Alzheimer’s disease was first described by Alois Alzheimer in 1906, and now, more than 100 years later, doctors have an effective drug to treat the cognitive disorder.

On June 7, the U.S. Food and Drug Administration (FDA) approved aducanumab, developed by the U.S.-based biotech Biogen and Japanese pharmaceutical company Eisai. But the drug’s approval comes with a caveat. The FDA is requiring Biogen to conduct an additional placebo controlled study of the drug to verify it’s effectiveness in improving people’s memory and cognitive symptoms.

That request stems in large part from the conclusion of an expert panel convened by the FDA last November, which almost unanimously decided that the evidence presented by the drug’s developers did not justify approval. The committee’s recommendation then went to the FDA, and the agency extended the deadline for making a decision from last March to June 7.
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The drug’s rocky road of failed and halted clinical trials has generated divided opinions among brain experts about how useful the drug actually is, with some, including the Alzheimer’s Association, supporting approval as the first treatment for the disease—the currently approved therapies for Alzheimer’s only address the symptoms of Alzheimer’s and not its root causes—and others not convinced the data prove that the benefits of the drug outweigh its potential risks.

Aducanumab made headlines in 2016 when an early trial showed the first encouraging results of an Alzheimer’s treatment in decades. Previous efforts to develop drugs and vaccines to control the expansion of amyloid protein plaques in the brain were frustrating failures. Experts in the field were divided over whether the clusters of amyloid protein in the brain, which are the hallmark of the disease and what doctors use to diagnose it, were even the right target for a drug. Cells in the body make amyloid, but it seemed that in some people, the protein accumulated in the brain at dangerous levels, strangling delicate nerve cells and their connections and ultimately compromising memory and then other body functions. Would removing the plaques be sufficient to save memory and slow the disease?

In the breakthrough study of aducanumab, it seemed the answer was yes. Levels of amyloid in people with mild to moderate Alzheimer’s who received monthly infusions of the drug for a year were lower than those among people getting placebo. And more encouragingly, the people getting the drug seemed to show improvements in cognitive tests, an important indicator of how well they could perform daily activities like dressing themselves, driving and shopping.

The results were encouraging enough for the company to push ahead with larger late-phase clinical trials in two studies involving more than 3,200 people with mild to moderate disease. In March 2019, however, it started to seem that perhaps the initial excitement had been premature, when Biogen scientists analyzed the data from the trials and found that people randomly assigned to get the drug did no better on cognitive tests than those who got placebo. The company decided that there was no reason to continue the studies, and halted them.

Neil Corkery, one of the participants in the studies, was devastated by the news. Corkery had finished the 18-month study and, as part of his participation, was set to receive aducanumab for another two years—and, he says, feeling like his memory was improving. Once the company stopped the trial, he stopped getting the drug. “I could sense my memory was affected,” says Corkery. “I couldn’t remember names as quickly as I used to. And I was really frustrated.”

Corkery was off the drug for another 18 months. Several months after halting the trials, Biogen and Eisai made the stunning announcement that their initial read of the data was incomplete, and that in fact, the studies showed aducanumab was actually effective. While the companies promised to put people like Corkery who participated in the trials back on the drug, that took many more months to happen.

Biogen and Eisai explained that their two key studies began at different times, and that dosing changed after the trails were started. So people in the first study, in which Corkery participated, may not have received the adequate dose of the drug. One possible side effect of aducanumab is an inflammation of the brain known as ARIA, and the condition is more common among people with a genetic predisposition to developing Alzheimer’s. When the studies began, these people with the genetic risk—certain forms of the ApoE gene— were started on lower doses of the drug to protect them from the inflammation. But as the studies continued, experts at the various hospitals leading the studies learned that the inflammation was manageable as long as they monitored people with regular brain MRIs and then titrated back their doses if they saw any inflammation. So people in the studies with the higher-risk ApoE gene were eventually given the same dose of aducanumab as the other study participants, but this didn’t happen until close to the end of the 18-month study period.

“In retrospect, the analysis [last spring] was incorrect,” Dr. Alfred Sandrock, chief medical officer at Biogen told TIME in Oct. 2019, when the company issued its first report on the re-analysis. The data from participants given lower doses of the drug, the company said, skewed the results to show less effect. However, because the second study started later, it had more people at the correct, adequate dose of the drug—and showed more positive results. After consulting with the FDA, Biogen and Eisai decided to apply for approval of aducanumab to treat early Alzheimer’s disease.

When the companies presented these data in November 2020 to the FDA committee reviewing the application, however, the independent group of experts tasked with analyzing the results and deciding whether to recommend the drug for approval were not convinced. In fact, while the FDA review concluded that aducanumab was effective, the FDA’s statistician, as well as the neurology, Alzheimer’s, aging and biostatistics experts on the committee raised concerns about whether the data actually showed that the drug was effective. In particular, “There is no question all of this is terrifically one-sided,” Dr. Scott Emerson, professor of biostatistics at University of Washington, and a member of the expert committee, said during the meeting. “I’m highly critical of the fact that the FDA presentation today was heavily weighted to giving the same conclusions as the sponsor [Biogen].”

Many prominent Alzheimer’s experts, including Dr. Jason Karlawish, co-director of the Penn Memory Center and professor of medicine at the Perlman School of Medicine at the University of Pennsylvania, did not think the FDA should approve aducanumab yet. “In general the data on the relationship between the amyloid changes and the clinical changes are not as strong as we hoped they would be. We do need to wait for more data.” His stance is backed by the Institute for Clinical and Economic Review (ICER), a nonprofit organization that analyzes medical evidence, which determined that the evidence provided by the two studies was “insufficient” to determine whether aducanumab could benefit Alzheimer’s patients or not. Karlawish advocates conducting another randomized, placebo-controlled study with consistent dosing to see if the drug indeed can both lower amyloid levels in the brain, and contribute to improvements in cognitive function before approval.

The FDA is indeed requiring the company to start a new study to verify the drug’s effectiveness, even after approval. In a statement announcing the approval, the agency said “If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.”

Dr. Stephen Salloway, professor of neurology at Brown University and director of neurology and the memory and aging program at Butler Hospital, is one of the principal investigators for the aducanumab trials, and understands the skepticism. But, he says, “I probably have the most experience in the world with this drug, and to me, Alzheimer’s disease is a terminal illness, and what we are trying to do is to delay the disabling phases of the disease and preserve quality of life. And although the data has issues, this drug offers some chance of doing that.”

Dr. Ron Petersen, director of the Mayo Clinic Alzheimer’s disease research center, agrees. “I think the positive results are real. I do think that all five clinical measures in those studies that were positive weren’t by chance. But while I think there is a clinical effect, I think it’s modest.”

Petersen also points out that it might be possible that the benefits of aducanumab were not completely captured in the relatively short studies. Amyloid builds up over a period of decades in the brain, until it accumulates to levels high enough to damage neurons. “If the process takes that long to evolve, is it reasonable that if we reduce part of that or even reverse part of that process by removing amyloid in the brain over 12 to 18 months, that we are likely to see any clinical impact? I think that’s a big ask.”

He also notes that the amyloid build-up occurs at the same time as other aging processes, making amyloid only one of potentially a handful of things that need to be targeted to slow down the disease. “For most people in their 70s and 80s with cognitive impairment, there are likely multiple pathologies going on,” he says. “If we take all of these into consideration, and we fix or treat one of them, amyloid buildup, what is the likelihood that we are going to have a major clinical impact? Probably small.”

But even that small impact is crucial, he says, to moving toward an eventual cure or, at least, a more effective treatment for the disease. “I view this as a possible entrée into disease-modifying therapy. There will probably be better mouse traps down the road. But I think it’s time to take the chance and this [drug] may be the entry point into having more disease-modifying therapies.” Ultimately, Petersen says, Alzheimer’s may need to be treated in the same way as infectious diseases like HIV, with a combination of drug treatments that together provide a stronger chance of slowing the damage from amyloid than any one drug alone.

Even then, the drug won’t be a slam dunk for everyone with Alzheimer’s. Salloway notes that aducanumab was only studied in people with the mildest forms of disease—those who show the first signs of memory or cognitive problems, and have amyloid plaques in their brains. The drug likely won’t be as effective, if it is at all, in people who are further along in the disease progression. But that won’t stop those patients from asking their doctors if they can try the treatment. There will likely be strict criteria defining which patients qualify to take it; for example, doctors will need to screen people before they get the drug for any microbleeding in the brain, which could make them more vulnerable to complications from the inflammation. Anyone receiving the drug should also be tested for amyloid levels, either through cerebral spinal fluid or with PET imaging, before they start the drug to make sure they indeed have amyloid build up in their brains.

If they don’t meet those criteria, says Petersen, “how do you tell somebody who has been living with the disease for five or six years, I’m sorry you don’t qualify to be treated with this drug? That’s a tough conversation and I’m worrying about that.”

It’s important that both doctors and patients understand what aducanumab can, and cannot do. It’s also critical that doctors prescribing the drug, which is given in monthly IV infusions, understand how to monitor patients for side effects like the brain inflammation—specifically, patients on the drug must undergo brain MRIs every three months.

Given all the complications, Salloway and Petersen believe that aducanumab should be prescribed by specialists initially, since they are most familiar with the best ways to identify the right patients, early in their disease, and monitor for any complications. “I think dementia experts should be managing this treatment, working with radiologists who are familiar with ARIA and detecting it,” says Salloway. Both recognize that the approval will also lead to some doctors who are more willing to prescribe it than others. But Salloway anticipates “the demand will come from patients and their families. After having the discussion of the risks and the potential benefit, and from their experience with what Alzheimer’s is, if the drug is something that has a reasonable chance of helping them, and it can be safely administered, many people are going to want it.”

Cost will be the other big challenge. For the Centers for Medicare and Medicaid Services and private insurers to reimburse for aducanumab, they would need to be convinced that treating someone with the drug for a year would be more cost effective than leaving that person untreated for decades, and needing increasingly complex medical care as their memory and cognitive functions decline. ICER has determined through modeling that means the drug would need to be priced at $2,500 to $8,300 per patient a year. However, while the companies have declined to comment on potential pricing, pharmaceutical analysts have predicted a price tag as high as $50,000 a year per patient.

“The elephant in the room is what the payors will have to say about it,” says Petersen. Because the infusion-based therapy is likely to be expensive, “we really don’t want a society of haves and have nots. That would be a disaster.”

In the meanwhile, the drug continues offering hope to people like JoAnn Wooding, whose husband Peter was diagnosed with Alzheimer’s in 2016, and was among the first group of patients to join the aducanumab trials. She’s realistic about the future, recognizing that the drug may not make a huge difference for Peter, since the suspension and restart of the trial cost him valuable time. When his trial was halted, Peter had completed the 18-month study period and had received five infusions of the drug as part of the two-year follow-up. When the study was stopped, he joined another trial of another promising drug in the hopes of slowing down his disease; it took him longer before he could resume aducanumab, since he needed to wait several months to “washout” any residual effect of that experimental treatment. Then he was diagnosed with a small melanoma on his foot which prevented him from joining the trial until he was in remission.

In May 2021, about two years after his last infusion, Peter finally started his monthly treatments of aducanumab again. “I think it’s too late for Peter frankly,” JoAnn says. “Two years is a very long time when someone has Alzheimer’s. If he had been able to continue two years ago, I think it might have been very valuable, but now his progression is such that I’m not sure it’s going to be very helpful. But we’re doing it for science. And there is always reason to hope.”

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