, and the time where they sort of pulled the plug, and they said, in one of these trials we see a slight benefit. In people who are taking the high dose they saw a slowing of cognitive decline of about 22% over 18 months. That’s about four months of slowing over 18 months, or a little over 2 and 1/2 months of slowing a year.

That was in one of the trials the other nearly identical trial showed absolutely no benefit of the drug over placebo. And so this is why this drug was so soundly rejected by the FDA’S advisory committee and by a number of Alzheimer’s experts. And they just say, look, you’ve got one positive and one negative trial. And why should we prioritize the results of the positive trial?

And then there’s also a question, that even if we do prioritize the results of that trial, is the benefit so slight? Just a few months of slowing of decline, that it outweighs the risks of this drug, and there are some risks.

JOHN DANKOSKY: And before we talk about the risks, I mean maybe you can just talk through a little bit more, how unusual this is to have trials that are in some ways so unsuccessful actually result in a drug being cleared for usage?

PAM BELLUCK: I think it’s very unusual. Certainly very unusual in the Alzheimer’s space. This kind of pathway to approval has been used by the FDA for a lot of cancer, immunotherapy drugs where there is sort of a suggestion of benefit, but they don’t have the kind of slam dunk evidence that the FDA likes to see.

Typically they’re supposed to look for two significant convincing clinical trials to grant approval, and this pathway that the FDA used, it’s a program called accelerated approval. And it’s often used for cancer drugs where there’s sort of this sign of a benefit, but it isn’t a slam dunk, and it’s combined with some sort of additional action that we can see that the drug does, usually sort of acting on a biomarker or some kind of physiological underpinning of the disease.

And that’s what the FDA chose to do here. They said, we get that the clinical evidence here is not a slam dunk. We think there’s a suggestion of benefit, but we get that this is really not as convincing as we would like. But we’re going to take that and add in the fact that the one thing everybody does agree on is that this drug reduces amyloid, and we’re going to take that and give it this approval.

And the approval is contingent on Biogen doing another trial, which kind of sounds like OK, get it out there and then have them come back and do another trial and see if it works. But in reality, there are some issues with that because the trial could take up to nine years. And so while that is going on, there are no restrictions on who can receive this drug, that a significant number of people in the scientific community are not confident actually works.

JOHN DANKOSKY: So what exactly then happens as this very long trial goes on, let’s say they find out it doesn’t work over time. Can it be unapproved?

PAM BELLUCK: Yes. And the FDA has done that with some drugs in the past. If what they call the confirmatory clinical trial does not confer benefit, then the FDA can revoke approval. But it doesn’t have to revoke approval. And in fact, there have been some pretty strong fights waged over cancer drugs that have not shown benefit in their follow up trials. And sometimes the FDA has said, well, we’re just going to let it stay on the market anyway.

And their stated reasoning for that is that these are very serious diseases with not a whole lot of other treatment options. And so I think there’s some element of, we understand the desperation of patients with these diseases. And if there’s any kind of suggestion that something might help, the FDA seems to be leaning in that direction.

JOHN DANKOSKY: You mentioned side effects. What are the possible side effects of this drug?

PAM BELLUCK: So the most serious ones are that the drug can cause brain swelling and brain bleeding. And in the phase three clinical trials, 40% of participants experienced those side effects. Now that sounds really serious, and in actuality, it can be very mild. And in many of those cases, it was very mild. People had the brain swelling, but they didn’t have any symptoms, or they had relatively manageable symptoms like headaches and dizziness.

But in some cases, it can be very serious. And in those trials 6% of participants had to drop out because these effects were very serious. So anybody who gets this drug will need– and by the way, it’s given as an intravenous infusion. It’s not a pill, it’s a monthly intravenous infusion. So you have to go into a center. And then you will need to get periodic brain MRIs to monitor and see if you’re getting any of this swelling or brain bleeding.

When you’re doing this kind of regimen in a clinical trial, there’s a whole lot of safeguards. It’s very strict. It’s very carefully conducted. It’s going to be harder to make sure that the memory clinics and the providers who are going to be giving this out to potentially millions of patients are equipped to deal with the correct safety protocols and trained enough to know how to read those brain MRIs.

JOHN DANKOSKY: How does this fit in with some of the other treatments that have already been approved, or are still in clinical trials?

PAM BELLUCK: Right, so this is the first new treatment for Alzheimer’s since 2003. So 18 years. And that’s obviously why there’s been such excitement. Prior to that, there were five drugs available. They’re still available. And this is the first drug, the Aducanumab that directly attacks some aspect of the biology of the disease. So the amyloid plaques, as we said.

The other five drugs are designed to basically try to treat the symptoms of forgetfulness and cognitive functional issues. And they do help, for some patients, and they can help patients in all stages of the disease. But they tend to have a limited amount of time that they’ll work. So depending on the person, depending on the stage, these drugs may help stave off decline for three, six, maybe nine months. About the same, even longer, I guess, than the promise of staving off a decline that Aducanumab has.

So everybody wants to have something new in the arsenal. That’s what the excitement is about. What is coming down the pike could be better. There are specifically two other monoclonal antibodies that also attack amyloid, that are in phase III trials now, and they have had pretty promising phase II trials that have shown that they reduce amyloid by a greater degree than Aducanumab does, and they do seem to show a somewhat stronger clinical benefit. And those are now in phase III trials, and if that continues and we know there have been many times when that hasn’t happened in the Alzheimer’s field, but if that continues then those could be ready for approval in maybe about three years.

So the interesting thing is that, well before we have the results of the confirmatory trial that shows whether or not there’s any benefit to Aducanumab we may actually have a couple of other treatments that could be a bit more promising. There’s a lot of concern in the field that in the effort to try to get something out there, it could hurt the ability to actually conduct trials on other things that might be more promising. And the reason is, that it’s very hard to get trial participants for Alzheimer’s trials to begin with.

And so if you were a patient with Alzheimer’s, and you are being told, hey, you could try something that’s out there on the market now, or you could participate in a clinical trial where you maybe have a 50% chance of getting a placebo, a lot of patients are going to say, well, let me take the bird in the hand. Let me try what’s out there. And so there’s concern that this could actually slow the pace of more promising research.

JOHN DANKOSKY: Pam Belluck is a science and health writer for the New York Times. Thanks so much for joining me today.

PAM BELLUCK: Thank you.

JOHN DANKOSKY: You can find some links to some of Pam’s recent articles on Aducanumab on our website at ScienceFriday.com.

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