FDA approves Alzheimer’s drug lecanemab amid safety concerns

Computer illustration of amyloid plaques among neurons.  Amyloid plaques are characteristic features of Alzheimer's disease.

Protein clumps called amyloid plaques (gold, among blue neurons in this data illustration) are a hallmark of Alzheimer’s disease.Credit: Juan Gaertner/Science Photo Library

The US Food and Drug Administration (FDA) has approved lecanemab, the second-ever treatment for Alzheimer’s disease intended to tackle the root of the condition and slow cognitive decline. Scientists welcome the decision, but the excitement is overshadowed by patient deaths and reports that the FDA acted incorrectly when it approved the first such drug last year.

By slowing the progression of the disease when taken in the early stages of Alzheimer’s, lecanemab will allow individuals to have “more time to participate in daily life and live independently,” said Joanne Pike, president and CEO of the Alzheimer’s Association in Washington, DC. in a statement.

Lecanemab, which will be sold under the brand name Leqembi, is the first Alzheimer’s treatment to slow cognitive decline in a robust clinical trial and the second to be approved in less than two years. It is made by the biopharmaceutical companies Eisai, in Tokyo, Japan, and Biogen, in Cambridge, Massachusetts. The drug, a monoclonal antibody, is infused intravenously into patients, enters the brain and removes the amyloid plaques believed to cause cognitive impairment and dementia in Alzheimer’s.

“The findings provide hope for patients and families, but it is also an important step in the development of successful ways to modify and prevent the clinical onset of the disease,” says Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix, Arizona.

Unclear influence

Lecanemab was authorized under the agency’s “accelerated approval pathway,” which is reserved for therapies for diseases that have few treatments; nor does it require data from phase III clinical trials. But researchers are hopeful about Biogen and Eisai’s phase III data, which was published in November 20221. This study, conducted on around 1,800 people with early-stage Alzheimer’s, found that the antibody slowed cognitive decline by 27% over 18 months of treatment.

The FDA’s decision does not take into account the phase III study – Biogen and Eisai requested accelerated approval based on phase II data, which they submitted before the latest trial results were announced. The phase II study found that lecanemab reduced plaque in the brains of 856 patients, but did not assess whether this affected the patients’ cognitive abilities. This is the same pathway used to approve its predecessor, aducanumab, a similar antibody also made by Biogen and Eisai.

It is unclear what impact the 27% effect will have on the lives of people with Alzheimer’s – or whether that effect will persist after 18 months. That could mean, says Reiman, “an extra 6 months of recognizing a loved one’s face, or performing a valued activity”. But that will require future research, he says. Meanwhile, the FDA says, lecanemab should only be used in people with mild cognitive impairment — the same cohort as in the clinical trials.

Treatment risk

Diana Zuckerman, president of the National Center for Health Research, a nonprofit organization in Washington, DC, isn’t sure the benefit will be worth the risk. “You’re dealing with people with mild cognitive impairment who are functioning, and you’re putting them at risk,” both health-wise and financially, she says. Eisai says that a year of lecanemab will cost $26,500 in the United States.

The last few months have Science and STAT News reported three people who had been enrolled in the phase III study of lecanemab and then died during the extension phase of the study, when patients receiving placebo can request to receive the drug. They died of complications involving cerebral hemorrhage and seizures. According to these reports, researchers believe the patients may have died due to a set of conditions known as amyloid-related imaging abnormalities (ARIA). They suspect that the antibody weakened the blood vessels in the brain as it attacked the amyloid plaques lining them. All patients were taking anticoagulants at the time, which may have worsened the bleeding.

Eisai has said it is inappropriate to draw conclusions based on individual cases and that it reported the deaths to the FDA as required. Still, the FDA’s approval requires lecanemab to include a warning about ARIA, and for doctors to monitor the condition, which it says is rarely serious or life-threatening.

The controversy surrounding aducanumab, which the FDA granted accelerated approval on June 7, 2021, has cast a shadow over lecanemab. Many researchers believed that aducanumab, which also goes by the brand name Aduhelm, did not show a strong signal of cognitive decline. The FDA’s own scientific advisory panel recommended not approving the antibody by a vote of 8–1, and three panel members resigned after the FDA approved it anyway. The FDA did not hold a public advisory meeting for lecanemab before it was approved.

In aducanumab’s shadow

Since aducanumab’s approval, Biogen and the FDA have come under further scrutiny that has limited the rollout of the treatment. A congressional investigation released last month found that the agency had violated its own rules by improperly guiding Biogen through the aducanumab approval process. The report said the process was “riddled with irregularities” and raised “serious concerns about the FDA’s lapses in protocol and Biogen’s disregard for efficacy,” but did not impose any penalties on the FDA or the companies.

The US Centers for Medicare and Medicaid Services (CMS) has refused to cover aducanumab under federal insurance plans unless a person is enrolled in a clinical trial, and most patients must pay more than $28,000 for a year’s treatment. CMS — and several clinics that refused to prescribe the drug — cited its questionable efficacy, drawing the ire of advocacy groups that say it should be readily available.

Despite the controversy, Reiman hopes that lecanemab’s success will open the way for more accelerated approvals in the future. He is currently working with the pharmaceutical company Eli Lilly to test the similar monoclonal antibody, donanemab, in a phase III trial that he says is promising so far. The FDA is expected to decide whether to approve donanemab in the coming weeks.

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