The U.S. Food and Drug Administration (FDA) today approved a controversial Alzheimer’s disease treatment for broad use—with caveats. The drug, an antibody called lecanemab, is the first to clearly slow cognitive decline in patients with early-stage disease, fueling excitement in the Alzheimer’s field and hope for patients and families. But its benefits appear modest, and it comes with potentially serious side effects, including brain swelling and bleeding. At least three people taking lecanemab in a clinical trial died after brain bleeds or swelling and some others had serious brain injuries. The drug’s makers, Eisai and Biogen, say lecanemab wasn’t necessarily at fault.
In a nod to safety concerns, the drug’s label will include a warning about developing a type of brain swelling or bleeding called ARIA, which stands for amyloid-related imaging abnormalities, and recommend that anyone taking lecanemab have three MRIs in roughly the first 6 months of treatment to watch for those side effects. The label also suggests “additional caution” be exercised in giving blood thinners to patients on lecanemab, which may heighten the risk of brain bleeds. Two of the trial participants who died had also been given such drugs.
Today’s announcement is unlikely to heal deep divisions over whether lecanemab is a breakthrough for Alzheimer’s patients and their families, or a risky drug with limited benefits. The approval comes under FDA’s “accelerated approval” pathway for conditions with unmet medical needs. The companies had applied last summer based on early evidence of benefit from the antibody. Since then, the firms have reported and published results from a pivotal trial of lecamenab in nearly 1800 people, and Eisai has announced plans to file for traditional, full FDA approval by the end of March.
A looming question is whether and when the Centers for Medicare & Medicaid Services (CMS), the federal agency that pays for many treatments for older Americans, will reimburse for lecanemab—key to its uptake among potential recipients in the United States. In April 2022, CMS announced it would decline to reimburse for another Alzheimer’s antibody, aducanumab, also made by Biogen and Eisai, except in the context of certain clinical trials. Both drugs help clear away or prevent the creation of amyloid plaques, a buildup in the brain of a protein widely thought to drive the cognitive decline and other symptoms of Alzheimer’s disease. But the evidence of clinical benefit is weaker for aducanumab. CMS also said it would only consider covering drugs in this class after full FDA approval.
At an Alzheimer’s meeting in San Francisco last month, Maria Carrillo, a neuroscientist and chief science officer of the Alzheimer’s Association, argued that CMS ought to back lecanemab and all drugs given FDA’s blessing. “Any drug that receives accelerated approval should be covered by CMS,” she said.
Lecanemab is “a win for all of us,” Carrillo said at last month’s meeting. There, the mood was celebratory even as reservations about lecanemab simmered. Last month, a letter describing lecanemab as a “foundational advance” began collecting signatures from researchers and medical practitioners; to date, nearly 230 people have signed it. “Every day of delay in patient access to this therapy may result in treatable patients progressing,” the letter reads. (Many, but not all, signers are recent consultants or grant recipients of Eisai or Biogen.)
“I’m of the side that it’s not perfect, but it’s a step in the right direction,” says Joy Snider, a neurologist and head of the Knight Alzheimer’s Disease Research Center Clinical Trials Unit at Washington University School of Medicine in St. Louis. Snider was one of the researchers on the recently published phase 3 lecamenab study and a cosigner of the letter.
But although Snider is excited about the drug, she also stresses that it should be “only the beginning,” and she hopes other, better therapies will follow. Among other concerns, Snider worries about lecanemab’s potentially high cost. After the FDA approval, Eisai suggested it would have an annual cost of more than $25,000 for an average person, with additional costs for its infusions and monitoring. The antibody must be given intravenously every 2 weeks and the repeated MRI scans recommended by FDA will be expensive.
Among lecanemab’s opponents is neurologist Alberto Espay of the University of Cincinnati. He believes the benefits of lecanemab across a population are minimal and its risks significant, and recently co-authored a preprint with 11 other academics expressing such concerns. “I think this drug should not be approved,” said Espay in an interview the day before FDA’s announcement. But agency officials, he added, “are victims of an artificially low bar” they set in 2021 by greenlighting aducanumab. FDA’s own advisory committee had voted against that approval but was overruled. Just last week, a congressional report described FDA’s approval process for aducanumab as “rife with irregularities.”
When it came to lecanemab, FDA did not turn to its advisory committee for guidance despite calls from some scientists and the drug watchdog Public Citizen to do so.
Clinical trials showed lecanemab was remarkably efficient—more so than aducanumab—in mopping up amyloid plaques. But the drug’s effects on cognition were modest: On a commonly used 18-point cognition scale, derived from the experience of patients and their caregivers, those getting the drug on average declined 0.45 points less than those getting placebo after 18 months. Neurologists disagree over whether and to what extent patients and caregivers would perceive this lesser decline. Snider believes it would likely be noticeable. For example, on the part of the scale that assesses orientation, she says, an individual who scores 0.5 “can still drive” and get around independently. “If you go to a one, you’re going to start getting lost.”
The most serious hazard for those on lecanemab appears to be ARIA, which has been seen with other antiamyloid drugs tested in clinical trials. Although Eisai has stressed that the numbers of deaths were similar in the placebo and lecanemab-treated groups in the antibody’s latest trial, some scientists have linked the drug to the catastrophic brain bleeds and swelling, including in three people who died after receiving the drug during an extension of the phase 3 trial. STAT reported one, involving a man in his 80s, in October 2022 and Science described the deaths of a 79-year-old Florida woman and a 65-year-old woman who were in the early stages of Alzheimer’s disease. The case of the 65-year-old was also chronicled this week in The New England Journal of Medicine.
Espay worries, too, about patients who may develop less severe ARIA while taking lecamenab. For at least some of them, “I cannot imagine it’s irrelevant or inconsequential,” he says.
Snider would like to see a new national database to track ARIA and any other side effects of lecanemab usage and help doctors and researchers understand who is at greatest risk. (The drug’s label suggests physicians can contribute reports on side effects to an existing, voluntary Alzheimer’s drug registry called ALZ-NET.) People with two copies of the APOE4 gene, which predisposes to Alzheimer’s, may be at higher risk of ARIA. In lecanemab’s large clinical trial, 9.2% of people with two copies of the gene variant had symptomatic brain swelling, compared with 1.4% of people with no copies. Alzheimer’s patients aren’t routinely tested for APOE4 because it hasn’t traditionally affected diagnosis or treatment.
Although some scientists had hoped FDA would rule against giving lecanemab to people with two copies of APOE4, the agency declined to do so, suggesting only that people “consider testing” for APOE4 status “to inform the risk of developing ARIA when deciding to initiate treatment.”
For providers, the road ahead remains uncertain. “Those of us in AD [Alzheimer’s disease] research and patient care will continue working on how best to offer this new medication to our patients,” Snider says.
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