The US Food and Drug Administration on Monday approved the antibody drug Aduhelm (generic name aducanumab) to treat Alzheimer’s disease. Aduhelm is the first new Alzheimer’s drug to earn FDA approval since 2003. It’s also the first drug to target a theoretical cause of the irreversible neurodegenerative disease—clumps of beta-amyloid peptides that build up in the brains of Alzheimer’s patients—rather than just treating the disease’s symptoms.
The approval is, without a doubt, a landmark. It could provide hope to millions of patients, who currently have few options. And, given those limited options, it will certainly provide a massive money-maker for its developer, Biogen, which has already set the list price for a year’s worth of Aduhelm at $56,000. Analysists estimate that the drug will bring in $5 billion to $6 billion worth of sales per year in the US alone.
But, the FDA’s approval is far from a celebrated decision and the drug is far from a clear success. Since the FDA’s approval yesterday, researchers and pharma watchers have called the agency’s decision “disgraceful,” “a grave error” and a “dangerous precedent” that will end up “eroding confidence in the agency as a whole.”
Critics of the decision note that that Aduhelm has little data indicating it is effective at treating Alzheimer’s and it comes with a hefty risk of painful brain swelling. In fact, Aduhelm initially flunked out of two randomized, double-blind, placebo-controlled Phase III clinical trials in 2019. An early analysis dubbed the drug “futile” and Biogen ended the trials early.
But, later that same year, Biogen shockingly resurrected the drug, saying that residual data from one of the trials indicated a modest, statistically-significant benefit. According to Biogen, later analyses showed that people who received a high dose of the drug (which was the dosage approved by the FDA Monday) saw a small reduction in beta-amyloid plaques over 78 weeks. And participants in one of the trials saw a small improvement on a cognitive test. Participants in the other trial still saw no benefit, though. Meanwhile, around 40 percent of people who got the approved dosage developed brain swelling.
And with that, Biogen submitted the data to the FDA for review—which went badly.
A statistical evaluation by FDA reviewers (page 247) thoroughly dismantled Biogen’s analysis, concluding that “there is no compelling substantial evidence of treatment effect or disease slowing” and “another study is needed to confirm or deny the positive study and the negative study.”
Likewise, in November of 2020, an independent advisory committee for the FDA roundly rejected the drug and Biogen’s data. Ten of the 11 committee members voted “no” to the question of whether it was “reasonable” to consider the limited data Biogen collected as “primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease.” The 11th member voted “uncertain.”
One no-voting committee member later remarked on the “incongruity” of Biogen’s rosy take on the drug and the actual data behind it. “It just feels to me like the audio and the video on the TV are out of sync, and there are literally a dozen red threads that suggests concerns about the consistency of evidence—a dozen,” member, Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, said at the meeting. “For every point that you can find suggesting support, there’s another point or two that raises concerns.”
Still, the FDA approved the drug Monday based on that same data. The agency justified the decision saying it didn’t approve Aduhelm based on efficacy, but rather a “surrogate endpoint,” which in this case was the potential for the drug to clear out the beta-amyloid clumps—that may or may not be the root cause of the disease.
In a posting explaining the agency’s decision, Patrizia Cavazzoni, Director of the FDA’s Center for Drug Evaluation and Research, wrote:
We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit… [T]reatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit. After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for Accelerated Approval.
The decision stunned and appalled outside researchers.
“This sets a dangerous precedent for future drugs in the fight to combat Alzheimer’s and other complex diseases,” Mark Dallas, a neuroscientist at University of Reading, said in a statement. “In many ways the clinical trials undertaken do not present a clear picture that this medicine will be of tangible benefit to individuals living with dementia.”
Robert Howard, a psychiatry professor at University College London, echoed the point, saying: “As a dementia clinician and researcher with personal family experience of Alzheimer’s disease, I want to see effective dementia treatments as much as anyone. I consider the approval of aducanumab represents a grave error that will have only negative impact on patients and their families and that could derail the ongoing search for meaningful dementia treatments for a decade.”
Pharmaceutical industry watchers, meanwhile, worried that the FDA’s approval will set a troubling precedent in which the need for an effective treatment trumps the need to establish whether a drug is actually effective.
Noted pharmaceutical industry veteran and blogger, Derek Lowe didn’t hold back, calling the FDA’s decision “disgraceful.” He envisioned a scenario in which other drug makers could seek approval will little efficacy data, leading to a market of approved drugs that have the efficacy track record akin to the dietary supplement industry.
“I think this is one of the worst FDA decisions I have ever seen, because—like the advisory committee that reviewed the application, and like the FDA’s own statisticians—I don’t believe that Biogen really demonstrated efficacy,” Lowe wrote.