Is lecanemab the drug against Alzheimer’s disease that will finally make a difference?

A drug that offers a small benefit to Alzheimer’s patients is causing a stir among doctors who treat the disease.

The drug, a monoclonal antibody called lecanemab, topped last week’s Alzheimer’s clinical trials meeting in San Francisco.

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

The study was funded by the pharmaceutical company Eisai, which is developing lecanemab in collaboration with the American company Biogen.

“There was a feeling of elation, like this was a milestone in the fight against Alzheimer’s disease,” said Dr. Eric Reiman, executive director of Banner Alzheimer’s Institute in Phoenix.

“We’re thrilled to finally have something,” says Dr. Reisa Sperling, who directs the Alzheimer’s Disease Research and Treatment Center at Brigham and Women’s Hospital in Boston. “It’s not a cure, but it really is a fresh start.”

The scientific event has become “a celebratory meeting”, explains Maria Carrillo, scientific director of the Alzheimer’s Association. “The data is undeniably positive.”

Other scientists, however, say the drug’s benefits are modest, while its risks, including brain swelling and bleeding, are significant.

“It’s a very small effect size with a drug that has side effects,” including brain shrinkage, says Dr. Madhav Thambisetty, a neurologist at the National Institute on Aging, part of the National Institutes of Health. What’s more, the evidence that it slows the disease is “far from convincing,” he says, adding that his opinions are his own and not those of the NIH.

A long and winding road

Lecanemab’s apparent success comes after decades of frustration with other similar drugs intended to slow or stop Alzheimer’s disease.

Lecanemab, like many of these other drugs, contains laboratory-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 disease and eventually forms the sticky plaques that have become a hallmark of the disease.

But a long list of antibodies targeting beta-amyloid failed to slow the decline in memory and thinking associated with Alzheimer’s disease. In fact, so many drugs have failed that some researchers have begun to question what’s called the amyloid hypothesis – the idea that amyloid is the primary cause of brain cell loss that leads to a decline in memory and thought.

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

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

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

A solid result, with reservations

The results with lecanemab are much clearer.

“It had effects on a range of cognitive and functional measures that are important to families and family caregivers,” Reiman said. “I’d be surprised if it didn’t get full approval” from the FDA.

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

But there are lingering safety issues with 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 received the drug experienced swelling and more than 17% bleeding.

“It seems very dramatic, to have brain swelling or bleeding in the brain,” says Dr. Sharon Cohen, medical director of the Toronto Memory Program in Canada, one of the sites that has tested 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 do appear, they’re usually transient, mild to moderate, and resolve.”

In rare cases, however, patients can suffer 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 take 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 good therapy.”

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

This concerns scientists, including Thambisetty.

“Brain shrinkage represents disease progression,” he says. “What worries me a bit is that these drugs could make the degenerative process worse.”

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

Just like Dr. David Knopman from the Mayo Clinic. “It’s going in the wrong direction,” he told a panel at the Alzheimer’s meeting.

Thambisetty wants Eisai to release detailed information about brain volume changes that occurred during his lecanemab study.

“The onus is on drug developers and researchers to try to 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 a lot [Alzheimer’s] patients and their doctors will be willing to take risks,” says Sperling. Our job is to minimize risk.