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 its 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.
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.
EARLIER TRIAL
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.
FDA SPLIT DECISION
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 committee of experts raised concerns about whether the data actually showed that the drug was effective.
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.”
APPROVED BUT MORE
PROOF NEEDED
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, one of the principal investigators for the aducanumab trials, 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.”
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.”
Not a Slam Dunk
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.
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.
COST
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.
“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