A crucial, overlooked question on the new Alzheimer’s drug: When should patients stop taking it?

For families and physicians grappling with the historic approval this month of the controversial Alzheimer’s drug Aduhelm, there’s no shortage of unanswered questions. But a critical one has largely been overlooked: Once patients start taking the medication, how will they know when it’s time to stop?

“We don’t have any guidance on how long to give this medication to someone who doesn’t experience adverse events,” said William Mantyh, a behavioral neurologist at M Health Fairview University of Minnesota Medical Center. “With a drug like aducanumab where the upfront demonstrated efficacy is up in the air, it really makes it hard for a clinician to figure out when to stop the drug based on a patient’s clinical symptoms.”

Doctors who care for Alzheimer’s patients told STAT it will be critical — and exceedingly difficult — to know whether the drug is working, and if it is, whether those effects are waning with time. It’s a risk-benefit calculus inherent in the decision to start or stay on any medication. But with a drug like Aduhelm, which comes with the risk of serious side effects and a steep price tag of $56,000 a year, the stakes are even higher. And that math is made only more complicated by the contentious debate over whether Biogen even showed enough benefit to warrant the drug’s approval.

In approving Aduhelm, the FDA overrode its own advisory panel, which found the data unconvincing that Biogen’s drug offered any benefit to patients. (Three members have since resigned from the panel in protest.) The FDA also employed an irregular process, which allowed the agency to greenlight Aduhelm based on a surrogate measure: how well it clears toxic tangles of a protein called beta-amyloid from patients’ brains. But whether lowering these levels of protein plaques can slow the cognitive ravages of Alzheimer’s remains a topic of intense scientific debate.

Despite that debate, the FDA granted the drug a broad label that places no limits on the types of patients who might receive it, even though Biogen only tested the drug in people in the earliest stages of Alzheimer’s disease. And though consensus among clinicians has begun to coalesce around only prescribing the drug to similar patients — as became clear at a lengthy virtual discussion hosted by the Alzheimer’s Association Monday — doctors may be pressured by desperate families to dole the drug out more widely.

That could leave doctors in a pinch to know not only whether to prescribe the drug, but also when to take a patient off Aduhelm. The progression of Alzheimer’s disease varies from person to person, with an average life expectancy of about 10 years after diagnosis. But some people decline more slowly, and some deteriorate in just a year or two. Predicting who will go which way is still an emerging science.

If a doctor puts a patient on Aduhelm, and that patient progresses along the average trajectory, does that mean the drug isn’t working? Or does it mean that without it, would they have fared far worse?

“When we enroll families in studies of treatments like aducanumab, we try to educate them that they should not expect large improvements in cognition or function,” Joshua Grill, director of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, said in an email to STAT. The drug can’t stop disease progression, only potentially slow it, a change that he warns would likely be imperceptible. “If we can’t expect families to know if the drug is working, how would we expect them to know when it is no longer working?”

Doctors told STAT they’re concerned that the lack of a clear stopping point may lead to patients staying on the drug when it’s no longer useful  — racking up revenue for Biogen while straining Medicare, placing massive financial burdens on patients and their families.

“It’s all very well not to start something, but quite frankly, it’s harder to stop it once you’ve started,” said Jason Karlawish, co-director of the Penn Memory Center and a professor of medicine, medical ethics, and health policy at the University of Pennsylvania’s Perelman School of Medicine. (He is also a site investigator on clinical trials sponsored by Biogen, Eisai, and Eli Lily, and has been outspoken regarding his reluctance in prescribing Aduhelm.)

In the early 2000s, Karlawish set out to understand how caregivers made treatment decisions for their loved ones with Alzheimer’s, and specifically, when they stopped valuing interventions that could slow the disease’s progression. He interviewed about 100 families and found that 1 in 5 wouldn’t want a hypothetical drug that could slow down disease progression, even if it had no side effects and was free.

“It’s a very personal decision, and everyone is different. But there’s no question that there’s a point in the disease where for some people it’s just not worth continuing to treat their loved one,” said Karlawish. What drove those decisions was the severity of the disease, but also the perception of an individual’s quality of life.

“This is a drug that medicalizes someone’s life,” said Mantyh. Besides the hourlong, once-monthly infusions, an Aduhelm prescription comes with frequent lab tests and brain scans to monitor for signs of swelling or bleeding. In two of Biogen’s clinical trials, more than one-third of participants who received Aduhelm developed painful brain swelling; about 17% to 19% had small bleeds in their brains. Headaches, dizziness, nausea — all might trigger more time spent in the hospital. Such constraints could make it difficult to travel internationally or spend time with family members in other states.

“Not having a stop date for a drug that you’re not sure if it’s working could waste a lot of the quality time that people have left,” Mantyh said.

But a conversation about when to stop a drug like Aduhelm also has to address the question of what comes next. Karlawish recalled a patient of his who died a few months ago, after spending four weeks in hospice. When she passed, her husband told Karlawish that he wished he’d known about the option to start palliative care sooner.

“As physicians, we need to listen to that,” said Karlawish. To him, there’s a flaw in how society conceptualizes Alzheimer’s care. Things like helping someone bathe or dress is considered care, and medicines like Aduhelm are thought of separately as treatment. “In truth, they’re all part of care,” he said. “And if we were more thoughtful in describing care as anything that benefits the brain of the person, then we could have more mature conversations about how to deliver care for these patients, because it wouldn’t be about stopping one thing to then start another.”