Two years ago, an experimental drug was pronounced yet another failure in the long and fruitless search for an Alzheimer’s treatment.
On Monday, the FDA approved it.
The highly controversial drug, aducanumab, is now the first FDA-endorsed treatment that targets the purported cause of the debilitating and devastating condition. But many scientists say the data on the drug’s efficacy is contradictory and inconclusive. In a nearly unanimous vote in November, an FDA advisory panel declined to endorse aducanumab. Nevertheless, it was championed by patient advocacy groups — including some funded by the pharmaceutical companies that make it.
With the approval, the FDA rejected the panel’s recommendation, an unusual move that critics say prioritizes business interests over public health and gives patients and their families false hope.
“The FDA’s decision to approve aducanumab shows a stunning disregard for science and eviscerates the agency’s standards for approving new drugs,” Michael Carome, who tracks the pharmaceutical industry for the watchdog group Public Citizen, told BuzzFeed News. “Because of this reckless action, the agency’s credibility has been irreparably damaged.”
The more than 6 million Alzheimer’s patients in the US are desperate for new treatment options. While dementia and other cognitive side effects related to Alzheimer’s can be temporarily improved by a handful of existing drugs, the most recent of which was approved nearly 20 years ago, aducanumab targets what is believed to be the underlying cause for the disease.
The demand is expected to translate into a huge windfall for Biogen and Eisai, the biotech companies that developed the drug, which will have a list price of $56,000 a year per patient. Biogen’s stock had been climbing in anticipation of an approval; on Monday, it soared 38% to $395.85.
The decision was also a victory for patient advocacy groups like the Alzheimer’s Association, which made public pleas to the FDA to approve aducanumab. But the influential organization’s statements contributed to the controversy around the drug, since the group did not disclose that it has received at least $1.4 million in funding from Biogen and Eisai since 2018.
The Alzheimer’s Association says that the donations make up a small slice of its revenue and do not influence its decisions. However, some scientists are speculating that its apparent conflicts of interest, plus pressure from patients and their families, played a role in its endorsement, given that the evidence for aducanumab is so murky.
In explaining why the FDA approved the drug, Patrizia Cavazzoni, who leads its Center for Drug Evaluation and Research, cited how “devastating” Alzheimer’s is and acknowledged the “considerable public debate” over the drug’s fate. She said that aducanumab ultimately met the criteria for an expedited review. For serious diseases without other treatment options, the FDA can speed up approval of therapies that are expected to be beneficial, even if there is “some residual uncertainty regarding that benefit.” In the case of aducanumab, the agency concluded that the benefits outweighed the risks, though it is requiring the companies to submit more trial data to demonstrate that the drug works as expected.
But others didn’t buy this explanation. Public Citizen has accused the FDA of working too closely with Biogen, forming a relationship that “dangerously compromised the integrity of the agency’s review,” and has asked the Department of Health and Human Services’ inspector general to investigate.
And Jason Karlawish, a professor of medicine at the University of Pennsylvania’s Perelman School of Medicine and codirector of the Penn Memory Center, said he anticipates aducanumab to cause, not solve, problems for millions of people and their physicians.
“My patients and their family members are eager to have a treatment we say with confidence is slowing down the progression of disabling cognitive impairments,” he said. “It’s sad, though, that this is the drug that’s going to assuage that need.”
Aducanumab is a lab-made antibody targeted at amyloid, a protein that is believed to be the main cause of Alzheimer’s. The proteins clump together in the brain, damaging brain cells. For decades, the theory has been that this brain damage leads to the long-term degradation of memory and cognition that are the hallmarks of Alzheimer’s.
A 2016 study showed that aducanumab reduced the amount of the protein in the brain and suggested that it could slow down cognitive declines.
So Biogen and Eisai — based in Massachusetts and Tokyo, respectively — started testing the drug in two large, identically designed clinical trials. But before they finished, an independent committee conducted a prescheduled analysis of the data produced by that point. The analysis found that neither trial was likely to meet its main goal, which was to reduce memory loss and other signs of cognitive decline among patients with mild early Alzheimer’s. So in March 2019, the companies said they were discontinuing the trials.
But aducanumab wasn’t dead yet. In October 2019, Biogen and Eisai dropped the bombshell news that they’d run a new analysis — and would now be applying for FDA approval.
Using a larger dataset over more weeks than that of the original analysis, the companies argued that one of the trials had succeeded. Compared to patients given a placebo, those who took high doses of aducanumab had better performance in cognition and function.
The second trial, however, still didn’t meet its goals. But Biogen argued that the drug had appeared to work in a subset of Alzheimer’s patients in this group — those who’d had “significant exposure” to high doses. In its submission to the FDA, Biogen selected that data and combined it with the promising results from the other trial, along with that of a smaller, earlier study.
These results divided regulators and scientists. The FDA granted aducanumab an expedited review. And when Biogen presented at a November meeting with the federal health agency, staff agreed with its interpretation that the data, pooled and analyzed as it was, showed that the drug worked. Except for one FDA statistician: “There is no compelling substantial evidence of treatment effect or disease slowing,” he wrote, arguing that another study should be done to resolve the dispute.
Those arguments resonated with the committee that advises the FDA on neurological drug candidates. In an unusually sweeping rejection, members voted 10–0, with one abstention, against recommending aducanumab.
Even so, the FDA asked Biogen for more data at the beginning of 2021 and pushed back the deadline for its decision from March to June.
Some experts have questioned whether the FDA was a little too eager to see aducanumab succeed. The agency worked with Biogen on the reanalysis as part of what it called a “‘working group’ collaboration.” Given the enormous need for Alzheimer’s treatments, the FDA explained in summer 2019 that it was “imperative” to use “extensive resources” to reach “a maximum understanding of the existing data.” Public Citizen called this partnership “unprecedented and inappropriate.”
FDA spokesperson Courtney Rhodes told BuzzFeed News that the dataset for the drug “was very complex, and our review has been thorough.” She added that the health agency would be “holding the company accountable for conducting an additional study.”
While Biogen sought approval, patient advocacy groups publicly pushed for it.
One group, UsAgainstAlzheimer’s, asked the FDA to approve aducanumab but did not mention in its letter that it has received an undisclosed amount of funding from Biogen and Eisai. It disclosed it elsewhere, such as in an op-ed on the biomedical news website Stat, where the group’s cofounder and a neurologist (who is also a Biogen consultant) defended the company’s working relationship with the FDA. “This partnership was not only appropriate but is expected by the FDA as defined in its recommended best practices for communication,” they wrote.
In October, the Alzheimer’s Association endorsed aducanumab in a letter to the FDA advisory committee ahead of its meeting. Biogen and Eisen had donated $1.4 million to the group between 2018 and 2020, which the group did not disclose. A spokesperson for the Alzheimer’s Association defended the group, noting that the funding from Biogen and Eisen comprised only 1.09% of all donations it had received from pharmaceutical companies during that time.
In 2020 alone, Biogen gave $275,000 and Eisai $250,000. In the prior year, those amounts were $380,000 and $361,250, respectively, according to the Alzheimer’s Association. Biogen and Eisai have also sponsored conferences that the association has hosted or plans to host. A spokesperson for the group said the fact that donors are listed on its website and accessible to “anyone with even the slightest curiosity” meant it was sufficiently transparent about such contributions.
But Carome of Public Citizen believes those ties can’t be overlooked. “Those companies ultimately expect something from that investment,” he said. “And that type of financial support can’t help but influence the positions that those organizations take.”
The question of whether the Alzheimer’s Association has conflicts of interest with its sponsors also arose in connection with a paper published in a scientific journal that it owns. In the paper, a trio of researchers wrote that there was no evidence that aducanumab worked. After one of them tweeted a link to a not-yet-final version of their paper, the journal, Alzheimer’s & Dementia, put the scientists on a two-year publishing probation and sent letters notifying their bosses.
One of the researchers, Stanford neurologist Michael Greicius, said at the time that he felt the move was retaliation for heavily criticizing aducanumab. In February, the executive editor of Alzheimer’s & Dementia told Stat that the journal “took a path that we believed addressed this serious matter.” A spokesperson for the Alzheimer’s Association told BuzzFeed News that it had zero involvement in the decision.
In an interview, Greicius said that the Alzheimer’s Association’s lobbying for the drug created “the illusion of progress in a setting where there isn’t actually any objective progress.” He added, “The stakes are too high to base a decision like this on severely insufficient data that doesn’t support efficacy.”
In rare cases, Aducanumab can cause severe side effects, which, in Greicius’s view, make the drug even less worth taking. In clinical trials, 1.3% of patients taking high doses experienced serious brain swelling (compared to less than 0.1% of the placebo group), and less than 1% had serious brain bleeding (compared to 0%). About 40% of phase 3 trial participants taking high doses experienced brain swelling or bleeding of any severity (compared to 10% of the placebo group).
Harry Johns, the president and CEO of the Alzheimer’s Association, told BuzzFeed News that “no donation from anyone, any company, has any effect” on the organization’s decisions. And while he acknowledged that aducanumab “is not a cure,” he said, “it is an improvement for people to gain some cognitive time, some functional time, that makes a real difference for those individuals and their families.”
Johns was optimistic that aducanumab’s approval would stimulate investment in other, better medications, pointing to how cancer drugs have improved over the decades. “First treatments are not perfect,” he said. “We should not let the pursuit of perfection be the enemy of the good for so many people who can benefit by a treatment.”
He is not alone in that belief in the scientific community. But other researchers worry that aducanumab will stifle, not stoke, development. Once an FDA-approved drug is available, patients may be less willing to enroll in clinical trials where they could receive a placebo instead of the experimental treatment.
Until now, the field of amyloid-targeting treatments has been strewn with failed candidates. While there are reasons why each didn’t make it, and other promising amyloid-targeting drugs are making their way through the pipeline, some scientists believe it may be time to rethink the strategy altogether. For Karlawish, the University of Pennsylvania physician, the amyloid theory may still hold the key to promising Alzheimer’s therapeutics. “I think that that approach still remains viable and needs to be studied,” he said.
In any case, aducanumab is now here. Will anyone pay for it?
A monthly infusion of the therapy will come with a list price of $4,312 per patient on average, Biogen announced Monday, which would total about $56,000 annually. But the Institute for Clinical and Economic Review had previously concluded that, based on the “insufficient” evidence for its benefits, the drug is worth a fraction of that amount: $2,560 to $8,290 annually. Given that stinging assessment, it’s uncertain whether insurers will agree that the bill is worth footing. That, in turn, will affect who gets access to the drug in the first place.
“This is a great day for Biogen and its shareholders,” Greicius said, “but a bleak day for the field of Alzheimer’s research.”
This story has been updated with more information about aducanumab's side effects.