06 Jan 2023

In Phase 3, the anti-amyloid antibody lecanemab caused the edema known as ARIA-E in one in eight participants. It was typically asymptomatic or mild, but serious reactions did occur. These are drawing scrutiny with recent reports of three deaths in the open-label extension trial that are potentially linked to the drug. All three were people who had cerebral amyloid angiopathy (CAA) and some use of blood thinners or clot-busting drugs. Together, the reports suggest physicians should exercise extra care in prescribing lecanemab to patients who fit this profile.

The first death occurred in June 2022, and was reported by STAT news in October. An 87-year-old man who was taking the common blood thinner apixaban (trade name Eliquis) for atrial fibrillation developed ARIA. Doctors paused both lecanemab and apixaban. The next month, the man suffered a heart attack and was briefly put on another blood thinner. Four mini-strokes and a brain bleed followed, leading to his death. The site investigator suggested the combination of CAA, apixaban, and lecanemab conspired to weaken his cerebral blood vessels, precipitating the hemorrhage. Eisai considers this death unrelated to lecanemab.

In the second case, a 65-year-old woman who carried two copies of the APOE4 allele received three doses of lecanemab in the trial's open-label extension (OLE). Four days after her last dose, she suffered an ischemic stroke, with blockage of her middle cerebral artery. In the emergency room at Northwestern University Hospital in Chicago, doctors gave her the clot-busting drug t-PA. Her blood pressure spiked, massive bleeding started in her brain, and she began seizing. She died a few days later. The death was first reported by Science in November, and formally published January 4 in the New England Journal of Medicine (Reish et al., 2023). In an accompanying response, Christopher van Dyck at Yale School of Medicine in New Haven, Connecticut, and Marwan Sabbagh at Barrow Neurological Institute in Phoenix noted that t-PA can cause massive bleeding in people with CAA even in the absence of anti-amyloid therapy (Sabbagh and van Dyck, 2023). 

The third case was a 79-year-old woman in Florida who received two doses of lecanemab in the OLE. After the second dose, she experienced headaches, confusion, and speech difficulties. Shortly thereafter she had stroke-like symptoms and seizures, and was briefly given the blood thinner heparin. An MRI scan showed severe ARIA. She died a few days later, as reported December 21 in Science. Outside experts consulted by Science said her death was likely caused by lecanemab. Eisai said it is still analyzing the data.

It is unclear how these incidents will affect the prescribing information for lecanemab, which today was approved by the Food and Drug Administration (see related story). Clinician-researchers are currently developing Appropriate Use Recommendations specific to lecanemab, as they previously did for aducanumab (Aug 2021 news).—Madolyn Bowman Rogers