A festive air pervaded an Alzheimer’s disease conference yesterday in San Francisco, where attendees cheered what several described as a monumental breakthrough: the first treatment to clearly, albeit modestly, slow the disease’s seemingly inexorable cognitive decline. In so doing, some scientists say, it substantiated the long-held hypothesis that the brain protein known as beta amyloid is a major driver of the illness. The news is “a celebration for all of us in the field,” said neuroscientist Maria Carrillo, chief science officer of the Alzheimer’s Association, at the meeting.
But the buoyant mood was tempered by doubts about how well the experimental therapy, an antibody called lecanemab, worked in its pivotal clinical trial—especially in people who carry two copies of APOE4, a gene variant that predisposes them to Alzheimer’s. Safety was also a concern, with scientists debating the treatment’s risks of brain swelling and bleeding. Some have linked the drug to the deaths of two trial participants and to serious brain injuries in others, although the Japanese biotech Eisai Co., lead sponsor of the clinical trial, suggested lecanemab was not to blame.
Dennis Selkoe, a Harvard University neuroscientist and a longtime supporter of the amyloid hypothesis, says he has waited decades for this moment. “For the first time in my career, I see objective evidence” that reducing amyloid in the brain produces better cognitive outcomes. “I’m on the right side of history.” Besides vindicating the amyloid hypothesis, Selkoe says, the trial results herald a promising treatment. We don’t “need perfection to offer this to patients.”
Others strongly disagreed with both conclusions. “I do not think the benefits seen in this trial clearly outweigh the risks and despite the general excitement around a possible new treatment, I will be advising my patients to keep waiting,” Matthew Schrag, a Vanderbilt University physician and neuroscientist, tweeted yesterday.
Eisai and its partner Biogen designed lecanemab to remove certain forms of beta amyloid, which clumps between brain cells in people with Alzheimer’s and is widely thought to cause the disease’s memory-robbing neurodegeneration. Other experimental therapies, including antibodies, have removed amyloids, but patients showed little sign of benefiting from those earlier drugs.
In presentations at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, along with a paper in The New England Journal of Medicine, the companies and several researchers expanded on a September press release that briefly detailed the results of the phase 3 lecanemab trial, which enrolled 1795 early-stage Alzheimer’s patients. The talks and paper confirmed that lecanemab, given by intravenous infusion every other week, on average slowed the patients’ rate of cognitive decline by 27% after 18 months, compared with people on a placebo. That corresponded to a 0.45-point separation on the 18-point dementia scale used to assess participants.
It’s a “highly statistically significant” difference, said Christopher van Dyck, director of the Alzheimer’s Disease Research Unit at Yale University and a study leader. The antibody also thoroughly mopped up beta amyloid, according to brain scans.
But neurologists disagree on whether the reported slowing in cognitive decline would be perceptible to many patients or caregivers. And they are keen to see whether the drug maintains its benefits. “What happens in the next 18 months?” David Knopman, a neurologist at the Mayo Clinic, said at a CTAD panel discussion. “Will the effect expand, which is what we hope, will it stabilize, or will it decline?”
Knopman and other scientists also point out that not all participants appeared to benefit equally. Women and people under age 65 showed no significant boost from the antibody, for example. The subgroups analyzed were not large enough to draw firm statistical conclusions, Selkoe counters.
The randomized portion of the lec anemab trial ended last year, and both the placebo and treated groups were then offered the chance to join an “extension” trial in which all received lecanemab. Together, the trials are helping bring the therapy’s risks into sharper focus. Like other antibodies that target amyloids, lecanemab sometimes produced a form of brain swelling or bleeding, called amyloid-related imaging abnormalities (ARIA). Routine MRI scans showed roughly 21% of those on lecanemab had such side effects, compared with just over 9% of those on placebo. Many did not notice any symptoms.
Still, 3.2% of 898 participants on the antibody in the recent trial developed ARIA with symptoms, including headache, confusion, and visual problems. (In the placebo group, 0.2% experienced this.) Schrag and others fear the bleeding risk is especially acute for Alzheimer’s patients also taking anticoagulants, which interfere with clotting and are often prescribed to older people for various health problems. (Eisai declined to disclose full data on ARIA in participants who took anticoagulants while on lecanemab.)
Adding to the concern, two patients in the extension trial died following brain hemorrhages; both were on anticoagulants. One was a 65-year-old physically active woman with minimal cognitive decline. In an exclusive interview with Science recently, the woman’s spouse described the catastrophe that unfolded after she arrived at Northwestern University Medical Center with a suspected stroke. Doctors gave her a common stroke treatment, the powerful clot–busting medication tissue plasminogen activator (tPA). In short order, she suffered massive bleeding throughout her brain’s outer layer, according to an unpublished case report by Northwestern physicians, obtained by Science. She died a few days later without regaining consciousness.
“There’s zero doubt in my mind that this is a treatment-caused illness and death. If the patient hadn’t been on lecanemab she would be alive today,” says Rudolph Castellani, a Northwestern neuropathologist who studies Alzheimer’s and conducted the patient’s autopsy at her husband’s request. Although tPA does carry a risk of brain bleeds, including fatal ones on rare occasions, independent experts who reviewed the unpublished paper for Science said lecanemab likely played a key role in the hemorrhage and death. (Castellani, whom the husband authorized to speak to Science about his wife’s case, says his comments reflect his personal views, not those of Northwestern.)
At the meeting, Marwan Sabbagh of the Barrow Neurological Institute presented further data on the trial’s adverse events, including brain “macrohemorrhages” more than 1 centimeter in diameter. Such bleeding occurred in five out of 140 people—or 3.6%—on both lecanemab and anticoagulants, a far higher rate than in people only getting the antibody. One of those five was the woman who had the stroke; a second was an 87-year-old man whose death was reported in October by STAT. A third macrohemorrhage patient using anticoagulants experienced a devastating brain injury, according to a September paper by French researchers involved in the trial.
Besides taking anticoagulants, both people who died turned out to have cerebral amyloid angiopathy (CAA), a condition in which amyloid builds up around brain blood vessels. In attacking amyloid plaques, antiamyloid antibodies also strip away the amyloid around blood vessels—and, in doing so, can weaken them, increasing the risk of bleeds. CAA can be hard to diagnose before death and afflicts about half of Alzheimer’s patients—particularly those who carry two copies of APOE4.
At the CTAD conference, Sabbagh disputed that lecanemab has precipitated fatal brain injuries, suggesting the deaths were caused by tPA complications in the woman and a heart condition in the older man. But Nicolas Villain, a neurologist at Sorbonne University and an investigator on the lecanemab trial, is more uneasy. He was on the French team that described severe brain injuries—a macrohemorrhage and a serious brain swelling—in two participants on anticoagulants and urges great caution when mixing lecanemab and blood thinners.
Villain especially worries that Alzheimer’s patients who have strokes while on lecanemab could die if treated with tPA, like the 65-year-old woman. Regulators “should take this case report seriously into account,” agreed Andreas Charidimou, a neuroscientist at Boston University. “When there’s so many unknowns it’s better to be more conservative.”
Pinning down the causes of deaths and severe side effects in trials can be difficult, some scientists stressed. Others argued that people with early Alzheimer’s should be allowed to make their own choices about risks and benefits. “If you ask patients what risk they’re willing to take with this disease, you may be surprised,” Sharon Cohen, a neurologist at the Toronto Memory Program and investigator on the lecanemab trial, said during a press conference last week.
Amid this debate, lecanemab appears on the cusp of being greenlit by the U.S. Food and Drug Administration (FDA). The agency approved aducanumab, another antiamyloid antibody, last year on weaker evidence of cognitive benefits despite the complexities and costs of the treatment. Such therapies, lecanemab included, must be given intravenously, could require periodic brain scans for safety, and are likely to cost tens of thousands of dollars a year. The agency is expected to rule on lecanemab by 6 January 2023.
If it approves the antibody, FDA should at the very least require a warning against it being “given concurrently with anticoagulation or other significant blood thinners,” Schrag says. He and some other scientists worry especially about people with two copies of APOE4. In the trial, those participants both benefited less from the treatment and faced higher risks: 9.2% of people with two copies of the gene variant showed symptomatic brain swelling, compared with 1.4% of people with no copies. Other studies of antiamyloid antibodies have also seen signs of higher risk in APOE4 carriers.
That’s a red flag even to some fans of Eisai’s drug. Lecanemab is “truly a breakthrough” and “I do look forward to prescribing it,” says Jason Karlawish, codirector of the Penn Memory Center at the University of Pennsylvania. But, he adds, “I will explain the benefits of APOE testing as a way to help a patient and family decide whether this is the right drug for them.”
Karlawish says FDA should seek guidance on lecanemab from an advisory committee. Currently, no such meeting is scheduled.
About the author
