In a celebratory crowded San Francisco conference room yesterday, optimistic company officials and scientists presented detailed clinical trial data on the first Alzheimer’s treatment shown to significantly, if only slightly, slow the normal cognitive decline of the disease. Antibody therapy has given a boost to an area marred by decades of failure. Now it appears to be on the verge of getting the green light from the U.S. Food and Drug Administration (FDA). Still other researchers warn of potential risks, including brain swelling and cerebral hemorrhage, which have been linked to the recent deaths of two study participants who received the antibody. Officials at the company’s main sponsor, Eisai Co., yesterday confirmed the two deaths but denied they were a result of the experimental therapy.
The Japanese company has developed the monoclonal antibody lecanemab to remove a protein called amyloid-beta in early-stage Alzheimer’s disease. The protein accumulates in the brains of people with the disease and is widely thought to cause its neurodegeneration. Other antibodies and strategies have pursued amyloid removal, but lecanemab is the first to do so, significantly delaying the onset of dementia symptoms. Many scientists and advocates are hailing these results as the strongest confirmation yet of the Alzheimer’s amyloid hypothesis.
The new data “confirm that this treatment can significantly alter the course of disease in people with the earliest stages of Alzheimer’s disease,” the Alzheimer’s Association said in a statement.
In a series of presentations late Tuesday at the Clinical Trials on Alzheimer’s Disease Conference, along with a concurrently published article in The New England Journal of Medicine (NEJM), Eisai, its partner Biogen and several researchers followed a September press release that briefly described the results of the pivotal lecanemab study, which enrolled 1,795 early-stage Alzheimer’s patients. Yesterday’s presentations and papers confirmed the earlier announcement that lecanemab, given as an intravenous infusion every two weeks, slowed the rate of cognitive decline by 27% in people who took it for 18 months, compared to similar participants on placebo.
From this top-line result, the Lecanemab Lecanemab Lectures and Papers showed that on an 18-point cognition ranking commonly used in dementia, the treated group started with an average score of 3.17 and increased by 1 .21 points deteriorated. The placebo group started at 3.22 and worsened by 1.66 points over the same period. (Higher scores mean more severe dementia.) That 0.45-point difference between the treated and untreated groups after 18 months of treatment was “highly statistically significant,” said Christopher van Dyck, director of the Alzheimer’s Research Unit at Yale University and a Director of Studies.
“Longer experiments are justified,” write van Dyck and colleagues in the NEJM Paper. The 18-month study ended in March 2021, and since then patients have been offered the option to participate in an ‘extension study’ where they can receive lecanemab infusions every two weeks if they so choose.
The antibody also managed to thoroughly mop up amyloid-beta, according to regular brain scans of a subset of participants. Some level of amyloid formation in the brain is necessary to qualify for the study, van Dyck noted, but “at the end of the 18 months, those in the treated group were, on average, “below the threshold … that would even exist.” first to the study.”
But a key question that remains unanswered is whether such a slowdown in cognitive decline represents a meaningful improvement for people with Alzheimer’s disease. Neurologists are divided over whether the difference of 0.45 on the dementia scale will be noticeable to many patients or caregivers – and whether any cognitive benefit induced by the treatment persists or improves with continued use of the antibody.
“I’m not convinced the treatment is ‘disease-modifying,'” wrote Matthew Schrag, a neuroscientist and physician at Vanderbilt University, on Twitter. “Almost all of the benefit of the treatment occurred in the first year. The differences only increase over time,” he continued.
“I don’t think the benefits seen in this study clearly outweigh the risks, and despite the general excitement surrounding a possible new treatment, I will advise my patients to keep waiting,” Schrag also tweeted.
One of Schrag’s concerns is that the study results also show that, like other antibodies that target the amyloid protein, lecanemab carries a significant risk of brain swelling and bleeding, especially in the months after starting treatment. However, many of the people who experienced these side effects did not notice any symptoms, and the changes were only picked up by routine MRI scans.
In the new lecanemab study, 2.8% of participants with the antibody had brain swelling that caused symptoms, typically headaches, confusion and vision problems. The risk of swelling and bleeding in the brain was higher in the approximately 15% of participants who had two copies of a gene called APÖ4which greatly increases the likelihood of developing Alzheimer’s disease.
The likelihood of complications may be increased, particularly in Alzheimer’s patients who take anticoagulant medications, which are commonly prescribed to older people for a variety of health reasons. At the end of his presentation on the safety of lecanemab yesterday, Marwan Sabbagh of the Barrow Neurological Institute showed a slide showing that five out of 140 people – or 3.6% – had a “macro bleed” in the brain, which was devastating depending on the severity can be. on lecanemab and anticoagulants. Two of those five patients were in the extension study and died, Science reported earlier this week and last month STAT.
Two others, each receiving anticoagulants and lecanemab, suffered devastating brain injuries, according to a study by French researchers. In general, the macrobleeds occurred much more frequently in patients who took anticoagulants with lecanemab than in those who received the antibody alone, the data presented by Sabbagh show.
However, Sabbagh has denied concerns that lecanemab causes severe cerebral hemorrhage in some people. “There was a lot of fuss … about security-related issues,” he said. But there are “no causes of death” related to the swelling, and typically only minor cerebral hemorrhage is associated with lecanemab, he argued. The two deaths announced by STAT and Sciencehe suggested were caused by the stroke in one patient, a 65-year-old woman, and heart disease in the other, an 87-year-old man.
Researchers not involved in the lecanemab study — and even one that is — have been more reluctant to declassify the antibody. Nicolas Villain, a neurologist at the Sorbonne, one of the study’s investigators and also a co-author of the September study, urged caution when mixing lecanemab and anticoagulants. He is particularly concerned that Alzheimer’s patients who are treated with lecanemab and then have a stroke could die when treated with the common stroke drug called tPA. This therapy was administered to the 65-year-old woman who later died.
In an interview, Schrag says the 3.6% macrobleed rate is “too high for comfort.” He believes the FDA should require a label urging that lecanemab not be “administered concomitantly with anticoagulants or other significant blood thinners.” And, Schrag adds, “It may make sense to limit its use in patients who [have two copies] from APÖ4.”
However, others say that the data presented so far on lecanemab is largely reassuring. “In individual cases, it’s very difficult to draw conclusions about what’s causing what,” says Frederik Barkhof, a neuroradiologist at University College London and Amsterdam University Medical Center. He was not involved in the lecanemab study discussed yesterday, but is a member of the Data Safety Monitoring Board (DSMB) for another ongoing study of the antibody. “If I were in the DSMB for this study, I would ask for more details on the patients involved,” he says. “Show me scans, show me history,” hoping to understand if other health issues triggered a bleed or if experimental therapy was likely the culprit.
Barkhof is comforted by the fact that the study did not have a “super clean population.” That better reflects who could get the antibody if it’s approved, he says. For example, the study included many people with chronic conditions like diabetes, atrial fibrillation, and high blood pressure, who might be taking multiple medications. While Barkhof suspects that “there is some increased risk of bleeding” for people treated with both lecanemab and anticoagulants, he also notes that many with early-stage Alzheimer’s might be comfortable with that risk calculation.
“We have to remember that we are dealing with a terminal disease,” Sharon Cohen, behavioral neurologist at the Toronto Memory Program and investigator on the lecanemab trial, said during a news conference yesterday. “If you ask patients what risk they are willing to take with this disease, you will be surprised.”
A previous antibody from Eisai and its partner Biogen, aducanumab (marketed as Aduhelm), received FDA approval earlier this year, overriding the recommendation of the agency’s Advisory Committee of Independent Alzheimer’s Experts. The Centers for Medicare & Medicaid Services later refused to pay for the drug except as part of clinical trials, reducing its commercial potential. The FDA is expected to make a decision on lecanemab by January 6, 2023. No advisory committee meeting is currently scheduled, and an official at the Eisai company said yesterday he wasn’t aware that a meeting was in the works.