The U.S. Food and Drug Administration (FDA) has approved lekanemab, the second-ever treatment for Alzheimer’s disease, designed to target the cause of the disease and slow cognitive decline. Scientists welcome the decision, but emotions are overshadowed by patient deaths and reports that the FDA was wrong to approve the first such drug last year.
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By slowing the progression of the disease when taken in the early stages of Alzheimer’s, druganemab will provide individuals with “more time to participate in everyday life and live independently,” said Joanne Pike, president and chief executive officer of the Alzheimer’s Association in Washington, DC, in a statement.
Lecanemab, which will be marketed under the brand name Leqembi, is the first Alzheimer’s drug to slow cognitive decline in a robust clinical trial, and the second to be approved in less than two years. It is made by biopharmaceutical companies Eisai in Tokyo, Japan and Biogen in Cambridge, Massachusetts. The drug, a monoclonal antibody, is given to patients by intravenous infusion, enters the brain and removes amyloid plaques, which are thought to cause cognitive decline and dementia in Alzheimer’s disease.
“The findings offer hope for patients and their families, but they are also an important step in developing effective ways to modify the clinical onset of the disease and prevent it,” said Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix, Arizona.
Lecanemab has been approved under the agency’s “accelerated approval” procedure, which is reserved for treating diseases that have few treatment options; it also does not require Phase III clinical trial data. However, the researchers hope Biogen and Eisai’s Phase III data were released in November 2022.1. This study, conducted in about 1,800 people with early-stage Alzheimer’s disease, showed that the antibody slowed cognitive decline by 27% over 18 months of treatment.
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FDA decision does not include Phase III study – Biogen and Eisai requested fast-track approval based on the Phase II data they submitted prior to the announcement of the latest study results. The phase II study showed that druganemab reduced the number of atherosclerotic plaques in the brains of 856 patients, but whether this affected the patients’ cognitive abilities was not assessed. This is the same pathway used to approve its predecessor, aducanumab, a similar antibody also made by Biogen and Eisai.
It is not clear what impact this 27% effect will have on the lives of people with Alzheimer’s – or whether the effect will persist after 18 months. That could mean, says Reiman, “an extra 6 months of recognizing the face of a loved one or doing a worthwhile activity.” But that will require future research, he says. Meanwhile, the FDA says that druganemab is only to be used in people with mild cognitive impairment – the same cohort used in clinical trials.
Diana Zuckerman, president of the National Center for Health Research, a Washington-based nonprofit, isn’t sure if the benefits 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 in terms of their health and finances, he says. Eisai says that a year of lekanemab will cost $26,500 in the US.
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In recent months, Science and STAT news reported three people who were enrolled in a phase III study of drugemab and then died during the extension phase of the study, when patients receiving a placebo can request administration of the drug. They died from complications including brain bleeding and seizures. According to these reports, researchers believe the patients may have died from a set of conditions known as amyloid-associated imaging abnormalities (ARIAs). They suspect the antibody weakened blood vessels in the brain by attacking the amyloid plaques lining them. All patients were taking anticoagulants at that time, which could have intensified the bleeding.
Eisai said it was inappropriate to draw conclusions based on individual cases and that he reported the deaths to the FDA as required. Nevertheless, FDA approval requires lekanemab to carry an ARIA warning, and doctors monitor the condition, which it says is rarely serious or life-threatening.
The controversy over aducanumab, which the FDA granted accelerated approval on June 7, 2021, cast a shadow over lekanemab. Many researchers believed that aducanumab, which is also branded as Aduhelm, did not show a strong signal of cognitive decline. The FDA’s own scientific advisory panel advised against approving the antibody by an 8–1 vote, and three panel members resigned after the FDA approved it anyway. The FDA did not hold a public advisory meeting for lecanemab prior to its approval.
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Since the approval of aducanumab, Biogen and the FDA have come under further scrutiny that has limited the implementation of the treatment. A congressional investigation released last month found that the agency violated its own rules by improperly guiding Biogen through the aducanumab approval process. The report said the trial was “riddled with irregularities” and raised “serious concerns about the FDA’s protocol lapses and Biogen’s disregard for effectiveness,” but did not impose any penalty on the FDA or the companies.
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The U.S. Centers for Medicare and Medicaid Services (CMS) has refused to cover federal insurance plans with aducanumab unless a person is enrolled in a clinical trial, leaving most patients with more than $28,000 for a year of treatment. CMS – and several clinics that refused to prescribe the drug – cited its dubious effectiveness, drawing the ire of advocacy groups who say it should be readily available.
Despite the controversy, Reiman hopes that the success of lekanemab will open the door to faster drug approvals in the future. He is currently working with pharmaceutical company Eli Lilly to test a similar monoclonal antibody, donanemab, in a Phase III trial, which he says has shown promise so far. The FDA is expected to decide whether to approve donanemab in the coming weeks.