As some hail new antibody treatment for Alzheimer’s, safety and benefit questions persist

In a packed San Francisco conference room with a celebratory atmosphere, upbeat company representatives and scientists yesterday presented detailed clinical trial data on the first Alzheimer’s treatment shown to clearly, albeit modestly, slow the disease’s normal cognitive decline. The antibody therapy has buoyed a field marked by decades of failures. Now, it appears to be on the cusp of being greenlit by the U.S. Food and Drug Administration (FDA). Yet other researchers warn of potential risks, including brain swelling and brain hemorrhages that were linked to the recently disclosed deaths of two trial participants who received the antibody. Officials from the lead company sponsor, Eisai Co., confirmed the two deaths yesterday, but denied that they resulted from its experimental therapy.

The Japanese company has been developing the monoclonal antibody lecanemab to remove a protein called amyloid-beta in early-stage Alzheimer’s. The protein clusters in the brains of people with the disease and is widely thought to cause its neurodegeneration. Other antibodies and strategies have chased amyloid’s removal, but lecanemab is the first to do so and clearly delay the onset of dementia symptoms. Many scientists and advocates are hailing these results as the strongest validation yet of the amyloid hypothesis of Alzheimer’s.

The new data “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s,” 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 simultaneously released in The New England Journal of Medicine (NEJM), Eisai, its partner Biogen and several researchers followed up on a September press release that had briefly detailed the results of the pivotal lecanemab trial, which included 1795 early-stage Alzheimer’s patients. Yesterday’s talks and paper confirmed the earlier announcement that lecanemab, which was given by intravenous infusion every other week, slowed the rate of cognitive decline by 27% in people taking it for 18 months, compared with similar participants on a placebo.

Expanding on that topline result, the lecanemab talks and paper revealed that on an 18-point cognition ranking often used in dementia, the treated group started with an average score of 3.17 and worsened by 1.21 points over 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.) That difference of 0.45 points 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 leader of the study.  

“Longer trials are warranted,” van Dyck and colleagues nevertheless write in the NEJM paper. The 18-month study ended in March of 2021, and since then patients have been offered the chance to participate in an “extension” trial in which they can all receive infusions of lecanemab every other week if they wish.

The antibody also succeeded at thoroughly mopping up amyloid-beta, according to regular brain scans of a subset of participants. A certain level of amyloid buildup in the brain was necessary to qualify for the trial, van Dyck noted, but “at the end of 18 months those in the treated group” were, on average, “below the threshold … that would get them into the study in the first place.”  

But a key question, still unanswered, is whether such 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 perceptible to many patients or caregivers—and whether any treatment-produced cognitive advantage will persist or improve with continued use of the antibody.

“I am not convinced the treatment is ‘disease modifying,’” Matthew Schrag, a neuroscientist and physician at Vanderbilt University, wrote on Twitter.  “Almost all of the benefit of treatment occurred in the first year. With disease-modifying treatments, the differences continue to become bigger over time,” he continued.  

“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,” Schrag also tweeted.

One of Schrag’s concerns is that the trial results also show that, like other antibodies that target amyloid protein, lecanemab carries a significant risk of brain swelling and bleeding, especially in the months after starting treatment. Many of the people who had these side-effects did not notice symptoms, however, and the changes were only picked up by routine MRI scans.

In the new lecanemab trial, 2.8% of participants on the antibody had brain swelling that did produce symptoms, typically headache, confusion, and visual problems. The risk of swelling and brain bleeding was higher for the roughly 15% of participants who had two copies of a gene called APOE4, which greatly heightens the likelihood of Alzheimer’s disease.

The chance of complications may be especially elevated for Alzheimer’s patients taking anticoagulant drugs, which are commonly prescribed to older people for various health concerns. At the end of his presentation on lecanemab’s safety yesterday, Marwan Sabbagh of the Barrow Neurological Institute showed a slide indicating a brain “macro hemorrhage”, which can be devastating depending on its severity, occurred in five out 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 earlier this week by Science and last month by STAT.

Two others, who each received anti-coagulants and lecanemab, suffered devastating brain injuries according to a September study by French researchers. In general, the macro hemorrhages occurred much more frequently in patients who took anti-coagulants along with lecanemab than those getting the antibody alone, data presented by Sabbagh indicated.

Yet Sabbagh pushed back against concerns that lecanemab precipitates severe brain bleeds in some people. “There’s been a lot of buzz … around safety-related issues,” he said. But there were “no causes of death” related to the swelling and typically only minor brain bleeding was associated with lecanemab, he argued. The two deaths disclosed by STAT and Science, he suggested, were caused by the stroke in one patient, a 65-year-old woman, and a heart condition in the other, an 87-year-old man.

Researchers not involved in the lecanemab trial—and even one who is—were more hesitant to absolve the antibody. Nicolas Villain, a neurologist at the Sorbonne who is one of the trial investigators and also co-authored the September paper, urged great caution on mixing lecanemab and anticoagulants. He’s especially worried that Alzheimer patients who are on lecanemab and then have a stroke could die if treated with the common clot-busting stroke drug called tPA. This therapy was administered to the 65-year-old woman who subsequently died.  

In an interview, Schrag says the 3.6% macro hemorrhage rate is “too high for comfort.” He believes FDA should require labeling urging that lecanemab not be “given concurrently with anticoagulation or other significant blood thinners.” And, Schrag adds, “it may be reasonable to restrict its use among patients who [have two copies] of APOE4.”  

Others, however, say the lecanemab data presented so far are largely reassuring. “It’s very difficult in individual cases to make an inference on 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 part of the data safety monitoring board (DSMB) for another ongoing trial with the antibody. “If I was on the DSMB for this trial, I would ask for more details” on the affected patients, he says. “Show me scans, show me previous history” in hopes of understanding whether other health problems may have precipitated a hemorrhage, or whether an experimental therapy was likely the culprit.

Barkhof is comforted by the fact that the trial did not have a “super-clean population.” That’s a better reflection of who might receive 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 been on multiple medications. While Barkhof suspects “there’s some increased risk of bleeding” for people on both lecanemab and anticoagulants, he also notes that many with early Alzheimer’s may be comfortable with that risk calculus.

“We need to keep in mind that we are dealing with a fatal disease,” said Sharon Cohen, a behavioral neurologist at the Toronto Memory Program and investigator on the lecanemab trial, during a press conference yesterday. “If you ask patients what risk they’re willing to take with this disease, you may be surprised.”

A previous antibody from Eisai and its partner Biogen, aducanumab (marketed as Aduhelm) was approved earlier this year by FDA, overruling the recommendation of the agency’s own advisory committee of independent Alzheimer’s experts. The Centers for Medicare & Medicaid Services later declined to pay for the drug except within clinical experiments, sinking its commercial potential. FDA is expected to rule on lecanemab by 6 January 2023. Currently, no advisory committee meeting is scheduled, and an Eisai company official said yesterday he was not aware of one in the works.

 Source link

Back to top button