Two esteemed hospitals in the midwestern United States are a 5-hour drive apart, but when it comes to how they’re prescribing new drugs for Alzheimer’s disease, they might as well be on different planets.
“I’ve been worrying about these therapies for a long time,” says Alberto Espay, a neurologist at the University of Cincinnati Medical Center, where, to his knowledge, not a single patient has gotten the monoclonal antibody lecanemab or its more recently approved cousin donanemab. Both therapies clear the brain of the protein beta amyloid, which is widely thought to fuel the disease’s symptoms. In June, Espay wrote to his Alzheimer’s patients urging them to steer clear. “The risks are high,” his letter said, citing brain swelling and bleeding. “True benefits are minuscule.”
But travel a few states west, to Washington University in St. Louis (WUSTL), and the vibe is completely different. “Any patient I see with mild Alzheimer’s disease, I’m at least asking myself, ‘Should we recommend this?’” says Joy Snider, a neurologist at the university, where 230 people have received lecanemab. (Donanemab isn’t widely available yet.) “We don’t want to overplay these drugs,” Snider says. “It’s a small effect, but it’s compelling.”
The contrasting views underscore deep divisions and uncertainty. The treatments are the first that have been shown to change the course of a shattering and ultimately deadly disease. But their effectiveness is under debate and they can cause sometimes severe brain swelling and bleeding. Clinicians at centers offering the drugs meet regularly to discuss patient side effects, consider whether people with other health conditions can safely get the treatments, and experiment with lower doses or extra monitoring for higher risk patients. As Alzheimer’s experts converge in Madrid this week for the Clinical Trials on Alzheimer’s Disease (CTAD) conference, the antibodies’ real-world rollout is causing a stir.
Lecanemab, marketed by Biogen and Eisai, gained full approval from the U.S. Food and Drug Administration in July 2023; donanemab, from Eli Lilly and Company, was greenlit a year later. Clinical trials suggested that in early-stage disease, both drugs slow cognitive decline modestly, by about 25% to 30% over 18 months. The brain swelling and bleeding collectively known as ARIA showed up, on average, in between 21% and 37% of participants taking the drugs, and in a few cases the side effect was fatal. ARIA was more common in people who carry copies of the APOE4 gene, which predisposes to Alzheimer’s, and in those taking anticoagulant medications. Those on treatment also experienced brain shrinkage, which is still poorly understood.
Regulators, like doctors, diverge in how they read that evidence. Japan, China, South Korea, Hong Kong, Israel, the United Arab Emirates, and the United Kingdom have all approved lecanemab. But in a provisional decision, the U.K.’s National Health Service will not pay for it, and last week U.K. regulators made the same call about donanemab. The European Medicines Agency rejected lecanemab in July, a decision Eisai is appealing; Australia rejected it this month. In the U.S., labeling recommends that all prospective patients get APOE genetic testing, and the clinicians Science spoke to say they are following that guidance.
The patchwork of decisions “is a clear indication that the case for approval is not straightforward,” says Michael Greicius, a neurologist at Stanford University. Like Espay, he declines to prescribe lecanemab. “Neurologists like me are definitely in the minority, but I am certainly not alone,” he says. In his small division, one other physician doesn’t use the drug, Greicius calls another “quite skeptical,” and four are comfortable prescribing it.
One source of doubt involves the antibodies’ putative benefits. Trial participants and their doctors were not told who was getting drug versus placebo, but those who had ARIA or infusion reactions such as fever could make an educated guess. A “critical research question that has not been answered is whether and to what degree functional unblinding has contributed to the perceived effect of the drugs,” Greicius says.
More: https://www.science.org/content/article/new-alzheimer-s-drugs-create-prescribing-dilemmas-doctors
