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Is lecanemab the Alzheimer's drug that will finally make a difference?

In a large study, experimental drug lecanemab was able to slow down Alzheimer's, but not stop it. Some researchers think the drug will become the first to help many patients; others have questions.
Cemile Bingol
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In a large study, experimental drug lecanemab was able to slow down Alzheimer's, but not stop it. Some researchers think the drug will become the first to help many patients; others have questions.

A drug that offers a small benefit to Alzheimer's patients is making a big splash with doctors who treat the disease.

The drug, a monoclonal antibody called lecanemab, dominated last week'sClinical Trials on Alzheimer's Disease meeting in San Francisco.

At the meeting, researchers presented results of a study of nearly 1,800 people in the early stages of Alzheimer's. Those who got lecanemab for 18 months experienced 27% less decline in memory and thinking.

The study was paid for by the drug company Eisai, which is developing lecanemab in collaboration with the U.S. company Biogen.

"There was a feeling of elation, like this was a milestone in the fight against Alzheimer's disease," says Dr. Eric Reiman, executive director of Banner Alzheimer's Institute in Phoenix.

"We're pretty excited that we finally have something," says Dr. Reisa Sperling, who directs the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital in Boston. "It's not a cure, but it's really a new beginning."

The scientific event became "a celebratory meeting," says Maria Carrillo, chief science officer of the Alzheimer's Association. "The data is undeniably positive."

Other scientists, though, say that the drug's benefit is modest, while its risks, including brain swelling and bleeding, are significant.

"This is a very small effect size with a drug that has some side effects," including brain shrinkage, says Dr. Madhav Thambisetty, a neurologist at the National Institute on Aging, a part of the National Institutes of Health. Also, the evidence that it slows down the disease is "far from convincing," he says, adding that his views are his own and not those of the NIH.

A long and winding road

The apparent success of lecanemab comes after decades of frustration with other, similar drugs intended to slow or halt Alzheimer's.

Lecanemab, like many of those other drugs, contains lab-made monoclonal antibodies designed to remove a substance called beta-amyloid from the brain. Beta-amyloid is a protein that tends to form clumps in the brains of people with Alzheimer's, and ultimately results in the sticky plaques that have become a hallmark of the disease.

But a long list of antibodies that target beta-amyloid failed to slow down the declines in memory and thinking associated with Alzheimer's. In fact, so many drugs failed that some researchers began to question what's known as the amyloid hypothesis – the idea that amyloid is a primary cause of the loss of brain cells that leads to declines in memory and thinking.

Only one amyloid antibody has ever received approval from the Food and Drug Administration, and it has been mired in controversy.

Aducanumab, marketed under the name Aduhelm, received a conditional approval from the FDA in 2021, despite conflicting evidence about whether it provided a benefit to patients. The move came after an expert committee that advises the agency voted against approval.

Since then, the federal Medicare program has decided it will cover Aduhelm treatment only for patients enrolled in a clinical trial. As a result of that decision and widely negative publicity about the drug, few patients have received it.

A solid result, with caveats

The results with lecanemab are much clearer.

"It had effects on a range of cognitive and functional measurements that are important to families and family caregivers," Reiman says. "I'll be surprised if it doesn't get full approval" from the FDA.

The agency is expected to consider a conditional approval in early 2023 and a full approval later in the year. If approved, lecanemab is likely to be limited to people in the early stages of Alzheimer's. They make up about 2 million of the 6 million people with the disease.

But there are lingering safety concerns about lecanemab and most other drugs that remove amyloid from the brain. The most common concern is a condition known as ARIA, or amyloid-related imaging abnormalities.

Two forms of ARIA are often seen on brain scans of people taking amyloid drugs. One form involves swelling, the other bleeding.

In the lecanemab study, more than 12% of people who got the drug had swelling and more than 17% had bleeding.

"This sounds very dramatic, to have swelling in the brain or bleeding in the brain," saysDr. Sharon Cohen, medical director of the Toronto Memory Program in Canada, one of the sites that has been testing lecanemab. But the reality, she says, is less alarming.

"What we've learned over time is that a very small proportion of individuals will have symptoms," Cohen says, "and when symptoms arise, they are usually transient, mild to moderate, and resolve."

In rare cases, though, patients can experience brain damage or even death. So far, two deaths have been linked to lecanemab, although both patients had other conditions that could have contributed to the outcome.

The risk of ARIA appears to be higher in people who are taking blood thinners or who have genes that lead to very high levels of amyloid in the brain, Cohen says. As a result, she says, "there will be patients for whom this is not a good therapy."

Lecanemab and other drugs that remove amyloid have another side effect that is more mysterious: They seem to cause the brain to shrink.

That concerns scientists including Thambisetty.

"Brain shrinkage represents disease progression," he says. "What is a little worrying to me is that these drugs might be worsening the degenerative process."

Alzheimer's itself causes the brain to shrink, a sign that neurons are dying. So Thambisetty expected Alzheimer's drugs to limit shrinkage, rather than accelerate it.

So did Dr. David Knopman of the Mayo Clinic. "It's moving in the wrong direction," he said during a panel at the Alzheimer's meeting.

Thambisetty wants Eisai to publish detailed information about the changes in brain volume that occurred during its study of lecanemab.

"It's incumbent upon drug developers and researchers to try and prove that these changes are benign and do not represent a significant adverse event," he says.

Other scientists note that drugs for diseases like cancer often have serious side effects.

"I think many [Alzheimer's] patients and their physicians will be willing to take some risk," Sperling says. Our work is to minimize the risk."

Copyright 2022 NPR. To see more, visit https://www.npr.org.

Jon Hamilton
Jon Hamilton is a correspondent for NPR's Science Desk. Currently he focuses on neuroscience and health risks.
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