The hotly anticipated results of a clinical trial of an experimental Alzheimer’s drug suggest that the treatment slowed cognitive decline somewhat for people in the early stages of the disease but also caused some patients to experience brain swelling or brain bleeding.
The new data, released Tuesday evening, offered the first detailed look at the effects of the drug, lecanemab, and comes two months after its manufacturers, Eisai and Biogen, stoked excitement by announcing that the drug had shown positive results.
Alzheimer’s experts said the new information showed reason for both optimism and caution.
“The benefit is real; so too are the risks,” said Dr. Jason Karlawish, a co-director of the University of Pennsylvania’s Penn Memory Center, who was not involved in the research.
A report of the findings published in the New England Journal of Medicine said that over 18 months, lecanemab “resulted in moderately less decline on measures of cognition and function,” compared with patients receiving a placebo. Still, the study of nearly 1,800 patients with mild symptoms, which was funded by the companies and co-written by scientists at Eisai, concluded that “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”
The companies’ initial announcement in September had sent their stock prices soaring because the field of Alzheimer’s drug development has been marked by years of failures.
It also followed months of controversy over the Food and Drug Administration’s decision last year to approve another Alzheimer’s drug, Aduhelm, also manufactured by Biogen, despite studies that did not prove the treatment worked and showed it carried significant safety risks. After Medicare decided to sharply limit its coverage of Aduhelm, citing risks and unclear benefit, the expensive drug was essentially sidelined from the marketplace.
Like Aduhelm, lecanemab — given as an intravenous infusion every two weeks — is a monoclonal antibody that targets a protein, amyloid, which clumps into plaques in the brains of people with Alzheimer’s. Years of trials of various anti-amyloid compounds have not conclusively shown that clearing or reducing levels of the protein can help patients’ memory or thinking problems. Earlier this month, another anti-amyloid monoclonal antibody, gantenerumab, made by Roche and Genentech, failed to show any cognitive benefit.
That history gives the lecanemab trial added significance, marking the first time that attacking amyloid has clearly correlated with a slower rate of cognitive decline, experts say. But because the rate was not dramatically slower, several doctors who treat Alzheimer’s questioned whether the effect would be noticeable to patients or their families.
The clinical trial found that after 18 months, patients receiving lecanemab declined 27 percent slower — a difference of 0.45 of a point on an 18-point cognitive scale.
“The clear issue is what does this small benefit mean in terms of meaningful change for patients and caregivers,” said Dr. Kristine Yaffe, a professor of neurology and psychiatry at the University of California, San Francisco, who was not involved in the study. “And how do we balance that” with significant safety risks, the requirement for frequent infusions and “what will be, undoubtedly, a high financial cost,” she said.
Dr. Madhav Thambisetty, a neurologist and a senior investigator at the National Institute on Aging, said that “from the perspective of a scientist, it is exciting that an experimental treatment targeting brain amyloid in Alzheimer’s disease appears to slow cognitive decline.”
But, Dr. Thambisetty, who was not speaking on behalf of the federal aging agency, added: “From the perspective of a physician caring for Alzheimer’s patients, the difference between lecanemab and placebo is well below what is considered to be a clinically meaningful treatment effect.”
About six million people in the United States and roughly 30 million globally have Alzheimer’s, a number expected to double by 2050. Lecanemab was tested on patients with mild cognitive impairment or early-stage Alzheimer’s, whose brains contained higher-than-normal levels of amyloid — a description that applies to about 1.5 million Americans.
The F.D.A. is expected to decide by Jan. 6 whether to grant lecanemab the type of approval it gave Aduhelm — a designation called “accelerated approval,” which can be given to drugs with uncertain benefit if they are for serious diseases with few treatments and attack a biological element of the disease. Accelerated approval requires companies to conduct further trials to prove whether the drug works.
Eisai, which was presenting its data Tuesday night at a conference in San Francisco, has said it will use the new information to seek full approval early next year if the the January decision is favorable.
“While the prediction is that the F.D.A. will approve lecanemab, there are issues of safety,” said Dr. Sam Gandy, an Alzheimer’s clinician who is director of the Mount Sinai Center for Cognitive Health and was not involved in the study.
Concerns about the safety of lecanemab — at least for some types of patients, especially those taking blood thinners — have been fueled recently by news reports of the deaths of two patients who experienced brain swelling and brain bleeding. Swelling and bleeding are known side effects of several anti-amyloid drugs. If lecanemab ends up being considered unsafe for people taking blood thinners, then tens of thousands of patients could be excluded.
The study published Tuesday reported six deaths among the trial’s 898 lecanemab patients and seven deaths among the 897 patients receiving placebo. The authors wrote that no deaths were considered to be related to lecanemab or to have occurred with brain swelling or bleeding.
The two recently reported deaths occurred after the 18-month randomized portion of the trial, so the deaths of those trial participants are not included in the study and it is not known if those patients received lecanemab or placebo during that time. But after the 18 months, both patients opted to receive lecanemab in an open-label extension study.
The patients, whose cases were reported by the journal Science and STAT, had other medical complications. One case involved a 65-year-old woman who suffered a stroke and, after receiving a standard treatment for stroke-related blood clots, suffered serious brain bleeding and died a few days later. A neuropathologist who conducted an autopsy at the request of the woman’s husband told the journal that lecanemab likely weakened her blood vessels and made them vulnerable to bursting when she received the blood-clotting treatment.
The other case involved a man in his late 80s who was taking a blood thinner for a heart condition and had also experienced falls and ministroke-like events shortly before his death.
In a statement, Eisai, citing the patients’ other medical conditions and blood-thinning medication, said, “It is Eisai’s assessment that the deaths cannot be attributed to lecanemab.” The company said that in the trial’s randomized and open-label phases, the total rate of deaths with major brain bleeds was 0.1 percent for patients in both the lecanemab and placebo groups.
Dr. Thambisetty said the two deaths add to questions about lecanemab’s safety issues “in real world clinical practice where patients are likely to be sicker and have multiple other medical conditions in contrast to carefully selected patients in clinical trials.”
Nonetheless, the data on lecanemab, which Dr. Gandy noted attacks a different form of amyloid than previously tested drugs do, showed significantly lower rates of swelling and bleeding than with Aduhelm.
Nearly 13 percent of patients receiving lecanemab experienced brain swelling, which was mild or moderate in most cases, while less than 2 percent of patients receiving the placebo experienced such swelling, the study reported. Most brain swelling did not cause any symptoms and generally resolved within a few months. About 17 percent of lecanemab patients experienced brain bleeding, compared with 9 percent of patients receiving the placebo. The most common symptom from brain bleeds was dizziness, the study said.
The authors reported that “serious adverse events” occurred in 14 percent of lecanemab patients and 11 percent of those receiving placebo. Nearly 7 percent of lecanemab patients dropped out of the trial because of negative side effects, more than twice the percentage of placebo recipients who dropped out. More than a quarter of the lecanemab patients experienced adverse infusion-related reactions, which included fever and flu-like symptoms, usually with the first dose. A much smaller percentage of placebo patients experienced those reactions, the study found.
The main positive outcome of the study was that lecanemab patients declined cognitively by 1.21 points, while patients receiving placebo declined by 1.66 points on the 18-point scale, which assesses functions like memory, problem-solving and daily activities via interviews with patients and caregivers.
This result was supported by secondary measures in the trial, including three other cognitive tests, bolstering the possibility that the drug is having a real effect, experts said. In addition, on all the measures, patients began showing slower decline several months after starting lecanemab, and the pace slowed further during the 18-month trial.
The trial made an effort to include more participants of color than have typically been enrolled in Alzheimer’s trials. About 25 percent of those who participated in the trial in the United States were Black or Hispanic, the study reported. It also allowed people with various medical conditions to participate, including hypertension, diabetes, heart disease, obesity and kidney disease.
Experts noted that because patients in trials are carefully monitored, implications for the general population of Alzheimer’s patients can be harder to predict.
Dr. Yaffe said that “of all the amyloid antibody trials, this one seems most clearly positive and convincing,” which, she added, can be considered “good news overall for the field.”
Still, for “real world” patients with more varied Alzheimer’s pathology, “the effect will be most likely even less,” she said, adding, “I wonder if there are some folks who really benefit, but this trial cannot say.”