Are Alzheimer’s researchers thinking about the disease wrong?

For decades, there had been no real medical game changers in Alzheimer’s research—until last year. The FDA approved a controversial drug, one with only mixed clinical results. At this point, even the manufacturer of this drug, called Aduhelm, has all but abandoned it. There might be another medication on the horizon—lecanemab—but solely for people in the early stages of the disease. Why is it taking so long for Alzheimer’s patients and their families to get any relief? Damian Garde, a biotech reporter for Stat, says that a leading theory of disease may be to blame.

On last Sunday’s episode of What Next: TBD, I spoke with Garde about the recent developments in Alzheimer’s drugs and what the future may hold for those suffering from the disease. Our conversation has been edited and condensed for clarity.

Lizzie O’Leary: When a patient is having cognitive trouble and doctors finally get to the point when they mention the A-word—Alzheimer’s—there’s not actually that much that medicine can do.

Damian Garde: The spiel hasn’t changed very much in decades. There are medicines that are approved that are now generic that can, in the short term, basically boost memory is what they’ve been demonstrated to do, but they don’t actually slow or arrest the progress of Alzheimer’s. There’s by no means a cure for the disease.

For the past several decades, most of the research in defining a real cure for Alzheimer’s has focused on something called the amyloid hypothesis. The idea actually comes from the German doctor Alois Alzheimer, whom the disease is named for. He was investigating a 51-year-old woman who died with what he called pre-senile dementia in the early 1900s. In 1906 Alzheimer wrote that upon autopsy, the woman’s brain had “severe disease process of the cerebral cortex.” He found that her brain tissue was filled with plaques and neurofibrillary tangles.

And over the ensuing decades we have come to understand that those plaques and tangles are the result of a protein called amyloid, which in healthy function exists in the body for reasons we don’t entirely understand. But in the brains of patients confirmed to have Alzheimer’s disease, it appears to tangle up and form these plaques in the brain, which are thought to be toxic, are thought to destroy neurons and synapses and thus drive the Alzheimer’s disease symptoms that we recognize.

But this is where things get tricky. There isn’t much debate that amyloid plaques are in the brains of people known to have Alzheimer’s. The question is: What role do they play?

There’s a compelling theory that, as I said, these plaques are toxic and they’re destroying neurons. And thus if you could design a drug that would clear these plaques out, you would prolong the healthy function of a patient’s brain. There’s also a theory that actually whatever’s causing Alzheimer’s disease is upstream of these plaques. And so the plaques themselves are more like scar tissue, or I’ve heard people put it as, they’re the gravestones of the neurons, not the killers themselves. And so to clear them out of the brain, you’re just doing some kind of custodial work that maybe doesn’t have that much of an effect on patients’ brains.

Name a drug company, and there’s probably a failed Alzheimer’s medicine in its history. Elon, Johnson & Johnson, Eli Lilly, Pfizer, and Roche are just a few. But Biogen gave patients a glimmer of hope with Aduhelm, a drug that they began developing in 2014 along with Japanese company Eisai. Early clinical results in 2017 indicated that maybe they had finally refined the process for targeting amyloid.

It appeared to not only clear amyloid from patient’s brains but also seemed to have a dose-dependent effect on how well they did on these scores of cognition and function. So, stock price booms, everybody’s really excited. Biogen deciding not to waste time goes from, that’s a phase 1 study immediately to a phase 3 study, which is where they were enrolling thousands of patients in two identical studies and basically saying, “Let’s just pedal to the metal. We’ll get these data. These will support FDA approval.” It’s a long process. It’s an expensive process. So they skipped phase 2, which is usually what people call the proof-of-concept study, the point where you kind of test-drive a phase 3 trial before really investing in it.

But phase 3 did not turn out like Biogen or the Alzheimer’s community had hoped. What happened?

So, cut to 2019: We learn from Biogen that they’re actually discontinuing these two studies. Their independent data monitors told Biogen, “We’ve looked at the data and we’ve conducted what they call a futility analysis. And we’ve concluded, based on lots of mathematics, that futility is the most likely outcome.”

It was crushing. But then something even more unusual happened. Biogen took another look at one of its studies and decided that it did work. Patients on Aduhelm outperformed the placebo by 20-odd percent on certain tests. The right people on the right dose at the right time was enough for the company to try to get approval from the FDA.

The real shocking part came last year, when we learned that the FDA agreed with Biogen and decided that this drug did merit approval. But what’s curious is, Biogen had filed for a full approval, which is, basically, they asked the FDA to weigh the evidence of whether taking Aduhelm is likely to delay the effects of Alzheimer’s compared to placebo.

But that is not what the FDA did. It granted Aduhelm accelerated approval, a program designed to get medications for serious diseases to patients based on what’s called surrogate data, a sort of data breadcrumb trail. Can you explain that process?

So, for example, if it were a cancer drug, the hard data would be: Do patients who take the drug live longer than patients who don’t? The surrogate data would be: Does it shrink tumors in the short term? So the FDA has often approved cancer drugs based on that, because it’s pretty reasonable to say if you’re shrinking tumors, you’re going to live longer. Doesn’t always happen, but we can see the kind of breadcrumb trail there. Now, in this case, the FDA approved Aduhelm based on data that it cleared amyloid from the brain as a surrogate to “that must mean that patients who get the drug will do better than those on placebo.” But as we mentioned, the notion that clearing amyloid from the brain helps people remains a relatively controversial idea.

Another big kind of wrench in all of this was when the Centers for Medicare and Medicaid Services refused to cover Aduhelm under Medicare unless you were in a clinical trial. That, to me, seemed like the government saying, “This drug isn’t worth it.”

Basically, yeah. And it was kind of shocking because traditionally, CMS defers to the FDA as to whether a drug is good. So, typically they will cover any FDA-approved medicine according to the label that the FDA agrees on, because that’s just sort of the separation of powers in Health and Human Services. What was striking about CMS’s decision with Aduhelm is that they implicitly and somewhat explicitly said, “The FDA was wrong to approve this medicine.” I mean, this was really the death blow for Aduhelm as a commercial entity. There had been arguments over the price of the drug.

It cost a tremendous amount of money, right?

It was rolled out at a list price of $56,000 a year. The issue was, basically, Medicare looked at that number and said, “We don’t see a value proposition here.” And that was particularly debilitating for Biogen because Alzheimer’s disease is a Medicare population in this country. It predominantly affects people who are elderly. And something like 75 percent of the potential Aduhelm customers would be covered by Medicare.

What did all this mean for people who had been taking it or had been really excited about the potential for a new medication?

It was confusing and, in some cases, devastating. I talked to a couple people who were in the clinical trials who insisted that they felt like they had experienced a benefit being on the drug. I know there was disappointment with the price that Biogen chose to charge. I don’t think anybody in the patient or physician community defended that. But also, yeah, it’s important to remember there is just such desperation for anything that might work here. And there’s no waiting. Every day is a day that conceivably you are less yourself than you were yesterday if you have Alzheimer’s disease.

After this huge drama, there is maybe a new contender on the horizon. Tell me about lecanemab.

There has been this backup molecule, for lack of a better term—this other amyloid-targeting medicine that Biogen and its partner, the Japanese pharmaceutical company Eisai, had been developing simultaneously. Lecanemab had always been perceived as kind of the younger sibling with maybe a little less promise to Aduhelm, in part because Eisai did run a phase 2 study, the step that Biogen skipped with Aduhelm. And the data were a little confusing. They tested multiple doses. The data—someone described them to me as uninterpretable because some doses seemed to do well. Higher doses seemed to do kind of less well. There were disparities between the placebo group and the treatment groups such that the observed benefit might have been statistical noise.

Coming out of that, there was a prevailing sense of lecanemab was a less promising shot on goal than Aduhelm had been. And yet, earlier this year, we got the press release from Eisai, which is leading the development of lecanemab, saying that it succeeded in a phase 3 study of its own.

Patients who got lecanemab did 27 percent better on cognitive tests than those who got the placebo. But there are some important caveats. This trial focused on early-stage disease and all the patients had some degree of decline on what’s called the clinical dementia rating: an 18-point scale that determines cognitive function. Zero means you have no signs of cognitive decline; 18 is severe dementia. In practical terms, the trial meant that patients who got the drug did about half a point better on the scale than those who didn’t. What does all this mean in real life?

The debate immediately among clinicians is, what is half a point on the CDR scale over the course of 18 months? Does that mean someone who might have had to give up driving doesn’t or does so less quickly than someone else? Does it mean it’s easier to have longer conversations, recall the names of grandchildren? It’s difficult to tie these sort of conceptual, numerical outcomes to the everyday lives of people with Alzheimer’s disease. There was a pretty good study published where researchers looked at thousands and thousands of patients’ medical records and talked to the physicians who administer these scores, basically asking them: What is the smallest difference on the CDR that you would classify as a clinically relevant difference for a patient? People generally said between 1 and 1.5 points, but the minimum was about 0.5 points. So that would suggest that this drug is kind of doing the bare minimum that clinicians would say actually makes an observable difference in someone’s life.

And remembering the names of your grandchildren. God, that’s a big deal.

Right, exactly. And that’s the difficulty in extrapolating large clinical trials. It could be something as meaningful as that for one patient. It could be something totally imperceptible for another.

We really focused this conversation on these two drugs, but I wonder what else is out there. Is there anything else waiting in the wings that feels promising?

Lecanemab was really the initiation of a nine-month period that promises to transform how we think about Alzheimer’s disease. That phase 3 study, at least on the top line, was a success. Within weeks, we will learn the top-line results of another phase 3 study from another anti-amyloid antibody, this one from the company Roche. We’re going to find out, basically, whether lecanemab does indeed herald a new era where people have figured out how to attack amyloid or whether it might be a one-off success.

So, there’s a situation in which, over the course of about 12 months, we find out that three anti-amyloid drugs worked to varying degrees, potentially. And that would truly change everything for patients and for physicians.

A larger question raised by lecanemab and Aduhelm is whether focusing on the amyloid hypothesis in Alzheimer’s disease and pursuing drugs based on it has given researchers tunnel vision or crowded out other promising ideas.

I think it’s just inarguable that, if not for the field’s dogmatic adherence to the amyloid hypothesis, we would be further along in Alzheimer’s research. We would have more to offer patients who have this disease. And so, keeping all of that in mind while looking at this drug, which is a product of the amyloid hypothesis, ostensibly a product of that dogmatic focus, it’s kind of bittersweet because we probably wouldn’t have lecanemab if not for that. But what would we have? There are really promising theories about neuroinflammation playing a role in how Alzheimer’s disease works. It’s been tied to different pathogens, including bacteria and viruses. And there’s really interesting data showing that if you have, for example, gingivitis, you are more likely to develop Alzheimer’s disease, which people are still unpacking.

Where does all of this leave patients and their families?

This medicine does appear to at least slow the decline of Alzheimer’s disease, which can only be good news for patients and their families, provided they can access the drug. But I think it’s important to keep in mind, the field and the drug industry has focused on early-stage Alzheimer’s disease because that is the population in which it seems like you can make a difference with, at least the interventions we know about. There are about 6 million people in the United States with Alzheimer’s; maybe 1 to 1.5 million fit into that early-stage category. So if you have even moderate dementia or severe dementia, science doesn’t have anything to offer you right now.

When you talk to people in neuroscience, quite often they are M.D. Ph.D.s, so they also spend a lot of their time in examination rooms with patients and their families explaining what the diagnosis means, what the prognosis is. They’re very, very well in touch with the frustration and with just how devastating that moment can be. And I think they balance that in their minds when they talk about a potential new medicine that, even if lecanemab turns out to work as well as the company says it does, we’re still leaving behind the vast majority of patients with Alzheimer’s disease. There is still so much more work to do.