Long-awaited results from a clinical trial of an experimental Alzheimer’s drug suggest that the treatment slowed cognitive decline somewhat in people in the early stages of the disease, but also caused some patients to experience brain swelling or brain bleeding.
The new data, released on Tuesday, offer the first detailed look at the effects of the drug, lecanemab, and come two months after its makers, Eisai and Biogen, were excited to announce that the drug had shown positive results.
Alzheimer’s experts said the new information gives cause for optimism and caution.
“The benefit is real; so are the risks,” said Jason Karlawish, co-director of the Penn Memory Center at the University of Pennsylvania, 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 a moderately smaller decline in measures of cognition and function” compared with patients receiving placebo. Still, the company-funded study of nearly 1,800 patients with mild symptoms, co-written by Eisai scientists, concluded that “longer trials are needed to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”
The companies’ initial announcement in September sent their stock prices soaring as the field of Alzheimer’s drug development has been marred by years of failure.
There have also been months of controversy over the FDA’s decision last year to approve another Alzheimer’s drug, Aduhelm, also made by Biogen, despite studies that failed to prove the treatment works and showed risks. significant to security. After Medicare decided to sharply limit its coverage of Aduhelm, citing unclear risks and benefits, the expensive drug was essentially pulled from the market.
Like Aduhelm, lecanemab — given by intravenous infusion every two weeks — is a monoclonal antibody that targets a protein, amyloid, that builds up in plaques in the brains of people with Alzheimer’s. Years of testing various anti-amyloid compounds have not conclusively shown that eliminating or reducing levels of the protein can help patients with memory or thinking problems. Earlier this month, another anti-amyloid monoclonal antibody, gantenerumab, made by Roche and Genentech, did not show any cognitive benefit.
That story gives the lecanemab study added significance, marking the first time that amyloid attack was clearly correlated with a slower rate of cognitive decline, experts say. But because the rate wasn’t drastically slower, several doctors who treat Alzheimer’s disease questioned whether the effect would be noticeable for patients or their families.
The clinical trial found that after 18 months, patients receiving lecanemab declined 27% more slowly — a difference of 0.45 points on an 18-point cognitive scale.
“The clear question is, what does this small benefit mean in terms of meaningful change for patients and caregivers?” said Kristine Yaffe, 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 undoubtedly be a high financial cost,” she said.
Madhav Thambisetty, a neurologist and senior investigator at the National Institute on Aging, said, “From a scientist’s perspective, it’s exciting that an experimental treatment targeting cerebral amyloid in Alzheimer’s disease appears to slow cognitive decline.”
But Thambisetty, who did not speak on behalf of the federal aging agency, added: “From the point of view of a physician caring for patients with Alzheimer’s, the difference between lecanemab and placebo is well below what is considered a clinically significant treatment effect. “.
About 6 million people in the United States and about 30 million worldwide have Alzheimer’s, numbers that are expected to double by 2050. Lecanemab was tested in patients with mild cognitive impairment or early-stage Alzheimer’s whose brains contained levels above the normal amyloid —a description that applies to about 1.5 million Americans.
The FDA is expected to decide by Jan. 6 whether to grant lecanemab the kind of approval it gave Aduhelm — a designation called “accelerated approval,” which can be given to drugs with uncertain benefits if they are for serious illnesses with few treatments and attack a biological element of the disease. Accelerated approval requires companies to conduct more tests to prove the drug works.
Eisai, which presented its data late on Tuesday at a conference in San Francisco, said it would use the new information to seek full approval early next year if the January decision is favourable.
“Although the FDA is expected to approve lecanemab, there are safety concerns,” said 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 recently been fueled by news reports about the deaths of two patients who had brain swelling and brain hemorrhage. Swelling and bleeding are known side effects of many anti-amyloid medications. If lecanemab turns out to be unsafe for people taking blood thinners, tens of thousands of patients could be excluded.
The study published on Tuesday reported six deaths among 898 patients taking lecanemab and seven deaths among 897 patients taking placebo. The authors wrote that no deaths were considered to be lecanemab-related or occurred with brain swelling or bleeding.
The two newly reported deaths occurred after the randomized 18-month portion of the study, so the deaths of these study participants are not included in the study and it is unknown whether they received lecanemab or placebo during this period. But after 18 months both patients opted to receive lecanemab in an open-label extension study.
The patients, whose cases were reported by Science and STAT, had other medical complications. One case involved a 65-year-old woman who suffered a stroke and, after receiving standard treatment for stroke-related blood clots, she suffered severe brain hemorrhaging and died a few days later. A neuropathologist who performed an autopsy at the request of the woman’s husband told the paper that the 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 an anticoagulant for a heart condition and also suffered falls and small stroke-like events shortly before his death.
In a statement, Eisai, citing the patients’ other medical conditions and blood-thinning medications, said: “It is Eisai’s assessment that the deaths cannot be attributed to lecanemab.” The company said that in the randomized, open-label phases of the study, the overall rate of death from major brain bleeds was 0.1% for patients in the lecanemab and placebo groups.
Nearly 13% of patients receiving lecanemab experienced brain swelling, which was mild or moderate in most cases, while less than 2% of patients receiving placebo experienced such swelling, the study reported. Most brain swelling does not cause any symptoms and usually resolves within a few months. About 17% of patients on lecanemab experienced brain bleeding, compared with 9% of patients on placebo. The most common symptom of brain hemorrhage was dizziness, the study said.
The authors reported that “serious adverse events” occurred in 14% of patients on lecanemab and 11% of those on placebo. Nearly 7% of lecanemab patients dropped out of the study because of negative side effects, more than double the percentage of placebo recipients who dropped out. More than a quarter of lecanemab patients experienced infusion-related adverse reactions, which included fever and flu-like symptoms, usually with the first dose. A much smaller percentage of placebo patients experienced these reactions, the study found.
The main positive result of the study was that patients on lecanemab had a cognitive decline of 1.21 points, while patients receiving placebo declined 1.66 points on the 18-point scale, which assesses functions such as memory, problem solving and daily activities. , through interviews with patients and caregivers.
That 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. Furthermore, on all measures, patients began to show a slower decline several months after starting lecanemab, and the pace slowed further during the 18-month study.
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