Verified by 
Key points
- Aducanumab is an antibody that removes amyloid molecules associated with Alzheimer's disease.
- The drug was approved by the FDA in spite of showing a lack of adequate clinical efficacy and causing brain bleeds and swelling.
- There have been serious concerns about possible ethical improprieties at the heart of aducanumab’s approval.
Since the Food and Drug Administration (FDA) approved Biogen’s drug aducanumab (marketed as Aduhelm) on June 7, it has been quite a bumpy ride on a predominantly downhill slope. We thought we’d do a quick check-in about our concerns over the controversial biologic and speculate as to where things might be going.
What Happened?
Aducanumab is an antibody lab-engineered to bind to and remove amyloid molecules that are a constituent part of the plaques associated with Alzheimer’s disease. While many anti-amyloid approaches have been undertaken over the past two decades, with a fail rate of 100 percent, aducanumab is the first to gain FDA approval.
That decision was instantly met with disbelief and pushback and with good reason. Most glaringly, the drug did not adequately prove clinically efficacious but was, instead, granted approval for its capacity to lower amyloid as a surrogate endpoint, a so-called “biomarker.”
There is an obvious problem here: amyloid does not equal Alzheimer’s—unless you reductively try to define it that way, as some unfortunately do. Moreover, and most importantly, removing amyloid is not associated with clinical improvement, and this unvalidated biomarker should not have been used to justify accelerated approval. In the scientific community, the amyloid hypothesis was on its way to the graveyard of failed theories at the end of the last decade. However, the stunning approval of aducanumab, which was in March 2019 declared a failure in Biogen’s futility analysis, has given both the drug and the hegemonic theory itself a zombie-like rebirth.
Biogen also priced the treatment, delivered via multiple intravenous infusions, at $56,000, significantly higher than nearly all analysts had predicted. Add-on costs from PET scans necessary to monitor the drug’s propensity to cause micro-bleeds and swelling (40 percent of its high-dosage recipients experienced these adverse “Amyloid-Related Imaging Abnormalities” in clinical trials) and other medical care and the drug projects to cost around $100k annually per patient.
Pushback and Investigation
Dr. Aaron Kesselheim, who led the FDA’s internal panel that unanimously declined to endorse the drug, has called it perhaps the FDA’s worst approval in the history of the country, a feeling shared by many, including us.
So far, funders have spoken resolutely against paying for the drug. Major health systems, including the Veterans Administration, the Cleveland Clinic, and other academic hospitals in Cleveland, Mount Sinai, Excellus, Mass General Brigham, and others, have decided not to pay for or administer aducanumab. Experts in other countries like Canada have encouraged their regulatory agencies not to approve the drug.
Even so, Biogen is offering aducanumab on the market and is estimated to have been administered to approximately 100 patients at present. Recent reporting has suggested that, as might have been expected once the drug began to be used in more diverse clinical populations, an alarming number of patients have been affected by the swelling/micro-bleeds mentioned above.
Biogen received much scrutiny for immediately rolling out a post-approval website called It’s Time We Know to actively direct older adults concerned about memory loss to infusion sites via a dubious cognitive health “quiz” that invariably leads users to consider cognitive screening at memory clinics carrying Aduhelm. The company also purchased a deceptive paid ad in The New York Times called “When Memory Fades,” telling the story of a 70-something woman with mild cognitive impairment and, again, steering people to its proprietary website. This was all a part of Biogen’s “Project Javelin”—an internal plan aimed at steering customers concerned about memory loss to infusion sites as quickly as possible.
There have been substantial concerns about possible ethical improprieties at the heart of aducanumab’s stunning approval. Investigations into the close relationship between Biogen and the FDA are ongoing, including the Inspector General’s office. Many have posed the broader question of why the FDA receives such substantial funding (roughly 45 percent of its budget) from industry user fees and its effects on the integrity of its regulatory role. The influence of lay groups like the Alzheimer’s Association that pushed hard for approval despite questionable evidence for efficacy and clear risk to patients are being scrutinized. For those groups, the need to deliver a long-promised drug, regardless of its actual value, seems to have distorted a more clear-eyed approach.
Controversy has also swirled around the fact that Biogen failed to publish data from their two clinical trials and pulled its paper from the Journal of the American Medical Association after reviewers demanded edits.
At this point, many of us have lost count of the red flags cropping up around this disaster.
Meanwhile, other companies leverage the FDA’s decision to seek accelerated approval for their anti-amyloid drugs. The thinking is that if the FDA has set a precedent of simply requiring medications to lower amyloid (i.e., a “biomarker”) to gain approval without showing clinical efficacy, other compounds can certainly meet surrogate criteria. The incoming flood of “me-too” drugs is a significant setback for actual innovation in the Alzheimer’s research world, which, as alluded to above, has been bogged down by the amyloid cascade hypothesis for decades.
That is admittedly a lot of turmoil in the space of only four months. Increasingly, responsible voices argue that aducanumab should eventually be taken off-market, which is certainly a possibility.
Staying Informed
Those concerned should stay apprised of the rapid developments, including the results of the various investigations into Biogen and the FDA’s conduct in the years preceding approval. Psychologists should be particularly interested because the focus of funding biomarkers and biologics potentially diminishes the critical role of psychologists in the diagnostic and treatment process (a topic we will return to in future posts).
We have also written about the likelihood of pharmacologically curing Alzheimer’s in a recent Psychology Today article.
Those interested in reading more granularly about the aducanumab disaster should check out an excellent article in Nature by Kathy Liu and Robert Howard.
Supposing you’d like to read more about our broader thoughts on aducanumab, drug development, and brain health, we would encourage people to explore our recently published book American Dementia: Brain Health in an Unhealthy Society.
And, of course, we’ll be posting here concerning any future developments.
