In a landmark decision, the Food and Drug Administration on Monday granted the first approval to a medicine meant to slow the progression of Alzheimer's disease.
Until now, the only treatments available to Alzheimers' patients and their doctors were for symptoms like memory loss, rather than for the underlying disease. With Monday's decision, the FDA cleared the way for what many predict will become a lucrative and highly sought-after option — though a fierce debate continues over whether the medicine, known as aducanumab, actually benefits patients' daily lives.
What is clear, according to experts, is that aducanumab will have profound and lasting effects on Alzheimer's care and drug development. Aducanumab took a highly unusual path before its makers, Biogen and Eisai, asked for approval. Along the way, it proved to be one of the rare drugs that can inspire patients, divide doctors, pressure insurers and test the limits of the FDA.
Regulators based their approval on a large study that found patients with early Alzheimer's who were given a high dose of aducanumab for enough time appeared to do better on a cognitive test than those who were given a placebo.
Yet, the strength of those results have been repeatedly called into question. Another, identically designed study found the opposite to be true, with the placebo arm outperforming the drug arm. These contrary results, together with the ways Biogen handled the data, led the FDA's own statisticians and advisers to strongly oppose aducanumab's approval.
The disparate results have also left healthcare providers without a clear view of how helpful aducanumab will be for the people they treat. Doctors who spoke to BioPharma Dive said that without other options, they will probably prescribe the drug, but don't have high hopes that it will work for all their patients.
The FDA chose to clear aducanumab on a conditional basis, meaning Biogen and Eisai will be required to run another trial to confirm the drug's benefits and risks — a study that will likely be very expensive and need years to complete. The agency noted that if confirmatory testing doesn't prove clinical benefit, it has procedures in place to remove the drug from market.
In the meantime, the FDA may find itself under a greater amount of scrutiny.
Amid the speedy development and rollout of coronavirus drugs and vaccines, the FDA has faced immense pressure to maintain public trust and show its decisions are rooted in science. But on several occasions last year the agency made calls that appeared driven by politics, and were later walked back or reevaluated. That the FDA went against the recommendations of its statisticians and advisers to approve aducanumab could suggest to critics that it bowed to the demands of patient groups or drug companies, further damaging its credibility.
"We are well-aware of the attention surrounding this approval," Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research, said in a statement.
"At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward," Cavazzoni added. "We examined the clinical trial findings with a fine-tooth comb, we solicited input from [advisers], we listened to the perspectives of the patient community, and we reviewed all relevant data."
As for Biogen and Eisai, their high-stakes gamble on a first-of-its-kind Alzheimer's drug appears to have paid off. Biogen, in particular, bet its future on aducanumab, trusting it to offset mounting problems in the company's business. Analysts expect the drug, which the companies will sell as Aduhelm, to quickly generate billions of dollars in annual sales.
Biogen set the drug's price at an average of roughly $56,000 a year, higher than some expected and far exceeding what the Institute for Clinical and Economic Review, an influential nonprofit, recently said would be cost-effective.
Company shares climbed by more than 50% Monday, rising as high as $468.55 before trading back to about $400 each.
A highly controversial decision
Before Monday, it had been nearly two decades since the FDA last approved an Alzheimer's treatment. Though new, promising drugs emerged regularly — many of them working in similar ways to aducanumab — none were able to successfully make it through the final stages of human testing.
The series of failures has been devastating to the estimated 6 million people living with Alzheimer's in the U.S., as well as their families and caregivers.
"Everyone thinks it's just memory, but that's not all it is. It breaks the mind and the body down. It just breaks you down," 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 sits on the board of UsAgainstAlzheimer's, a patient advocacy group.
Aducanumab, too, looked as though it would join the list of failed drugs. In early 2019, an interim analysis of those two large clinical trials concluded that the drug was unlikely to work, which led Biogen to stop them early.
Only after a subsequent review with more data did the company claim that one of the trials was actually positive, with patients on the high dose of its drug having modestly slower cognitive decline.
Since that reversal, debate has raged over whether there's enough evidence to say aducanumab helps patients and is worth approving.
To many patients and their loved ones, the drug represents an important and needed glimmer of hope. "Nothing's perfect, but this is the most perfect drug right now," O'Brien said.
But to others, aducanumab's approval sets a worrisome precedent. The FDA worked unusually closely with Biogen, and ultimately did not follow the recommendations of its advisors. Those choices could — and to some extent, already have — set the agency up for criticism.
"The FDA would be cheapening its standards by a remarkable degree to approve the product based on the evidence that has been publicly shared to date," said Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, in an interview ahead of Monday's verdict. Alexander was also one of the external experts who advised the FDA not to approve aducanumab.
Pros and cons
Like many drugs in development, Biogen's goes after a protein called amyloid, which can form sticky plaques if it folds incorrectly. These plaques are often seen in the brains of Alzheimer's patients, leading many researchers to believe they're the underlying cause of the disease.
Yet the relationship between lowering amyloid and improving patients' cognition and function remains unclear, as almost all amyloid-targeting drugs have failed in human testing.
By granting conditional approval, the FDA is betting that aducanumab's effects on amyloid are "reasonably likely" to translate to a slowing of cognitive decline in Alzheimer's patients.
"We believe that the data supports accelerated approval while holding the company accountable for conducting an additional study to confirm the benefits observed in one of the trials, which we fully intend to do," Cavazzoni told reporters Monday.
"We acknowledge that it will take some time to conduct a confirmatory trial," she added. "However, the agency is very encouraged by the incredible progress being made in the Alzheimer's drug development space, and it is our hope that in the years to come we will have the opportunity to approve additional treatment options."
Still, many have reservations about how useful aducanumab will end up being to patients.
Alzheimer's doctors who spoke to BioPharma Dive said that, to have a chance at improving patients' daily lives, a drug would need to show at least a one- or two-point benefit on a widely used scale that measures cognition. In the study Biogen deemed successful, aducanumab appeared to slow cognitive decline by less than half a point.
The drug also comes with potential risks, including brain swelling and bleeding. The FDA is requiring that patients be monitored for these side effects. But some doctors fear how feasible this would be given the sheer size of the patient population, as well as the fact that monitoring is done through brain scans, which are often not covered by insurance.
"I'm quite concerned that the data doesn't support its use, and even practically, that we don't have a good plan for how it could be used safely," said Mary Sano, director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine.
With an average price of $56,000 per year, aducanumab could be far more expensive than many patients can bear. Cigna, one of the nation's largest health insurers, estimates that some eligible patients may face $10,000 or more in annual out-of-pocket costs, according to The Wall Street Journal.
Michael Sherman, the chief medical officer for Harvard Pilgrim, a New England-based insurer, told BioPharma Dive ahead of Monday's decision that he would consider a price tag of $10,000 or more "expensive" for aducanumab.
Even so, insurers may not have many options but to cover Biogen's drug, given the lack of other options.
"Many of our families, including my own, have suffered from the effects of Alzheimer's," Sherman said. "But a drug that is approved and not believed to be efficacious just creates a lot of noise and ill will, and pits patients against payers against physicians against the FDA."