Medical experts are raising new questions about the safety of the anti-Alzheimer’s drug lecanemab, which is marketed as Leqembi by drugmakers Biogen and Eisai.
One study, which looked in detail at the death of a participant in a Leqembi research trial, suggests that people with a condition that affects as many as half of those with Alzheimer’s Disease may be at risk for severe, and even fatal, brain bleeding if they take the drug. And most troubling, the condition that endangers these people is extremely hard to diagnose. The result: Many of those who decide to take the drug won’t know how much risk they are taking.
At the same time, the independent research organization the Institute for Clinical and Economic Review (ICER) said in an April report that the drug “mildly slows the loss of cognition in patients with early Alzheimer’s disease.” But, it warned, “given the risks of brain swelling and bleeding, particularly when lecanemab is used outside of clinical trials…significant uncertainties remain as to whether the average benefits… will exceed its risks.”
ICER’s conclusion: “Current evidence is not adequate to demonstrate a net health benefit of lecanemab when compared to supportive care alone.”
ICER’s concerns were buttressed by an autopsy of a woman who participated in the Leqembi trial and died from a severe brain hemorrhage.
Even before the FDA tentatively approved Leqembi last January, research trials showed that it could result in brain bleeds for some patients, but it generally considered those incidents minor. In its initial approval, the FDA recognized the risks of brain bleeds in patients with several conditions.
It said the drug may not be appropriate for people with amyloid-related imaging abnormalities (ARIA). Though ARIA, usually small brain bleeds or swelling, often has no symptoms, the agency noted that “life-threatening events rarely may occur.”
Similarly, patients taking blood thinners, such as those with heart disease, may be at higher risk for these Leqembi-related brain bleeds. And those with two copies of a gene variant called APOE4 also may have higher risk of brain swelling and bleeding. While small share of Alzheimer’s patients have the genetic variant, a large fraction take blood thinners because they also have heart disease, which is common among all older adults.
But the careful study of one patient’s death appears to be strong evidence that yet another subset of patients, those with a condition known as cerebral amyloid angiopathy (CAA), may also be at higher risk for severe brain bleeds and strokes if they take Leqembi. With CAA, the same amyloid beta protein that attaches to brain cells in Alzheimer’s patients also weakens the walls of blood vessels in their brains. When drugs such as lecanemab remove the amyloid, the weakened vessels can leak, causing bleeding.
CAA may affect as many as half of all Alzheimer’s patients. Unfortunately, testing for CAA is complicated and expensive so the vast majority of people with condition don’t know they may be at elevated risk for this bleeding if they take an amyloid-busting drug such as lecanemab.
The analysis of the patient’s death was done by neuroscientists and pathologists at Vanderbilt University, Boston University, and the University of Florida. The results of the case report were first disclosed by Charles Piller of Science magazine.
Good news, and bad
Leqembi has excited researchers because it is the first that appears to slow the progression of Alzheimer’s Disease. Patients with early-stage Alzheimer’s (the only people in the trial) saw the disease progress about four months more slowly over the 18-month trial, though the benefits appeared to wane in the latter stages.
Like similar antibodies, this one significantly reduced the amount of the amyloid beta protein in the brains of users. Amyloid beta is closely associated with Alzheimer’s but it is not known if it causes the disease. The difference between Lecanamab and other drugs: It is the first of its class that provides clinical benefit for some patients.
The FDA plans a hearing in June to determine whether it should grant full approval of Leqembi. On a separate track, Medicare must decide whether it will pay for the drug, which makers Biogen and Esai plan to sell for a retail price of $26,500 for a year’s treatment. The drug must be taken by infusion for the patient’s lifetime, or as long as it appears to slow the condition.
Even if it gives full approval, FDA also must decide whether to add a warning label to inform physicians and patients of its risks, and it must figure out how restrictive that warning should be. Whatever FDA says, people living with early-stage Alzheimer’s and their families will face an agonizing choice.
Do you take a drug that may slow the disease’s progression, even if it costs $26,500 annually and no one knows how long it will be beneficial? Do you take it knowing it benefits some patients but may not help you? And do you take it if you don’t know whether you are at elevated risk of severe complications or even death from the drug?
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