An effective drug for Alzheimer’s disease has long eluded doctors and the patients they treat who have this memory-robbing condition. After nearly 20 years with no new treatments for the disease, a novel Alzheimer’s drug would seem like cause for celebration. Instead, the US Food and Drug Administration’s historic and controversial approval of Biogen’s Alzheimer’s therapy, Aduhelm, left neurologists exasperated. Many believe that the drug doesn’t work and that, even if it does, its benefits are marginal at best.
“I suspect there was a lot of pressure to approve, but I was quite disappointed,” says Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine. “It will be very interesting to see what will happen internationally. I am not convinced it will get approval in other countries.”
Biogen spent developing Aduhelm before FDA approval
Estimated average annual cost of Aduhelm before insurance
Estimated number of people 65 and older with Alzheimer’s in the US
Increase in deaths due to Alzheimer’s between 2000 and 2019
Projected cost of caring for people with Alzheimer’s and other dementia in the US in 2021
Number of Alzheimer’s drug candidates in clinical studies
Sources: Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation.
Others are more optimistic. “It is a step forward,” says Oscar L. Lopez, director of the Alzheimer’s Disease Research Center at the University of Pittsburgh. “You have a drug that slows down progression. It is not a cure, but it opens the door to better treatments in the future.”
Aduhelm, also known as aducanumab, is a monoclonal antibody that targets amyloid beta (amyloid-β) plaques that aggregate in the brains of many—though not all—people with Alzheimer’s disease. Neuroscientists have long thought that getting rid of these plaques, which are tied to brain cell death, could slow or halt the progression of Alzheimer’s disease. This so-called amyloid hypothesis has dominated Alzheimer’s research for decades. Yet study after study has shown that drugs targeting amyloid-β don’t seem to alter the course of the disease.
Biogen’s drug was set to change that. In 2015, the company demonstrated that aducanumab dramatically lowered amyloid-β plaques in the brains of people with early Alzheimer’s disease. That small trial prompted Biogen to launch two larger, and nearly identical, clinical trials to see if the drug could also slow cognitive decline.
In March 2019, Biogen pulled the plug on those studies; an early analysis of the data suggested that there was no hope the drugs would work. But the firm reversed course that October, saying additional data indicated the drug was slowing cognitive decline in one trial, though not the other.
Even though the FDA normally requires two positive trials for drug approval, Biogen argued that Aduhelm should be approved based on data from its single positive trial. For many scientists, the conflicting results between the two trials was a nonstarter.
“You have to look at both studies, and there is no logical reason to focus on one study and not the other,” says David S. Knopman, a clinical neurologist at the Mayo Clinic and a site investigator for one of the Biogen trials. He says he was “completely taken by surprise” when the FDA granted Aduhelm an accelerated approval based on its ability to lower amyloid-β plaques in the brain, rather than a standard approval based on proving that the drug slows cognitive decline.
After 18 months of treatment, Aduhelm reduced amyloid-β plaques by 71% in one trial and by 59% in a second, as measured by positron emission tomography (PET). “There is no doubt that this drug removes amyloid from the brain—that was really obvious from PET imaging,” says Elizabeth Mormino, an Alzheimer’s imaging researcher at Stanford University. “This drug really brings people down to the normal level, and it does so quite quickly.”
But Mormino and others note that the amyloid hypothesis has been called into question for the very reason that dramatic reductions of amyloid-β plaques don’t consistently correlate with a slowing of Alzheimer’s. By approving Aduhelm based on the amyloid data, the FDA “skirted the question” of whether or not the drug actually makes a meaningful difference for people with Alzheimer’s, Sano says. “They have created a pathway for approval that doesn’t require any symptomatic benefit, and that is pretty distressing.”
Scientists also take issue with the FDA’s approving Aduhelm for anyone with Alzheimer’s, even though Biogen tested it only in people with mild disease who had a PET scan confirming the presence of amyloid-β plaques. “I completely disagree with it being approved,” says David Holtzman, an Alzheimer’s neuroscientist at Washington University School of Medicine in St. Louis. Labeling the drug a therapy for anyone with Alzheimer’s was “definitely not justified at all,” he adds.
The disconnect between the FDA’s broad label and the narrower group of people the drug was tested on raises an ethical dilemma for neurologists who will inevitably face families desperate for a treatment. “We are going to have some difficult conversations with patients, and I suspect we will end up discouraging its use in more people than we end up encouraging it in,” says Jeffrey Burns, the codirector of the Kansas University Alzheimer’s Disease Center. “I am not going to prescribe it unless I have measures that suggest someone has elevated levels of amyloid in the brain,” he adds, and those would have to come from an expensive PET scan or a painful cerebrospinal fluid test. “It is not stated on the label, but I think that is mandatory for this drug, based on its mechanism of action.”
Even though Aduhelm seemed to lower amyloid-β plaques within the first 6 months of treatment, it took longer for tests to reveal cognitive benefits. In Biogen’s positive trial, it took 18 months before a statistically significant difference appeared between the cognitive decline of people who got the drug and those who got a placebo. At that time, the memory and function of people who got Aduhelm was declining about 22% more slowly than those who got a placebo.
Aduhelm’s FDA approval carried an asterisk that Biogen must conduct an additional clinical trial to confirm that it actually slows cognitive decline. Holtzman says that if Biogen can replicate or exceed that 22% slowing of decline in another clinical study, he thinks the approval is warranted. “But it is really right on the border of what you’d want. Anything less than that is pretty marginal,” he says.
Biogen has not announced any details about how it will run that study or when it will start. The FDA has given the company until 2030 to submit the data.
Many scientists say they wish the agency had required that Biogen conduct a confirmatory study before it granted the approval. When the FDA’s advisory committee for neurological drugs met in November 2020 to discuss the Aduhelm data, 10 of the 11 members said Biogen’s single positive study did not provide evidence of aducanumab’s effectiveness. The 11th member voted “uncertain”. Although the panel’s vote isn’t legally binding, scientists were shocked that FDA officials would buck an effectively unanimous recommendation. “I am very surprised that they went against such consistent feedback,” Mormino says.
After Aduhelm’s approval, two scientists resigned from the advisory committee in protest: Joel Perlmutter from Washington University in St. Louis and Mayo’s Knopman, who had recused himself from the panel during the review of aducanumab since he was an investigator in one of the trials. “I don’t wish to be in a position in the future where my role on the advisory committee is treated with such disdain and disrespect that the FDA showed this committee,” he tells C&EN.
In addition to having questionable benefit, the drug is not always safe. Some 41% of people treated with Aduhelm, compared with 10% of those who got a placebo, had a potentially troubling brain scan that neuroscientists call an amyloid-related imaging abnormality (ARIA).
For the most part, ARIA “is relatively benign, and it goes away when you stop or reduce the drug,” Burns says. But it can indicate problems such as brain bleeding and swelling, he adds. About a quarter of people who got Aduhelm and had ARIA developed side effects including confusion, dizziness, headaches, and nausea, and some had severe side effects that included microhemorrhages in the brain.
The FDA requires doctors to check for ARIA with a magnetic resonance imaging (MRI) scan before treating a person with Aduhelm and twice during the first year of treatment.
Biogen estimates that 1–2 million people in the US with mild cognitive impairment or mild dementia would have amyloid-β pathology if they were tested. At an average list price of $56,000 a year, Aduhelm could be a financial windfall for the company even if only a fraction of potential patients are prescribed the drug. Biogen will share profits with the Japanese drugmaker Eisai, which has helped develop the drug since 2017. Neurimmune, a small Swiss biotech firm from which Biogen licensed aducanumab in 2007, will get a $100 million milestone payment for Aduhelm’s approval, plus royalties on sales.
Scientists disagree on whether the approval will spur innovation of better Alzheimer’s therapies or simply lead to a series of marginally effective, or ineffective, amyloid-β-lowering drugs. But researchers largely agree that the approval will have historic repercussions. “For better or worse, it is very exciting that something like this has made it to this point,” Mormino says. “It is a field-changing moment, and we have entered uncharted territory.”