In a crowded San Francisco conference room with an atmosphere of celebration, optimistic company representatives and scientists yesterday presented detailed clinical trial data on the first Alzheimer’s treatment that has been shown to modestly clearly slow the disease’s normal cognitive decline. Antibody therapy has sustained a decades-long field of failure. Now, it appears to be on the verge of approval by the U.S. Food and Drug Administration (FDA). Still, other researchers warn of potential risks, including brain swelling and brain hemorrhages, linked to the recently announced deaths of two trial participants who received antibodies. Officials from lead corporate sponsor Eisai Co. confirmed the two deaths yesterday, but denied they were caused by experimental therapy.
The Japanese company is developing the monoclonal antibody lecanemab to eliminate a protein called amyloid-beta in early-stage Alzheimer’s. The protein clumps in the brains of people with the disease and is commonly thought to cause neurodegeneration. Other antibodies and strategies followed removal of amyloid, but lecanemab was the first to do so, clearly delaying the onset of dementia symptoms. Many scientists and advocates hail these results as the strongest confirmation yet of the amyloid hypothesis of Alzheimer’s.
“New data confirms that this treatment can significantly alter the course of the disease for people in the early stages of Alzheimer’s,” the Alzheimer’s Association said in a statement.
A series of presentations and simultaneous presentations at the Conference on Clinical Research on Alzheimer’s Disease late Tuesday New England Journal of Medicine (NEJM), Eisai, his partner Biogen, and several researchers followed up in a September press release briefly detailing the results of the pivotal study of lecanemab involving 1795 early-stage Alzheimer’s patients. Yesterday’s talk and article confirmed the previous announcement that lecanemab given as a biweekly intravenous infusion slowed the rate of cognitive decline by 27% in people who took it for 18 months, compared to similar participants who took a placebo.
Extending this top ranking result, the lecanemab interviews and article revealed that, on an 18-point cognition ranking commonly used in dementia, the treated group started with an average of 3.17 points and worsened by 1.21 points at 18 months. The placebo group started at 3.22 and worsened by 1.66 points over the same period. (Higher scores mean more severe dementia.) Christopher van Dyck, director of Yale University’s Alzheimer’s Disease Research Unit, said the 0.45-point difference between the treated and untreated groups after 18 months of treatment was “quite statistically significant,” and study leader.
“Longer trials are warranted,” however, write Van Dyck and colleagues NEJM paper. The 18-month study ended in March 2021, and since then patients have been offered the chance to participate in an “extension” trial where they can receive a biweekly infusion of lecanemab if they choose.
According to regular brain scans of a group of participants, the antibody also managed to completely clear amyloid-beta. Van Dyck notes that a certain level of amyloid deposition in the brain is required to qualify for the trial, but that “at the end of 18 months, those in the treated group were ‘on average’ below the threshold… get them in the study in the first place.
But the key question that remains unanswered is whether this slowing of cognitive decline represents a meaningful improvement for people with Alzheimer’s disease. Neurologists disagree on whether the 0.45 difference on the dementia scale will be perceived by many patients or caregivers, and whether any cognitive advantage produced by the treatment will persist or improve with continued use of the antibody.
“I am not convinced that the treatment is ‘disease-modifying’,” Matthew Schrag, a neuroscientist and doctor at Vanderbilt University, wrote on Twitter. “Almost all of the treatment’s benefits emerged within the first year. The differences continue to grow larger over time,” he continued.
Schrag also tweeted, “I don’t think the benefits seen in this trial outweigh the risks, and despite the general excitement about a possible new treatment, I will advise my patients to keep waiting.”
One of Schrag’s concerns is that trial results 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, most people with these side effects did not notice symptoms, and changes were only detected with routine MRI scans.
In the new lecanemab trial, 2.8% of participants who received the antibody had brain swelling, which typically causes symptoms such as headaches, confusion, and vision problems. The risk of swelling and brain hemorrhage was higher in roughly 15% of participants who had two copies of a gene called APOE4This greatly increases the likelihood of Alzheimer’s disease.
The likelihood of complications may be particularly increased in Alzheimer’s patients who take anticoagulant drugs that are commonly prescribed to older people for various health problems. Marwan Sabbagh of the Barrow Institute of Neurology showed a slide at the end of his presentation on the safety of lecanemab yesterday showing that five out of 140 people, or 3.6%, had a brain “macro hemorrhage” that could be devastating, depending on its severity. on both lecanemab and anticoagulants. As reported by Science earlier this week and last month, two of those five patients were in the extension trial and died. STAT.
Two others, each taking an anticoagulant and lecanemab, suffered devastating brain injuries, according to a September study by French researchers. Overall, macrobleeds occurred much more frequently in patients receiving lecanemab plus anticoagulants than in patients receiving antibodies alone, according to data presented by Sabbagh.
Still, Sabbagh repulsed concerns that lecanemab may precipitate serious brain haemorrhages in some people. “There’s a lot of rumors … about security matters,” he said. But he argued there was no “cause of death” associated with the swelling, and typically only minor brain haemorrhage was associated with lecanemab. Two deaths reported STAT and ScienceHe suggested that stroke was caused in one patient, a 65-year-old woman, and a heart condition in another, an 87-year-old man.
Researchers not involved in the lecanemab trial, and even those involved, were more hesitant to clear the antibody. Nicolas Villain, a neurologist at the Sorbonne and co-author of the September paper, urged extreme caution when mixing lecanemab and anticoagulants. He is particularly concerned that Alzheimer’s patients who take lecanemab and subsequently have a stroke may die if they are treated with a common anticoagulant stroke drug called tPA. This therapy was applied to the 65-year-old woman who later died.
In an interview, Schrag says the 3.6% macro bleeding rate is “too high for comfort.” He believes the FDA should mandate labeling so that lecanemab “should not be given at the same time as anticoagulation or other important blood thinners.” And, Schrag adds, “it may make sense to restrict its use among patients who are sick. [have two copies] of the APOE4”
But others say the lecanemab data available so far is largely reassuring. “It’s very difficult to make an inference about what causes what in individual cases,” says Frederik Barkhof, a neuroradiologist at University College London and the University of Amsterdam Medical Centre. He was not involved in the lecanemab trial discussed yesterday, but is part of the data security monitoring board (DSMB) for another ongoing trial with the antibody. “If I were in DSMB for this trial, I would like more details on affected patients,” he says. “Show me the scans, show me the previous history” in hopes to see if other health issues are precipitating a bleeding or if the culprit is possibly an experimental treatment.
Barkhof is comforted by the fact that the case does not have a “super clean population.” That’s a better reflection of who might get the antibody if it’s 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 taken more than one medication. While Barkhof suspects “some increased risk of bleeding” for people taking both lecanemab and anticoagulants, he also notes that many people with early Alzheimer’s may be comfortable calculating this risk.
“We have to keep in mind that we’re dealing with a deadly disease,” Sharon Cohen, a behavioral neurologist and lecanemab trial researcher at the Toronto Memory Program, told a news conference yesterday. “If you ask patients what risk they are willing to take with this disease, you might be surprised.”
Aducanumab (marketed as Aduhelm), an earlier antibody from Eisai and his partner Biogen, was approved by the FDA earlier this year, overriding the recommendation of the agency’s own advisory committee of independent Alzheimer’s experts. Centers for Medicare & Medicaid Services later refused to pay for the drug outside of clinical trials, lowering its commercial potential. The FDA is expected to make a decision on lecanemab by January 6, 2023. No advisory committee meetings are scheduled at this time, and an Eisai company official said yesterday that he was not aware of the work.