In a watershed moment for the field, the U.S. Food and Drug Administration today approved the first Alzheimer’s treatment that tackles the underlying disease pathology. Biogen and Eisai’s anti-amyloid antibody aducanumab, now called Aduhelm, removes amyloid plaque from the brain, but its ability to slow cognitive decline has remained uncertain in trials to date. It got the green light under the FDA’s accelerated approval program, which grants a marketing license based on a demonstrated effect on a surrogate endpoint—in this case amyloid plaque reduction—that is expected to lead to a subsequent clinical benefit. This pathway requires post-approval trials to demonstrate such a benefit. Approval can be withdrawn if the treatment does not pan out, though the FDA has drawn criticism for lax enforcement on this point.
- FDA grants marketing license to aducanumab via its accelerated approval pathway.
- This requires post-approval studies to demonstrate clinical efficacy.
- The label provides no guidance on which patients would benefit most.
Reactions among Alzheimer’s researchers spanned the gamut. Some were enthusiastic. Jeffrey Cummings at the University of Nevada, Las Vegas, wrote, “The FDA has taken a courageous stand to approve a drug when there were many loud—and often well-reasoned—voices to the contrary … This is a huge step forward for Alzheimer’s care and research.” Some were cautiously pleased. “I am happy for our patients with Alzheimer’s disease and think this was the best path forward: Approve now and require demonstration of clinical benefit in the near future,” Ron Petersen at the Mayo Clinic in Rochester, Minnesota, wrote to Alzforum.
Others were skeptical. “Given that the FDA advisory committee was clear in its consensus that the data presented did not show a clear signal of efficacy with aducanumab, today’s decision is very surprising, to say the least,” said AdCom member Madhav Thambisetty at the National Institute on Aging in Bethesda, Maryland. David Holtzman at Washington University, St. Louis, wrote, “The FDA needs to hold Biogen to this Phase 4 trial requirement to ensure that this treatment truly benefits patients and that we are not wasting very large amounts of dollars on an ineffective therapy.”
The diverse opinions reflect conflicting data from clinical trials. Biogen’s marketing application rested on two incomplete Phase 3 studies, one positive and one negative, which generated intense controversy (Dec 2019 conference news; Nov 2020 news). The FDA’s advisory committee recommended against approval (Nov 2020 news). The American Geriatrics Society spoke against approval, questioning whether a putative functional benefit of the treatment outweighs its risk of brain edema and microhemorrhages (ARIA).
On the other hand, patient advocacy groups lobbied for aducanumab. The Alzheimer’s Association launched its “More Time” social media campaign in May, arguing that even a modest slowing of clinical decline would be meaningful to patients and their families. Us Against Alzheimer’s urged its members to write to the FDA in support of approval.
Some believe these influence campaigns did a disservice to the science. “I do worry when the scientific processes of evaluating potential efficacy of new drugs are influenced by nonscientific factors,” Todd Golde at the University of Florida, Gainesville, wrote to Alzforum. Many researchers pushed for another trial, noting that the data did not prove efficacy (e.g., Apr 2021 news).
In the face of these pressures, the agency turned to its accelerated approval mechanism. Patrizia Cavazzoni, director of drug evaluation and research at the agency, noted that this pathway is “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.” Cavazzoni added that this regulatory option was not discussed at the advisory committee meeting. In a letter to the committee, the FDA’s Billy Dunn, who runs the neuroscience office, explained the agency’s reasoning, citing “substantial evidence that the drug reduces Aβ plaque, and that this reduction is reasonably likely to predict clinical benefit.”
Lon Schneider at the University of Southern California, Los Angeles, believes the agency had backed itself into a corner by its enthusiastic embrace of the aducanumab data at AdComs. “This is face-saving by the FDA, who were obviously closely involved and strong advocates for aducanumab’s ‘substantial’ effectiveness … In a sense, this was all decided before the advisory committee meeting in November 2020,” he wrote to Alzforum.
Other researchers acknowledge continuing qualms about the efficacy data, but are now turning their minds to practical issues of how this approval will affect clinical practice and research. Gil Rabinovici at the University of California, San Francisco, raised questions about which patients should be eligible, and how they will be monitored. “I am hoping the design of the Phase 4 study will allow us to fill critical gaps in knowledge that remain unanswered following the Phase 3 trials,” he wrote to Alzforum. In an interview with CNBC, Biogen CEO Michel Vounatsos said the company has nine years to generate these data.
Daniel Gibbs, a retired neurologist at Oregon Health and Science University, Portland, who has Alzheimer’s, believes aducanumab will likely only help those at the earliest stages of the disease. “I worry that aducanumab may be used inappropriately on those with advanced disease for whom it is unlikely to be beneficial,” he wrote.
The FDA prescribing label for aducanumab gives the indication simply as “Alzheimer’s disease,” without specifying disease stage or requiring biomarker confirmation of amyloid positivity. Technically speaking, this label would include any clinical Alzheimer’s diagnosis. A baseline MRI is required, as well as two subsequent MRIs to monitor for ARIA. As is, this label leaves primary care physicians and specialists with little guidance on how to bring this new treatment into practice.
The broad label worries some. “I am concerned that under the current parameters, many patients would receive treatment that is unnecessary, either because they don’t have plaques or because their disease is too advanced to benefit from the drug,” Rabinovici said.
Whether public or private insurers will cover aducanumab is unclear. Biogen has placed the cost at $56,000 per year. This is more than analysts had predicted, and far higher than the $2,500 to $8,000 range a recent report by the Institute for Clinical and Economic Review had pegged as cost-effective. The company’s stock price rose more than 40 percent today, to a five-year high.
Golde noted that today’s decision may inspire pharma companies to invest more money into Alzheimer’s research and hopefully develop more efficacious treatments. “The field still has a lot of work to do,” he wrote to Alzforum. “I hope this approval is viewed only as a starting point.”—Madolyn Bowman Rogers
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