In a crowded conference room in San Francisco with a festive atmosphere yesterday, gleeful company representatives and scientists presented detailed clinical trial data on the first Alzheimer’s treatment that has been shown to clearly, if modestly, slow the normal cognitive decline of the disease. Antibody therapy has fueled a field marked by decades of failures. Now it seems to be about to get a green light from the US Food and Drug Administration (FDA). Still other researchers warn of potential risks, including brain swelling and cerebral hemorrhage associated with the recently disclosed deaths of two trial participants who received the antibody. Officials from 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 clusters in the brains of people with the disease and is widely believed to cause the neurodegeneration. Other antibodies and strategies have chased the removal of amyloid, but lecanemab is the first to do so and markedly delay the onset of dementia symptoms. Many scientists and advocates hail these results as the strongest confirmation yet of the amyloid hypothesis of Alzheimer’s disease.
The new data “confirm that this treatment can meaningfully change the course of the disease for people in 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 paper released simultaneously in The New England Journal of Medicine (NEJM), Eisai, his partner Biogen, and several researchers followed up with a press release that briefly described the results of the pivotal lecanemab trial, which included 1,795 early-stage Alzheimer’s patients. Yesterday’s readings and article confirmed the earlier announcement that lecanemab, administered every other week by intravenous infusion, slowed the rate of cognitive decline by 27% in people taking it for 18 months, compared to similar participants on a placebo.
Building on that topline result, the lecanemab readings and papers revealed that on an 18-point cognition ranking commonly used in dementia, the treated group started with a mean score of 3.17 and worsened by 1.21 points over 18 months . The placebo group started with 3.22 points 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 Disease Research Unit at Yale. University and a study leader.
“Longer trials are warranted,” van Dyck and colleagues nevertheless write in the NEJM paper. The 18-month study ended in March 2021 and since then, patients have had the opportunity to participate in an “extension” trial where they can all receive an infusion of lecanemab every other week if they wish.
The antibody also thoroughly cleared amyloid beta, according to regular brain scans of a subgroup of participants. A certain level of amyloid buildup in the brain was needed to qualify for the trial, Van Dyck noted, but “at the end of 18 months, those in the treatment group were ‘on average’ below the threshold…that would get them in the first place in the study.”
But an important question, which remains unanswered, is whether such a slowing of cognitive decline represents a meaningful improvement for people with Alzheimer’s disease. Neurologists disagree on whether the difference of 0.45 on the dementia scale will be detectable by many patients or caregivers, and whether any treatment-induced cognitive benefit will persist or improve with continued use of the antibody.
“I’m not convinced the treatment is ‘disease-modifying,'” Matthew Schrag, a neuroscientist and physician at Vanderbilt University, wrote on Twitter. differences become more and more over time,” he continued.
“I don’t think the benefits of this trial clearly outweigh the risks and despite the general excitement around 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 lecanemab, like other antibodies that target amyloid protein, carry a significant risk of brain swelling and bleeding, especially in the months after starting treatment. However, many of the people who had 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 the antibody participants had brain swelling that did cause symptoms, usually headaches, confusion and visual problems. The risk of swelling and cerebral hemorrhage was higher for the approximately 15% of participants who had two copies of a gene called APOE4which significantly increases the risk of Alzheimer’s disease.
The risk of complications may be especially higher for Alzheimer’s patients taking anticoagulants, which are commonly prescribed to the elderly for a variety of health conditions. At the end of his presentation on the safety of lecanemab yesterday, Marwan Sabbagh of the Barrow Neurological Institute showed a slide indicating a “macrobleed” in the brain, which can be devastating depending on its severity, which occurred in five of 140 people – or 3.6% – on both lecanemab and anticoagulants. Two of those five patients were in the extension trial and died, as reported by Science 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 September. Overall, the macrobleeds were much more common in patients taking anticoagulants with lecanemab than in patients receiving the antibody alone, according to data from Sabbagh.
Still, Sabbagh balked at concerns that lecanemab causes serious brain hemorrhages in some people. “There’s a lot of buzz … around safety-related issues,” he said. But there were “no causes of death” related to the swelling and typically only mild cerebral hemorrhage was associated with lecanemab, he argued. The two deaths revealed 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 trial — and even one who is — were more hesitant to release the antibody. Nicolas Villain, a neurologist at the Sorbonne who is one of the study investigators and also a co-author of the September paper, urged great caution when mixing lecanemab and anticoagulants. He is particularly concerned that Alzheimer’s patients who take lecanemab and then have a stroke could die if they are treated with the common blood-clotting drug called tPA. This therapy was administered to the 65-year-old woman who later died.
In an interview, Schrag says the macrobleed rate of 3.6% is “too high for comfort.” He believes the FDA should require labeling to insist that lecanemab is not given “concomitantly with anticoagulants or other significant blood thinners.” And, adds Schrag, “it may be reasonable to limit its use in patients who [have two copies] from APOE4.”
However, others say the lecanemab data presented so far is largely reassuring. “It is very difficult to draw a conclusion in individual cases about what causes what,” says Frederik Barkhof, a neuroradiologist at University College London and Amsterdam University Medical Center. He was not involved in the lecanemab trial discussed yesterday, but is on the data safety monitoring board (DSMB) for another ongoing trial with the antibody. “If I were on the DSMB for this trial, I would ask for more details” about the affected patients, he says. “Show me scans, show me history” in hopes of understanding whether other health conditions may have caused the bleeding, or whether an experimental therapy was likely the culprit.
Barkhof takes comfort in the fact that the trial did not have a “super clean population”. That’s a better reflection of who could get the antibody if approved, he says. For example, the trial included many people with chronic conditions such as diabetes, atrial fibrillation and high blood pressure, who may have been taking multiple medications. While Barkhof suspects that “there is an increased risk of bleeding” for people taking both lecanemab and anticoagulants, he also notes that many with early Alzheimer’s may be comfortable with that risk calculation.
“We have to keep in mind that we are dealing with a deadly disease,” Sharon Cohen, a behavioral neurologist with the Toronto Memory Program and investigator of the lecanemab study, said at a news conference yesterday. “If you ask patients what risk they are willing to take with this disease, you might be surprised.”
A previous antibody from Eisai and its partner Biogen, aducanumab (marketed as Aduhelm), was approved by the FDA earlier this year, overruling the recommendation of its own advisory committee of independent Alzheimer’s experts. The Centers for Medicare & Medicaid Services later refused to pay for the drug except within clinical trials, reducing its commercial potential. The FDA is expected to rule on lecanemab on January 6, 2023. Currently, no advisory committee meeting is scheduled, and an Eisai company official said yesterday that he was not aware of one in the works.