In one large study, the experimental drug lecanemab was able to slow the progression of Alzheimer’s disease but not prevent it. Some researchers think the drug will become the first drug to help many patients; Others have questions.
Photo Cemile Bingol / Getty
hide captions
switch captions
Photo Cemile Bingol / Getty
In one large study, the experimental drug lecanemab was able to slow the progression of Alzheimer’s disease but not prevent it. Some researchers think the drug will become the first drug to help many patients; Others have questions.
Photo Cemile Bingol / Getty
A drug that offers small benefits to Alzheimer’s patients is resonating with doctors treating the disease.
The drug, a monoclonal antibody called lecanemab, dominated last week Clinical trials of Alzheimer’s disease meeting in San Francisco.
At the meeting, the researchers presented the research results research of nearly 1,800 people in the early stages of Alzheimer’s disease. Those who took lecanemab for 18 months experienced 27% fewer impairments in memory and thinking.
The study was funded by the pharmaceutical company Eisai, which is developing lecanemab in partnership with the US company Biogen.
“There’s a sense of euphoria, like this is an important milestone in the fight against Alzheimer’s,” says Dr. Eric Reimanexecutive director of the Alzheimer’s Banner Institute in Phoenix.
“We’re pretty excited because we finally have something,” said 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’s really a fresh start.”
The scientific event has become “a celebratory meeting,” says Maria Carrillo, scientific director of the Alzheimer’s Association. “The data is undeniably positive.”
However, other scientists say the benefits of the drug are modest, while its risks, including brain swelling and bleeding, are significant.
“This is a very small effect size with a drug that has a number of side effects,” including brain shrinkage, says. Dr. Madhav Thambisetty, a neuroscientist at the National Institute on Aging, a division of the National Institutes of Health. Additionally, the evidence that it slows the disease is “far from convincing,” he said, adding that his views 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 aimed at slowing or stopping Alzheimer’s disease.
Lecanemab, like many 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 eventually leads to the sticky plaques that have become the hallmark of the disease.
But a long list of antibodies that target beta-amyloid cannot slow the memory and thinking decline associated with Alzheimer’s disease. In fact, there are so many failed drugs that some researchers have begun to question the so-called the amyloid hypothesis – the idea that amyloid is the main cause of brain cell loss leading to impaired memory and thinking.
Only one type of amyloid antibody has ever received Food and Drug Administration approval, and it has been controversial.
Aducanumab, marketed as Aduhelm, received conditional approval from the FDA in 2021, despite conflicting evidence about whether it benefits patients. The move comes after an expert committee advising the agency voted against approval.
Since then, the federal Medicare program has decided it will only pay for Aduhelm’s treatment to patients enrolled in clinical trials. Due to that decision and the widespread negative publicity about the drug, very few patients received it.
A sure result, with care
The results with lecanemab are much clearer.
“It works on a wide range of cognitive and functional measures that are important for families and family caregivers,” says Reiman. “I would be surprised if it didn’t get full approval” from the FDA.
The agency is expected to consider conditional approval in early 2023 and give full approval by the end of the year. If approved, lecanemab will likely be restricted to people in the early stages of Alzheimer’s disease. They account for about 2 million of the 6 million infected.
But there are lingering safety concerns about lecanemab and most other drugs that clear amyloid from the brain. The most common concern is a condition known as ARIA, or amyloid-associated imaging abnormalities.
Two forms of ARIA are commonly seen in brain scans of people taking amyloid drugs. One involves swelling, the other bleeding.
In the lecanemab study, more than 12% of people taking the drug experienced swelling and more than 17% had bleeding.
“This sounds very dramatic, there is swelling in the brain or bleeding in the brain,” says Dr. Sharon Cohen, medical director of the Toronto Memory Program in Canada, one of the sites that tested lecanemab. But the reality, she says, is less alarming.
“What we’ve learned over time is that a very small percentage of individuals will have symptoms,” Cohen said, “and when symptoms do arise, they are often transient, mild to moderate, and will heal on its own.”
However, in rare cases, patients can suffer brain damage or even die. To date, two deaths have been associated with lecanemab, although both patients had other medical conditions that may have contributed to the results.
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 said. As a result, she says, “there will be patients for whom this is not a good therapy.”
Lecanemab and other amyloid-removal drugs have another, more mysterious side effect: They seem to cause the brain to shrink.
That concerns scientists including Thambisetty.
“Shrinkage of the brain represents disease progression,” he said. “What worries me a little bit is that these drugs might exacerbate the degenerative process.”
Alzheimer’s disease itself causes the brain to shrink, a sign that neurons are dying. So Thambisetty expects Alzheimer’s drugs to limit shrinkage rather than speed it up.
also Dr. David Knopman of the Mayo Clinic. “It’s going in the wrong direction,” he said during a panel discussion at the Alzheimer’s meeting.
Thambisetty wanted Eisai to publish detailed information about the brain volume changes that occurred during the lecanemab study.
“Responsible drug developers and researchers try to demonstrate that these changes are benign and cause no serious side effects,” he said.
Other scientists note that drugs that treat diseases like cancer often have serious side effects.
“I think a lot [Alzheimer’s] patients and their doctors will be willing to take the risk,” Sperling said. Our job is to reduce risk.”
