FDA's Historic Approval of a Closely Watched and Controversial New Alzheimer's Drug
The FDA made a historic decision on Monday, approving for the first time a drug aimed at slowing the progression of Alzheimer's disease, aducanumab (brand name Aduhelm). Developed jointly by Biogen and Eisai, the drug's clinical trial results were contradictory, and the FDA did not follow the recommendations of its advisory committee, sparking widespread controversy. Experts expect the drug to profoundly impact the treatment and drug development of Alzheimer's disease, but issues such as its clinical benefits, pricing, and insurance coverage remain unresolved.
In a landmark decision, the U.S. Food and Drug Administration (FDA) on Mondayapproved for the first timea drug designed to slow the progression of Alzheimer's disease.
Previously, treatments available to Alzheimer's patients and their doctors were limited to alleviating symptoms such as memory loss, rather than targeting the disease itself. Monday's decision cleared the way for the drug, named aducanumab, to reach the market—a drug many predict will become a lucrative and highly sought-after option, despite ongoing debate over whether it can truly improve patients' daily lives.
Experts point out that what is certain is that aducanumab will have a profound and lasting impact on Alzheimer's care and drug development. Before Biogen and Eisai applied for approval, aducanumab had followed a highly unusual path. Along the way, it became one of the few drugs capable of inspiring patients, dividing doctors, pressuring insurers, and testing the limits of FDA regulation.
The regulatory approval was based on a large study that found that early-stage Alzheimer's patients who received high doses of aducanumab over a sufficiently long period appeared to perform better on cognitive tests than those on placebo.
However, the reliability of these results has been repeatedly questioned. Another identically designed study reached the opposite conclusion—the placebo group performed better than the drug group. These conflicting results, along with Biogen's handling of the data, led the FDA's own statisticians and advisors tostrongly opposethe approval of aducanumab.
The divergent results also made it difficult for healthcare providers to clearly determine how much aducanumab actually helps the patients they treat. Doctors interviewed by BioPharma Dive said they might prescribe the drug in the absence of other options, but they do not hold high expectations that it will be effective for all patients.
The FDA chose to approve aducanumab conditionally, meaning Biogen and Eisai will be required to conduct another trial to confirm the drug's benefits and risks—a study that could be costly and take years to complete. The FDA noted that if the confirmatory trial fails to demonstrate clinical benefit, the agency has procedures in place to withdraw the drug from the market.
Meanwhile, the FDA may face increased scrutiny.
During the rapid development and rollout of COVID-19 drugs and vaccines, the FDA has been under immense pressure to maintain public trust and demonstrate that its decisions are based on science. But last year, the agency made several decisions that appeared politically driven, only to be withdrawn or reassessed later. By approving aducanumab against the advice of its statisticians and advisors, the FDA may allow critics to argue that the agency yielded to patient groups or pharmaceutical companies, further damaging its credibility.
"We are fully aware of the attention surrounding this approval," said Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research, in astatement."
"At the end of the day, when the data were not clear-cut, we followed the conventional regulatory decision-making process," Cavazzoni added. "We carefully reviewed the clinical trial results, sought the input of [advisors], listened to the perspectives of patient groups, and evaluated all relevant data."
For Biogen and Eisai, the high-stakes gamble on this first-of-its-kind Alzheimer's drug appears to have paid off. Biogen, in particular, has bet its future on aducanumab, hoping it will offset growing problems in its business. Analysts expect the drug, which will be marketed under the brand name Aduhelm, to quickly generate billions of dollars in annual sales.
Biogen has priced the drug atan average annual cost of about $56,000, higher than some expectations and well above the level recentlyconsideredcost-effective by the influential nonprofit Institute for Clinical and Economic Review (ICER).
On Monday, the company's shares rose more than 50%, briefly reaching $468.55 per share before settling back to around $400.
A highly controversial decision
Before Monday, the FDA's last approval of an Alzheimer's treatment was nearly two decades ago. Although new drugs have continued to emerge—many with mechanisms similar to aducanumab—none have successfully passed the final stages of human trials.
This string of failures has been devastating for the approximately 6 million Alzheimer's patients in the United States, as well as their families and caregivers.
"Everyone thinks it's just a memory problem, but it's much more than that. It destroys the mind and body, causing a complete breakdown," said Greg O'Brien, a 71-year-old former journalist and father of three. O'Brien was diagnosed with Alzheimer's nine years ago and currently serves on the board of the patient advocacy group UsAgainstAlzheimer's.
aducanumab also seemed destined to join the list of failed drugs. In early 2019, an interim analysis of the two large clinical trials concluded that the drug was unlikely to be effective, prompting Biogen toterminate the trials early。
Only after a subsequent review based on more data didthe company claimthat one of the trials was actually positive, with patients receiving high doses showing a slight slowing of cognitive decline.
Since that reversal, debate has raged over whether there is sufficient evidence that aducanumab can help patients and warrants approval.
For many patients and their loved ones, the drug represents an important and much-needed beacon of hope. "Nothing is perfect, but this is the most perfect drug available right now," O'Brien said.
But for others, the approval of aducanumab sets a troubling precedent. The FDA workedunusually closely with Biogenand ultimately did not follow the advice of its advisors. These choices may—and to some extent already have—exposed the agency to criticism.
"If the FDA approves this product based on the evidence currently shared publicly, it would be lowering its standards to a great extent," said Caleb Alexander, professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, in an interview before Monday's decision. Alexander was also one of the external experts who advised the FDA not to approve aducanumab.
Pros and cons
Like many investigational drugs, Biogen's drug targets a protein called amyloid, which, if misfolded, can form sticky plaques. These plaques are commonly found in the brains of Alzheimer's patients, leading many researchers to believe they are the root cause of the disease.
However, the relationship between reducing amyloid and improving patients' cognition and function remains unclear, as nearly all drugs targeting amyloid have failed in human trials.
By granting conditional approval, the FDA is betting that aducanumab's effect on amyloid is "reasonably likely" to translate into slowing cognitive decline in Alzheimer's patients.
"We believe the data support accelerated approval, while requiring the company to conduct additional studies to confirm the benefit observed in one of the trials, and we fully intend to do so," Cavazzoni told reporters on Monday.
"We acknowledge that confirmatory trials will take some time," she added. "But the agency is very encouraged by the remarkable progress in Alzheimer's drug development, and we hope to have the opportunity to approve more treatment options in the coming years."
Nevertheless, many remain cautious about how much benefit aducanumab can ultimately provide to patients.
Alzheimer's doctors interviewed by BioPharma Dive said that to have a chance of improving patients' daily lives, the drug would need to show a benefit of at least one to two points on widely used cognitive scales. In the study that Biogen considered successful, aducanumabappeared to slow cognitive decline by less than half a point。
The drug also carries potential risks, including brain swelling and bleeding. The FDA requires monitoring of patients for these side effects. But some doctors worry that, given the large patient population and the fact that monitoring requires brain scans—which are often not covered by insurance—the feasibility of this requirement is concerning.
"I am very concerned that the data do not support its use, and even in practice, we do not have a well-established protocol to ensure its safe use," said Mary Sano, director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine.
At an average annual cost of $56,000, aducanumab may be far beyond what many patients can afford. Cigna, one of the largest health insurers in the United States, estimates that some eligible patients may need to pay $10,000 or more out of pocket each year,according to The Wall Street Journal。
Michael Sherman, chief medical officer of the New England-based insurer Harvard Pilgrim, told BioPharma Dive before Monday's decision that he would consider a price of $10,000 or more "expensive" for aducanumab.
Even so, due to the lack of other options, insurers may have no choice but to cover Biogen's drug.
"Many of our families, including my own, have been affected by Alzheimer's," Sherman said. "But a drug that is approved yet not considered effective will only create a lot of noise and hostility, pitting patients, payers, doctors, and the FDA against each other."