On Jan. 6, the U.S. Food and Drug Administration (FDA) approved a new drug to treat Alzheimer’s disease in its early stages.
Lecanemab, which will be available under the name Leqembi, can slow the cognitive decline associated with Alzheimer’s disease by 27%, according to data submitted to the FDA by the drug’s developers, Eisai and Biogen. It’s only the second medication to show any improvement in neurodegeneration, a key criterion in the FDA’s consideration for approval.
“For a long time, this is what we have been looking for,” says Dr. Sam Gandy, professor of neurology and psychiatry and director of the Mount Sinai Center for Cognitive Health (who was not involved in making or testing the drug). “We’d certainly like to see a larger benefit, but this is a step in the right direction.”
What is lecanemab?
Lecanemab is the latest in a long line of drugs that targets amyloid, a protein that builds up abnormally in the brains of people with Alzheimer’s. It works on a form of amyloid called protofibrils that are particularly toxic to brain neurons. The drug attaches to these pieces of amyloid, preventing them from clustering together to form the plaques that can compromise nerve function.
While the 27% improvement in cognitive test scores among the patients taking lecanemab compared to those receiving placebo over 18 months may not seem dramatic, it could slow decline enough to give patients months or even years of additional time with fewer memory problems.
That’s critical for people like Jerry Fair, who was diagnosed with Alzheimer’s in 2019 and participated in the trial of lecanemab at the Cleveland Clinic. “It’s not a cure-all,” he says. “But if we can slow [Alzheimer’s] down a little—if it gives us a little bit longer to be with our loved ones so we can recognize them—I’m all for it.”
What are the side effects of lecanemab?
The potential benefit for Alzheimer’s patients is tempered by some caution from experts about side effects related to the medication, including inflammation of the brain (which occurred in about 12.6% of people taking the medication in the studies) and bleeding in certain people. People who carry a genetic risk for Alzheimer’s in the ApoE gene are more vulnerable to the brain inflammation, known as ARIA (amyloid-related imaging abnormalities), which can be detected with regular brain scans and controlled with careful monitoring. The FDA’s approval includes a warning to doctors prescribing the drug about the risk of ARIA.
Several people involved in the drug’s trials have died, although researchers have not determined if lecanemab played a role in their deaths. The risk of bleeding was detailed most recently in a letter published in the New England Journal of Medicine on Jan. 4 by clinicians at Northwestern Feinberg School of Medicine. They described the case of a 65-year-old woman who had a genetic predisposition for Alzheimer’s and had participated in the Eisai study. She had a stroke after completing the 18-month study—during which it’s not known if she received lecanemab or placebo—and was participating in the next phase of the trial in which all participants receive the drug. She had completed three doses when she came to the emergency room with signs of stroke. Brain scans confirmed that diagnosis, and she was treated with an intravenous blood thinner called tissue plasminogen activator. She later died.
Whether lecanemab contributed to the multiple brain bleeding events she experienced isn’t clear yet, and Ivan Cheung, CEO of Eisai Inc, says the mortality among those receiving the drug in the studies is comparable to the rate among similarly aged people in the general population. But the case study highlights the importance of careful and considered prescribing of lecanemab for patients—especially those with genetic risk for Alzheimer’s, and those using certain medications to treat other conditions—that could potentially interact with the drug. Blood-thinning treatments were already known to interact negatively with anti-amyloid therapies like lecanemab.
Why Alzheimer’s drug treatments are historic—and controversial
Lecanemab is the second “disease-modifying” drug approved by the FDA to treat Alzheimer’s, which means it addresses one of the features—amyloid—of the disease. Other drugs used in Alzheimer’s patients, such as donepezil (Aricept) can minimize some of the memory symptoms of the the condition but don’t slow the gradual decline of brain nerve function. The only other approved disease-modifying Alzheimer’s drug, aducanumab, which also targets amyloid, showed less definitive benefit among those taking it compared to lecanemab. The data that the FDA reviewed about that drug’s efficacy was conflicting, with one study from Biogen, the drug’s developer, showing positive results and another negative, so doctors and patients in the Alzheimer’s community haven’t embraced the drug despite its approval in June 2021.
Whether lecanemab faces the same fate remains to be seen, but experts say the extensive and rigorous studies Eisai conducted that led to the FDA’s decision may give doctors and patients more confidence that lecanemab can slow the degeneration of neurons typical of Alzheimer’s. But it will be important to match the drug to the patients who are most likely to benefit — those with early signs of Alzheimer’s related cognitive issues. “I think it will require a change in the way Alzheimer’s is identified and diagnosed,” says Dr. Michael Irizarry, vice president of clinical research at Eisai Inc. With a drug like lecanemab, “it means physicians will have to evaluate for cognitive impairment earlier, and identify the cause of that impairment.”
Dr. Babak Tousi, head of the clinical trials program at the Cleveland Clinic Center for Brain Health (where patients participated in the trial for lecanemab), says it’s important to remember that the drug does not reverse damage to nerve function in the brain, but slows down the process driving the disease, so such screening could identify more people who could potentially benefit, and even lead to greater improvement over time. “It would be interesting to see if patients continue receiving the treatment for a longer period of time, whether they will see even more benefit compared to people not being treated,” he says. Fair, the patient who participated in the trial, doesn’t know if he received the drug or a placebo during the study, but he is now in the open-label part of the trial and will get lecanemab over 18 months. He and his wife don’t feel his memory issues have worsened since his diagnosis, and that’s an important achievement. Like Fair, patients in the study were considered to be in the early stages of Alzheimer’s and received the drug once every two weeks for 18 months by infusion, which means that any patients prescribed the drug will need to go to either their doctor’s office or an infusion clinic for their doses.
How much lecanemab will cost, and who will pay for it
Cost will be another factor determining how well the drug is received. Aducanumab’s high price of $56,000 a year proved to be a deterrent, especially when the Centers for Medicare and Medicaid Services (CMS) decided not to reimburse for the treatment unless people received the drug as part of a research study. That decision applied to all future anti-amyloid therapies that received accelerated, and not standard approval, which now includes lecanemab. The agency has said it would consider changing that policy, but only after the FDA grants full approval of lecanemab; Eisai’s Cheung says the company is currently working on submitting that request to the FDA for traditional approval.
CMS’s decision could be harmful to Alzheimer’s patients, says Maria Carrillo, chief science officer at the Alzheimer’s Association. “We estimate that each day, more than 2,000 individuals over age 65 years transition from mild dementia due to Alzheimer’s to a more advanced stage where they are no longer eligible for [drugs like lecanemab],” she says. “That’s unacceptable. If we have to wait eight months or more [for coverage], then how many thousands of individuals will be rendered ineligible? We feel that’s wrong.” The Association submitted a request last December to CMS to reconsider its policy and begin reimbursing for anti amyloid drugs like lecanemab upon accelerated approval.
Reimbursement by insurers, who normally follow CMS’s lead, will be critical for access in this population. Eisai announced that lecanemab would cost $26,500 a year initially. While that’s half of adcanumab’s cost, it still puts the treatment out of reach for most patients if it isn’t reimbursed.
Lecanemab—and other Alzheimer’s drugs—are still being studied
Lecanemab was approved under FDA’s accelerated approval process, which allows the agency to approve drugs when there is an unmet medical need—and with different standards than are usually required—if early safety and efficacy information is compelling enough. In lecanemab’s case, Eisai’s robust phase 2 studies, which showed the 27% improvement in cognitive skills, were enough for the FDA to consider the company’s request for approval, even while the last phase 3 stage of testing continued.
The hope is that lecanemab’s success will spawn more effective anti-amyloid therapies, as well as other treatments (targeting proteins like tau, for example, which are is also toxic in brain neurons) that in combination could hold off the most damaging processes of the disease. If these therapies are started earlier in the course of disease, before symptoms of memory loss or cognitive decline appear, it may be possible to avoid the devastating effects of neurodegeneration altogether. “We don’t have that yet, but that would be the ultimate goal,” says Gandy. Eisai is also conducting studies of lecanemab in people who are more vulnerable to developing Alzheimer’s, such as those with certain genetic risk factors, but have not shown signs of memory or other cognitive symptoms yet. The study will provide hints about whether it’s possible to delay or even prevent the disease altogether.
“I wouldn’t wish this [disease] on anybody,” says Fair. “I hope someday there’s a cure for [Alzheimer’s]. But you’ve got to take small steps in the beginning.”