Neurologist Matthew S. Schrag was surprised when he heard the Food and Drug Administration had approved a controversial Alzheimer’s drug. There was scant evidence the treatment worked, in his view.
Even more concerning to Schrag: the FDA’s apparent embrace of a long-debated theory about Alzheimer’s disease, which afflicts more than 6 million Americans. The amyloid hypothesis, which has dominated the field for decades, holds that toxic clumps in the brain, called amyloid beta, are the main driver of the disease and that removing them will slow cognitive decline.
But years of testing drugs that targeted amyloid had yielded a string of failures, and Schrag and others had been pushing the field to focus on other possible factors, including inflammation in the brain or damage to tiny blood vessels. Anti-amyloid efforts, they said, had squeezed out other approaches that might be more promising.
“We had been hoping for a recalibration of the field,” said Schrag, a researcher at Vanderbilt University Medical Center. Now, he’s worried drug companies will double down on an approach he thinks is a dead end.
The role of the sticky substance in the brain has long divided researchers and is at the forefront again amid the FDA’s recent clearance of the first drug to treat the disease in almost two decades. It is one of many controversies that has erupted since the FDA approved the drug, called Aduhelm, on June 7.
Members of Congress have vowed to conduct hearings on the relationship between the FDA and the drug’s maker, Massachusetts-based Biogen. Analysts worry the drug’s list price—$56,000 a year per patient—could wreck Medicare’s finances. Doctors are scrambling to decide who should take it, complaining that the FDA-approved label, which includes all Alzheimer’s patients, is far too broad.
But within the scientific community, it is the argument over the amyloid hypothesis that has set off some of the biggest fireworks and could have a sweeping impact on the future of Alzheimer’s treatment. The tumult in the field and within the FDA—where internal memos show staffers had sharply differing views of the drug—reflects fundamental disagreements over the role of amyloid beta. To some, logic and science dictate that getting rid of it is an important goal. To others, that notion is a costly distraction.
There is agreement on one point: Decades after the amyloid hypothesis was described, the relationship between the substance and dementia is “more complicated than originally thought,” wrote Peter Stein, director of the FDA’s Office of New Drugs, in a decision memo on Aduhelm.
Much of the uproar has centered on the FDA’s use of “accelerated approval” to clear the drug after concluding there was not enough evidence of clinical effectiveness for a full approval. In two large clinical trials for early-stage patients, Biogen found a modest slowing of cognitive decline in the high-dose group of one study and no clinical benefit in the other.
But Aduhelm, also called aducanumab, was effective at removing plaque, and the FDA concluded there was a “reasonable likelihood” that would help patients. The agency approved the drug based on the “surrogate marker” of amyloid reduction and directed Biogen to conduct another trial to verify the clinical benefit.
Accelerated approvals of medications were initiated decades ago to speed access to AIDS drugs. Today, they often are used for cancer drugs, with tumor shrinkage, for example, serving as a surrogate marker. The approval of Aduhelm was the first accelerated approval for an Alzheimer’s drug.
The decision sparked a firestorm, in part because a cause-and-effect link between amyloid reduction and a slowing of cognitive decline has not been established. Some worry the approval will offer false hope to patients and send research in unproductive directions. Halima Amjad, assistant professor of medicine at Johns Hopkins University, wrote on Twitter that the FDA had “single-handedly moved the field from debate over the amyloid hypothesis . . . to accepting it as fact. Shameful.”
In an interview, acting FDA commissioner Janet Woodcock, who said she was not involved in the decision, defended it as “very solid.” She said Congress has encouraged the agency to use its accelerated-approval authority to try to help patients with devastating diseases.
Now, she said, she is seeing “an outpouring of interest” from companies and investors eager to pursue strategies that go beyond anti-amyloid drugs. “My experience from other diseases is that this will lift all boats,” she said. In a field that has often been in despair, she added, “there is now hope.”
Some other experts agree that the FDA approval represents a pivotal moment for Alzheimer’s, even if the benefit to patients turns out to be small.
“I think the drug will clearly benefit some patients,” said neurologist Paul A. Newhouse, a colleague of Schrag’s at Vanderbilt. “And it will encourage companies, even small ones, that they actually can get an Alzheimer’s drug through the FDA.”
Questions about Alzheimer’s disease have swirled since 1907, when Alois Alzheimer, a German psychiatrist, described the mysterious case of a patient named Auguste D., who exhibited bizarre behavior before her death. Her autopsied brain showed extensive plaques and tangles, which became known as hallmarks of the disease.
Today, only a half-dozen Alzheimer’s drugs have been approved. Five aim to treat symptoms and have small effects, at most. Aduhelm, a monthly infusion, is the first designed to affect the course of the disease. The treatment is a monoclonal antibody—a protein made in the laboratory that can bind to substances in the body—originally derived from the cells of older people who did not have signs of cognitive problems.
Its approval already is changing the Alzheimer’s landscape.
Just two weeks after the FDA cleared the drug, Indianapolis-based Eli Lilly and Co. announced it would seek accelerated approval for its anti-amyloid drug, called donanemab, later this year, based on a small trial that showed the treatment reduced amyloid and slowed cognitive decline. That was a sharp change for the company, which earlier had said it would wait for the results of a large late-stage trial before seeking full FDA approval. Other companies, including Roche, also have amyloid-busting drugs in trials.
To critics of the Aduhelm approval, Lilly’s change of heart is Exhibit A that the FDA’s decision will spur drug companies to seek quicker approvals based on smaller studies and surrogate endpoints—rather than large clinical trials and concrete evidence that patients benefited.
“One of the consequences is that other companies will say, ‘If this is your new lower bar, we want our drugs approved on that basis,’ ” said Jason Karlawish, a University of Pennsylvania neurologist. “Companies are companies, I can’t fault them for doing what companies do, but we have now unleashed drugs that we are not sure what the benefits are, and that could have enormous consequences.”
Gil Rabinovici, a neurologist at the University of California at San Francisco, said he agrees Lilly should do a larger study before applying to the FDA. But he is optimistic about the possible benefits of newer anti-amyloid drugs.
“It’s very easy to be a nihilist and say the amyloid hypothesis is incorrect,” he said. “But if you really look at how the science has evolved, I think there really is a lot of evidence to support it.” For example, he said, the Lilly data “provided the most compelling evidence so far” that a sharp reduction in amyloid beta can slow the spread of tau tangles thought to correlate with severe dementia symptoms.
Last fall, in a presentation to an FDA advisory committee, Alfred Sandrock Jr., Biogen’s head of research and development, said earlier monoclonal antibodies that failed in drug trials had bound to all forms of amyloid beta and could not be given at high enough doses “to safely engage its target in the brain.” By contrast, he said, aducanumab “binds specifically to aggregated forms of beta-amyloid and recognizes amyloid plaques in brain tissue.” That allowed for higher doses.
Biogen also told the committee that earlier anti-amyloid trials may have failed because some of the patients enrolled probably did not have Alzheimer’s or were too sick to be helped by medication. Advanced imaging is now used to try to avoid those mistakes.
Other experts remain skeptical. Some say amyloid beta may be a symptom, not the cause of dementia. Others say that while it probably is a factor, it may not be the best target for treating the disease.
“Even if amyloid does cause Alzheimer’s disease, it does not necessarily mean you can cure the disease by removing it,” Vanderbilt’s Schrag said. “If someone came to the emergency room with a stab wound, just removing the knife wouldn’t cure them either.”
Dennis Gibbs, a 69-year-old retired neurologist with early-stage Alzheimer’s, was eager to participate in one of the Aduhelm trials. But after just four infusions, the Portland, Ore., physician wound up in the intensive care unit with explosive headaches and soaring blood pressure.
Such life-threatening reactions affect just a sliver of people, though up to 40 percent of those treated in the trials had side effects such as dizziness and small brain bleeds. The complications were easily managed in the trials, but some doctors worry they might pose safety risks in everyday clinical practice.
Gibbs, who won’t be able to try Aduhelm again, nevertheless believes “we are on the right track” with the drug, but that Biogen should have been required to conduct another study before receiving FDA approval. He said he is reminded of the excitement over Cognex, also called tacrine, which in 1993 became the first approved Alzheimer’s drug but eventually was discontinued because of serious side effects.
“Aducanumab may be the tacrine of today: the first drug of its class with likely effectiveness, but it will almost certainly be joined and possibly replaced by other, more effective drugs in the future,” he wrote on Alzforum, a site that publishes news and analysis on Alzheimer’s disease.
Other patients are enthusiastic about the treatment. Marc Archambault, a Rhode Island real estate agent who has early-stage Alzheimer’s, became one of the first patients in the country to receive the drug outside of a clinical trial.
“I am a happy guy, but hearing that the FDA had approved Aduhelm and that I am eligible for the treatment, I am living happier, of course,” Archambault said immediately before getting the infusion at Butler Hospital in Providence, R.I. “The thought that the last stage [of Alzheimer’s] may now be far away for me, or even that I might stay as I am, is incredible.” His biggest hope, he said, was that his three children would not have to worry about him.
The debate took a dramatic turn in August 2016, when the journal Nature published an eye-popping cover: brain scans illustrating results of an early-stage clinical trial of a Biogen amyloid-busting drug. The “before” scan showed lots of red, indicating an abundance of amyloid beta clumps. The “after” scan didn’t have any red. In addition to removing amyloid beta, aducanumab also appeared to slow cognitive decline, the accompanying article said.
Was this the long-awaited breakthrough for Alzheimer’s patients?
Less than three years later, Biogen halted two large late-stage trials midway through, saying independent assessments showed they would not reach their goal of slowing cognitive decline. Critics said it was time to step up efforts on other targets, such as tau, the other toxic protein.
But as additional data came in, Biogen thought the drug was sending a positive signal. In meetings with the FDA, the agency encouraged Biogen to submit the data. According to Stat, a website covering medical and science news, the agency early in the process outlined several possible paths to clearance, including accelerated approval—even though officials told an outside advisory committee later that the option was not under consideration. Woodcock, in an interview, said “accelerated approval is something that is always discussed in untreatable diseases.”
The FDA ultimately granted accelerated approval, based on the one large positive study and a much smaller study that had shown a cognitive benefit. In doing so, it overruled the advisory committee and its own statisticians who urged rejection of the drug and who said it was wrong to ignore the trial that showed the drug was not helpful.
On the controversial amyloid hypothesis, the agency seems of two minds. One memo included in the internal documents on the approval noted that the data from the Aduhelm trials was consistent with the theory, while another said the agency was not endorsing the hypothesis or trying to discourage other approaches.
FDA’s Stein, in the memo about the approval, explained the risk-benefit calculation. A rejection could mean patients “could suffer irreversible loss of brain neurons and cognitive function and memory” as the agency waited for definitive proof of effectiveness.
But he also cautioned that the expedited approval meant that “patients must be willing to accept some residual uncertainty regarding clinical benefit—and therefore be willing to take a drug that may ultimately prove ineffective along with the risks of the drug, in order to gain earlier access to a potentially valuable treatment.”
Under the terms of approval, the agency can take the drug off the market if a subsequent clinical trial by Biogen does not verify effectiveness. The results are due in nine years.
The process has been frustrating even for longtime proponents of the amyloid hypothesis. Paul Aisen, a University of Southern California neurologist, said he believes the evidence “is strong and getting stronger” that targeting amyloid will pay off in drugs that work.
But he’s unhappy the FDA-approved label says the drug is for all Alzheimer’s patients, rather than just for those with mild cognitive impairment and early dementia, who were the people studied in clinical trials.
“The evidence in the population studied is equivocal,” said Aisen, a longtime consultant for Biogen. “To spread it to the entire population creates a lot of confusion among practitioners and payers. It’s problematic.”
Amid the debate, there appears to be agreement on one point: If Aduhelm delivers a clinical benefit, it is likely to be modest. Most experts say combination therapies will be needed to treat Alzheimer’s, just as they are used to treat cancer and HIV.
“Even the most ardent supporters of the amyloid hypothesis don’t think that treating amyloid will be sufficient to make a big impact in improving cognition for patients,” said Rabinovici of UCSF. “This idea of combination therapies is becoming more and more key to approaches to treating Alzheimer’s disease.”