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 target 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 clumps of protein 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, in June.

Last week, the acting head of the FDA asked the inspector general of the Department of Health and Human Services to review the interactions between the agency and the drug’s manufacturer, following reports of numerous meetings between the two. Lawmakers have vowed to conduct hearings on the approval. Analysts worry the drug’s list price — $56,000 a year per patient — could wreck Medicare’s finances. The FDA recently narrowed prescribing information to patients with early-stage disease after being criticized for making any Alzheimer’s patient eligible.

But within the scientific community, it is the argument over the amyloid hypothesis that has set off some of the biggest arguments and could have a sweeping impact on the future of Alzheimer’s treatment. There is consensus that the buildup of amyloid beta is a hallmark of Alzheimer’s, which robs people of their memory and ability to do everyday tasks. To some, logic and science dictate that getting rid of the amyloid clumps is critical to helping patients. To others, the idea is a costly distraction.

That battle has reached a fever pitch over Aduhelm, known generically as aducanumab, which is made by Massachusetts-based Biogen. In 2019, the company stopped two large clinical trials early because the drug did not show results, but then reanalyzed the studies with additional information. The upshot, according to Biogen, was a modest slowing of cognitive decline in patients who got a high dose in one study but no clinical benefit in the other trial.

Given the uncertainty, the FDA decided against a full approval. Instead, it granted “accelerated approval” to the drug based on a “surrogate endpoint” — in this case, the drug’s ability to remove amyloid plaque from the brain. The agency concluded there was a “reasonable likelihood” that the plaque reduction would slow the disease. It directed Biogen to conduct another trial by 2030 to verify a benefit to patients.

The decision sparked a firestorm because a cause-and-effect link between amyloid reduction and a slowing of cognitive decline has not been established. 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 defended the decision, which she said she was not involved in, as “very solid.” She said Congress has encouraged the agency to use its accelerated-approval authority to help patients with devastating diseases and few treatments.

Now, she said, she is seeing “an outpouring of interest” from companies and investors eager to pursue a variety of strategies to tackle Alzheimer’s. “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 getting Aduhelm across the finish line represents an important 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 Paul A. Newhouse, director of Vanderbilt’s Center for Cognitive Medicine and a colleague of Schrag’s. “And it will encourage companies, even small ones, that they actually can get an Alzheimer’s drug through the FDA.”

Few drugs, little hope

Questions about Alzheimer’s disease have swirled since 1906, when Alois Alzheimer, a German psychiatrist, described the mysterious case of a patient named Auguste Deter, who exhibited bizarre behavior and cognitive impairment before her death. Her autopsied brain showed extensive plaques and tangles, which became known as characteristics of the disease.

Today, only a half-dozen drugs have been approved for Alzheimer’s. Five aim to treat symptoms and have modest effects, at most. Aduhelm, a monthly infusion, is the first designed to modify the underlying 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.

Accelerated approvals were initiated decades ago to speed access to AIDS drugs whose ultimate benefits were uncertain. Today, they often are used for cancer therapies — with tumor shrinkage, for example, serving as a surrogate endpoint. The approval of Aduhelm was the first accelerated approval for an Alzheimer’s drug. It already is changing the landscape.

Just two weeks after the FDA cleared the drug, Eli Lilly 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 plaques 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, co-director of the Penn Memory Center at the University of Pennsylvania. “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 said he is optimistic about the potential benefits of newer anti-amyloid drugs currently in testing.

“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. Abnormal tau proteins are thought to correlate with dementia symptoms.

Last fall, Biogen officials told an FDA advisory committee why they thought aducanumab might work better than monoclonal antibodies that had failed in trials. Alfred Sandrock Jr., the company’s head of research and development, said the earlier drugs 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.” But aducanumab, he said, “binds specifically to aggregated forms of beta-amyloid and recognizes amyloid plaques in brain tissue.” That allows for higher doses.

Biogen also said some of the patients enrolled in previous studies probably did not have Alzheimer’s or were too sick to be helped by medication. Advanced imaging is now used to avoid those mistakes.

Other experts are highly skeptical. Some say amyloid beta may be a symptom, not the cause, of dementia. Others say that while the protein probably is a factor in the disease, it may not be a good target for treatments.

“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.”

‘Living happier’

Daniel 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, is that his three children would not have to worry about him.

A breakthrough, then questions

The debate over treatments 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 the 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 abnormal 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’s advisory committee and staff statisticians urged the agency to reject the drug, saying evidence on effectiveness was lacking.

On the controversial amyloid hypothesis, the agency seems of two minds. One memo included in agency 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.

Peter Stein, director of the FDA’s Office of New Drugs, in a memo on the approval, wrote about 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 cautioned, 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 the approval, the agency can take the drug off the market if Biogen’s subsequent trial does not verify a benefit to patients.

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 FDA did not use its typical high standards for the approval. Still, he said, he thinks the evidence “is strong and getting stronger” that targeting amyloid will pay off in drugs that work.

“I believe we should pursue all plausible strategies but that amyloid is a very promising target, despite all of the negative studies conducted to date,” he said.

Amid the debate, there appears to be agreement on one point: If Aduhelm delivers a clinical benefit, it is likely to be modest at best. 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.”

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