Four reasons why approving the new Alzheimer's drug was a disaster

A few months ago, the FDA approved a new drug, aducamumab, to treat Alzheimer’s disease. This was the first time in 20 years that the FDA approved a drug for Alzheimer’s, and while that may sound hopeful, many experts have already pointed out that it was a colossal mistake, and a looming tragedy for Alzheimer’s patients. Here are 4 reasons why the approval of aducamumab (also called Aduhelm) is such a disaster.

1. The new drug just doesn’t work. The biggest problem is that Aduhelm doesn’t slow down or reverse the progress of Alzheimer’s. More than a year ago, I wrote about the failure of two trials of aducamumab. The two trials, designed to be identical to one another, were halted in March 2019 by the drugmaker, Biogen, due to a “futility analysis” that showed it just wasn’t working.

In other words, there was no point in continuing the trials. So Biogen halted them.

But then Biogen tried to rescue the drug. In what can only be described as torturing the data to try to find a result that they really, really wanted, they went back and looked at a subset of patients in one of the two trials, called EMERGE, and claimed that the higher-dose patients actually did get a benefit.

But the patients didn’t benefit. All that Biogen could argue was that some patients had lower levels of amyloid plaques in their brains. An independent group of scientists also looked again at Biogen’s data, and published a report saying that their analysis still didn’t support any benefit for patients.

It’s true that plaques do indeed accumulate in the brains of Alzheimer’s patients, and aducamumab does seem to reduce plaques. However, despite 30 years of research, no one has been able to show that reducing these plaques has any effect on the progress of the disease.

More to the point, the two trials run by Biogen, which measured clinical signs of disease, found that aducamumab didn’t affect the patient’s illnesses. It didn’t slow down or reverse the inevitable course of Alzheimer’s disease.

The FDA’s own outside panel of experts evaluated the evidence and strongly rejected aducamumab. (10 of 11 voted to reject it, and one panelist was uncertain.) The panel found that not only was there no clinical benefit, there was also a significant risk of harm, including dangerous swelling in the brain. About one-third of patients experienced these risks, and 10% of patients had to stop treatment because of adverse side effects.

And yet in July of 2021, in a nearly unprecedented action, the FDA approved the new drug. Three of the committee members resigned in protest.

Somehow, Biogen convinced the FDA to approve aducamumab based on the drug’s effect on a surrogate endpoint: the level of amyloid plaque in the brain. One could argue that this is similar to approving statins based on their effect on cholesterol levels: by reducing cholesterol, we can reduce the risk of heart disease. The analogy might be apt, but there’s a huge difference: we have data showing that lowering cholesterol does indeed reduce the risk of heart disease. In contrast, despite decades of study, we still don’t have any data showing that reducing the levels of amyloid plaques slows down or reverses Alzheimer’s.

2. A failed hypothesis. This leads to the second reason why the FDA’s action is such a disaster. For 30 years now, the Alzheimer’s community has pursued the “amyloid hypothesis,” which asserts that the buildup of amyloid plaques in the brain is the primary cause of Alzheimer’s. This was considered a huge breakthrough when John Hardy first proposed it back in 1991, and hundreds (perhaps thousands) of papers have been published since that time, exploring this hypothesis.

Over 100 drugs have been developed and tested for their ability to reduce plaques, and some of them (like aducamumab) do indeed reduce plaque levels. Unfortunately, none of them slowed down the course of the disease, so they never obtained FDA approval.

After 30 years of effort, it’s clearly time to recognize that the amyloid hypothesis is a failure. And yet the Alzheimer’s research community continues to cling to it, despite all the evidence that targeting plaques simply doesn’t work to treat the disease.

The FDA’s approval, over the objection of its own experts and a big outcry from the biomedical research community, will only breathe new life into this failed hypothesis. Even more unfortunate is that, by approving a treatment based on a surrogate endpoint, the FDA is now encouraging drugmakers to keep focusing on plaques, which will starve any efforts to find other causes–and other potential treatments–for this devastating disease.

This leads me to the third reason why the FDA’s approval of aducamumab is a disaster.

3. Greed wins. Why did Biogen work so hard to find some shred of evidence that they could use to convince the FDA to approve their new drug? The answer can be found in the price that Biogen set for the drug: $56,000 per year. As the editors of JAMA Internal Medicine have pointed out, if even one-sixth of Alzheimer’s patients in the U.S. alone were to take this drug, the annual cost would be $57 billion, which is far greater than the cost of all Medicare part B drugs combined in 2018.

In other words, aducamumab’s costs could bankrupt Medicare. Or to put it another way, Biogen doesn’t seem to care if Medicare goes bankrupt, as long as they can grab some massive profits.

What is still mysterious is why the FDA decided to overrule its own advisors. The FDA’s defense seems to be that they will require Biogen to continue collecting data “to verify the drug’s clinical benefit.” But they are giving Biogen 8 years to collect this data. That’s 8 years during which Biogen will reap massive profits, Medicare might collapse under the strain, and Alzheimer’s patients will continue to suffer.

In October, the FDA announced an investigation of its own approval process for Aduhelm. This seems rather bizarre: if the FDA suspects there was “improper contact” between Biogen and its own internal staff, then it should simply withdraw approval for the drug until the investigation is complete.

4. This whole affair is taking cruel advantage of a vulnerable, desperate group of patients. Finally, perhaps the worst aspect of this whole fiasco is how cruel it is to Alzheimer’s patients. As Dr. Jason Karlawish explained in JAMA Neurology, even though he disagrees with the FDA’s decision to approve this drug:

“I must preserve and protect each patients’ autonomy. One way I do this is by being teacher to patients and their caregivers so they can make choices about how to live well with this disease. I cannot deny them the choices the health care system gives them. Aducanumab is now a choice.”

Karlawish goes on to write that he will explain to patients that the benefits are uncertain, and the risks of brain swelling and other bad side effects are very real. But if the patients choose to try it, he will reluctantly prescribe Aduhelm.

We don’t have any effective treatment for Alzheimer’s, and it is a devastating illness. Patients and their families are likely to be desperate, and the mere fact of FDA approval will give them hope. I’ve no doubt that many will want to try Aduhelm, despite the risks. Giving them false hope is simply cruel.

And don’t forget that Biogen halted its own trials of Aduhelm due to “futility.”

The FDA made a huge mistake in overruling its expert panel and approving an Alzheimer’s drug that just doesn’t seem to work, that is outrageously costly, and that might cause serious harm to some patients. Let’s hope that this decision can be reversed. The world needs a safe and effective treatment for Alzheimer’s, and for now, we simply don’t have one.

New Alzheimer's disease treatment fails, then works, then fails again

 Alzheimer’s disease is one of the most devastating conditions of old age. By recent estimates, more than 5 million people in the U.S. have Alzheimer’s, and managing the disease will cost over $300 billion in 2020. As the population ages, this problem is growing worse, and yet we still have no effective treatment.

You might have seen rosy-looking ads for Alzheimer’s treatments, but nothing really works, not yet at least. That’s why many people were excited about the possibilities of a new drug, aducanumab, that showed early signs of being able to reduce the accumulations of “plaques” in the brain.

Background: in people with Alzheimer’s, a protein called beta-amyloid accumulates in the brain, forming plaques that seem to disrupt brain function. (This hypothesis is not fully proven, but it is widely considered credible.) Thus one way that we might treat Alzheimer’s would be to reduce or eliminate beta-amyloid plaques. That’s what Biogen’s new drug, aducanumab, is intended to do.

Biogen has run two separate trials, called “EMERGE” and “ENGAGE,” to test whether or not aducanumab (ADU for short) worked.

Here’s where things get murky. Back in March of 2019, both trials were halted due to “futility,” because ENGAGE was showing no benefits for the new drug. In EMERGE, the high-dose patients seemed to be getting some benefit, but Biogen had specified ahead of time that if either trial was failing, that would mean the drug wasn’t working. Thus they halted the trials, disappointing as it was.

Fast forward to October of 2019, though, and Biogen had a new story. They went back and looked at a subset of the patients in ENGAGE (the study that had failed), and said that there was a benefit after all, if they looked only at the high-dose patients. This past July, Biogen went to the FDA and applied for approval for ADU.

Just this past week, two very conflicting announcements about ADU appeared. First, on Wednesday, the FDA’s internal scientists released a very rosy report, saying that the data from one of the trials were “robust and exceptionally persuasive.” For the second trial, the scientists said that even though the drug initially seemed to fail, a closer review led them to conclude that overall, ADU did provide a benefit.

Biogen shares rose 45% that day, adding $17 billion to the company’s value.

Then on Friday, a panel of independent, external scientists released their conclusions, which resoundingly rejected the drug. The external panel said that the data from the two trials was unconvincing, and they pointed out “multiple red flags” in the analysis.

(Trading in Biogen stock was halted during the Friday meeting, but at the end of the day it was close to the high it reached on Wednesday.)

So what happened? It appears to be a classic case of cherry-picking: when the data from the ENGAGE study didn’t pan out, the company re-analyzed a subset of the data and found a more-positive picture.

That’s not really kosher, as explained by a separate group of scientists in a paper published just a few days ago in the journal Alzheimer’s & Dementia. In this paper, David Knopman and colleagues, from the Mayo Clinic and Stanford Medical School, analyzed data that Biogen has released from its two trials. (The trials haven’t been published, but some of the findings were released in a publicly-available slide presentation that the authors relied upon.)

Knopman and colleagues explained that after two conflicting trials, there simply isn’t enough evidence that ADU works, and they also offer alternative explanations for the positive findings. They argue that the best Biogen can do is to “perform another trial of high‐dose ADU of at least 78‐weeks duration,” which could determine whether or not the positive results were real or just coincidence.

It’s somewhat mysterious that the FDA’s internal panel released their rosy report about ADU on Wednesday, only to be slapped down just two days later by an independent outside panel of scientists. After reading the negative views of the external panel and the analysis in the paper by Knopman and colleagues, I’m very skeptical that ADU has any clinically significant effect. If it had a truly robust effect, it simply wouldn’t be so hard to tease it out.

So we still don’t have a good treatment for Alzheimer’s, but the world still needs one.

Does ginkgo biloba enhance memory? I forgot.

I recently saw an ad that claimed ginkgo biloba can treat the signs of dementia. A quick search on Amazon.com yielded hundreds of products, many claiming that gingko is a "brain sharpener" or that it "supports focus, memory, brain function and mental performance," or other similar claims.

Ginkgo biloba is a supplement made from the leaves of the gingko biloba tree, which is native to China. The supplements industry claims that gingko has been used for thousands of years to improve memory and stave off dementia. While that may be true (though I doubt it), the argument that a medical treatment was used by pre-scientific cultures is not exactly compelling. After all, people died very young in ancient times, and medical knowledge was little more than superstition, for the most part. I don't know about you, but when I'm looking for medicine, I want the latest stuff.

"But wait!" say ginkgo biloba's advocates: maybe those ancient folk doctors were onto something. Maybe so–and it didn't take me long to find multiple studies testing what those ancients supposedly believed about gingko biloba:

1. Here's a review from 2009 that looked at gingko biloba for dementia and milder cognitive impairment. It reported that "the evidence that Ginkgo biloba has clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable." Not exactly a ringing endorsement.
2. Here's another study, from 2012, looking at the effect of gingko biloba on memory in healthy individuals. Is it a "brain sharpener"? Well, no. This study found that gingko "had no ascertainable positive effects on a range of targeted cognitive functions in healthy individuals." In other words, a total dud.
3. And here's an even more recent study, from 2015. The result: "no convincing evidence ... that demonstrated Ginkgo biloba in late-life can prevent the development of dementia. Using it for this indication is not suggested."

Given that the science says this doesn't work, you might wonder how it is that hundreds of gingko biloba products are still on the market, all of them with claims about memory. Simple: it's a dietary supplement, not a drug, which means that it is essentially unregulated (in the U.S.). The FDA won't step in unless the marketing claims get so outrageous that they cross the line into medicine–and even then, the FDA rarely does more than send a sternly worded letter.

As I've written before, supplement marketing is like the wild west. You generally can't trust anything you read from the manufacturers, except perhaps the ingredients list. And even the ingredients are sometimes inaccurate and contaminated.

(By the way, I find it especially amusing when a pill that has no effect is advertised as "double strength," as Walgreens does for one of their gingko products, here.)

So be skeptical about the marketing claims for gingko biloba. Even NCCIH, the NIH institute whose mission is to promote "alternative" medicine, is remarkably clear about this, stating that:

• "There’s no conclusive evidence that ginkgo is helpful for any health condition.
• Ginkgo doesn’t help prevent or slow dementia or cognitive decline.
• There’s no strong evidence that ginkgo helps with memory enhancement in healthy people, blood pressure, intermittent claudication, tinnitus, age-related macular degeneration, the risk of having a heart attack or stroke, or with other conditions."

I must say, I'm feeling a bit better about NCCIH these days. They got this one right. The bottom line: don't waste your money on gingko biloba.

Jellyfish proteins: modern snake oil for brain health

Watching ABC's World News Tonight this week, I saw an impressive-looking ad for a pill that claimed to improve memory and cognition. The ad showed several adults, all looking very happy, presumably because they didn’t forget where they left their keys. In appearance, it looked like many of the drug ads that run on the evening news in the U.S. these days.

The ad described a product called Prevagen, which is sold as a supplement, not a drug. This is a critical distinction: supplements are almost completely unregulated, unlike real drugs. The FDA isn’t allowed to regulate supplements and their claims, thanks to Congress and the 1994 DSHEA law.

I was curious about what this memory pill could be. The Prevagen ad, website and packaging make a number of very strong claims, scientifically speaking. The biggest claim is that Prevagen improves memory*, something pretty much everyone would like. The website also includes the more specific claim that “Prevagen can improve memmory within 90 days.*” The package adds that Prevagen “supports healthy brain function*, [a] sharper mind*, and clearer thinking.*"

How can they make these claims if they aren’t true? Simple: every claim has a little asterisk (*) next to it. If you scroll all the way to the bottom of the Prevagen webpage, you’ll find what that means:

“*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”

Behind this blanket escape clause, supplement makers hide all kinds of unsupported claims. Thus Quincy Biosciences–Prevagen's manufacturer–can state that “Prevagen significantly improves learning,” add the asterisk, and voila! the FDA can’t touch them, as long as they don't make a claim to cure a specific disease.

And by the way, they also claim that “Prevagen improves the quality of sleep.*” There’s that asterisk again.

So what is Prevagen? It’s a pill that contains a protein called apoaequorin, which is found in a species of jellyfish that glows in the dark. These jellies produce two proteins, apoaequorin and green fluorescent protein (GFP), that help them fluoresce. It’s an amazing biological system, and the three scientists who discovered GFP were awarded the 2008 Nobel Prize in chemistry.

How (you might be wondering) this can be sold as a dietary supplement? After all, we don’t eat apoaequorin, and isn’t a supplement supposed to be related to something we normally eat? It sounds more like a drug. The FDA agrees with me–I’ll get to that below.

Despite Quincy Bioscience’s claims, I see no reason why eating this protein would have any effect at all on brain function. First of all, it’s not even a human protein, so it's unlikely to work in humans. Second, even if it did work in humans, eating it would not deliver it to our brains, because it would be almost certainly be broken down in the stomach. And third, the connection between this protein and memory is complex, so simply having more of it is not likely to improve memory.

Prevagen isn’t cheap, either. If you order direct from the company, a month’s supply of pills will cost you $66 with shipping. There’s even an “extra strength” version, though I cannot see how twice as much of an ineffective pill will be twice as effective. On the other hand, two times zero does equal zero.

I wrote to ask the president of Quincy Bioscience, Mark Underwood, if his company is claiming that Prevagen will provide any benefits to people suffering from dementia or Alzheimer’s. He didn’t answer that question, but he did respond that “our scientific basis for the claims we make related to Prevagen are on pretty solid ground.” He was careful to qualify this first, though, writing that

“Prevagen is intended to assist people with mild memory issues related to aging. Prevagen is not a pharmaceutical, nor is it approved by the FDA for the treatment of any neurodegenerative disease (Alzheimer’s, Parkinson’s, etc.).  We do not wish to confuse mild memory loss related to aging with Alzheimer’s disease or dementia in our advertising.”

I also asked Underwood if he could provide any peer-reviewed studies supporting his company's claims. He sent me several studies, but none of them was peer-reviewed: they include company-sponsored studies that are unpublished, and one published abstract from 2011, in the Journal of Alzheimer’s and Dementia. Abstracts, though, are not peer-reviewed: they are short summaries typically presented in oral form at conferences, and sometimes published (as this one was) in special supplements to journals. This abstract seems to be the basis of the claim on Prevagen’s website that “Prevagen was tested in a large double-blind, placebo-controlled study using computers to assess brain performance. 218 adults over 40 years old participated in the three month study. Prevagen significantly improved learning and word recall.*” (Note the asterisk again.)

Prevagen’s claims should be easy to test. If Prevagen really does improve memory, then it would be relatively cheap to run large, well-controlled studies on randomized subjects, and I’d expect to have seen multiple studies published since 2011. But because Prevagen is being marketed as a supplement, Quincy Bioscience doesn’t have to prove anything. They just have to be careful not to cross the line in their advertising.

I asked Ted Dawson, the Abramson Professor of Neurodegenerative Diseases at Johns Hopkins School of Medicine, what he thought of Prevagen’s claims.

“It is hard to evaluate Prevagen as to the best of my knowledge there is no peer-reviewed publication on its use in memory and cognition,” said Dawson. “The study cited on the company’s web site is a small short study, raising concerns about the validity of the claims.” 

Treating dementia, Alzheimer’s, Parkinson’s, and other age-related brain disorders is truly difficult. If you want to see what real scientists (not supplement maker) are doing to try to stave off or cure dementia, here’s a short video narrated by Dr. Dawson:

Dr. Mark Sager, a scientist at the Wisconsin Alzheimer’s Institute and a Professor at the University of Wisconsin, has been quoted saying that he does not recommend Prevagen “primarily because there’s no evidence that it does any good.” He recommends adopting a Mediterranean diet instead, which does have some scientific evidence to support it.

I’m not the first person to raise questions about Prevagen. In 2012, a class action lawsuit was filed against them in California, in which the plaintiffs argued that the Prevagen didn’t work and that the advertising campaign was false and misleading. Earlier this year, another class action lawsuit against Quincy Bioscience argued that Prevagen’s active ingredient, apoaequorin, "is completely destroyed by the digestive system.” And in 2012, the FDA sent Quincy Bioscience a warning letter (see it here), pointing out that the company was marketing Prevagen as a drug, not a supplement. The FDA stated that:

"Apoaequorin is not a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet ... nor is it a combination of dietary ingredients. Therefore, the synthetically produced apoaequorin used in your Prevagen products is not a dietary ingredient as defined in section 201(ff)(1) of the Act.... Accordingly, your Prevagen products could not be marketed as dietary supplements even if they were intended only to affect the structure or function of the body and not for use in the cure, mitigation, treatment, or prevention of disease."

Somehow, though, Quincy continues to sell Prevagen as a supplement. Their website claims they are the #1 selling brain health supplement in the U.S. today.

The appeal that Prevagen is making to consumers is a very old one: basically, they want you to think that if a protein is used in your brain, then eating that protein will make your brain healthier (even though apoaequorin is not a human protein). By this argument, I could package up hundreds of different proteins (perhaps thousands–the brain is a complex organ) and sell them as “brain food” This simplistic principle has been used for centuries in folk medicine: it’s the reason why some people think that eating the body parts of bears and tigers will make them more virile. But eating tiger organs doesn’t make you more like a tiger. It's a form of magical thinking, and there's simply no science to support it. In short, it's just wrong.

Human health isn’t that simple. You don’t acquire the properties of the food you eat. Eating chicken won't make you fly, and eating tuna won't make you a fast swimmer. Eating jellyfish proteins (Prevagen's main ingredient) won't improve your memory, nor will it allow you to emit green fluroescent light. There's no magic brain food, or supplement, that will make you smarter. But you can be a tiny bit richer by not spending your money on ineffective supplements.