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Scientists Tie Third Clinical Trial Death to Lecanemab, an Experimental Drug for Alzheimer’s Disease
TAKE-HOME MESSAGE
- A third death linked to lecanemab treatment, which appears to slow cognitive decline in some patients with Alzheimer's disease, was reported in a 79-year-old woman who experienced extensive brain swelling and bleeding as well as seizures. This case in addition to other reports of serious brain bleeding and swelling in the core clinical trial and two other deaths linked to this drug in the extension phase have raised concerns about the safety of the drug.
- Given these concerns, if the FDA approves lecanemab, the approval should come with warnings. Patients receiving lecanemab may be advised to undergo as many as five MRI examinations annually to closely monitor for amyloid-related imaging abnormalities, and a vast education program would be needed to ensure that clinicians outside of major medical centers can recognize problems found on the brain scans.
abstract
This abstract is available on the publisher's site.
Access this abstract nowAs enthusiasm mounts for a new experimental antibody that appears to slow cognitive decline in some Alzheimer’s patients, a third death linked to the drug during its clinical testing may amplify concerns about its safety. Science has obtained medical records showing a 79-year-old Florida woman participating in an ongoing trial of the antibody died in mid-September after experiencing extensive brain swelling and bleeding, as well as seizures. Multiple neuroscientists who reviewed the records at Science’s request believe her death was likely caused by the antibody, lecanemab.
Additional Info
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Lecanemab, an anti-amyloid monoclonal antibody (AAMA), was recently approved by the US FDA for the treatment of early Alzheimer’s disease (AD). AAMAs’ main adverse events are amyloid-related imaging abnormalities (ARIA): parenchymal and meningeal vasogenic edema (ARIA-E) and/or subarachnoidal and parenchymal microhemorrhages and macrohemorrhages (ARIA-H) related to the drug.1 Severe ARIA has recently been described when using high-dose AAMAs and can manifest as status epilepticus or cerebral macrohemorrhage.2,3 ARIA pathogenesis remains debated; however, it could be a drug-induced cerebral amyloid angiopathy (CAA) with inflammation.4 ARIA’s main risk factors are baseline microbleeds and APOE4 carrier status (with a dose effect).5 ARIA mainly occurs in the first 6 months following AAMA initiation, justifying close MRI monitoring.6 Patients who were on anticoagulants receiving lecanemab experienced more macrohemorrhages than patients who were not (2.4%–3.6% vs 0.6%–0.7%).6 Finally, CAA is a frequent comorbidity associated with AD. CAA prevalence based on pathology (48%) is twice that based on the presence of strictly lobar cerebral microbleeds (22%).7
The case report by Reisz et al8 from Chicago, Illinois, describes a 65-year-old patient (with biologically proven early AD, APOE4 homozygous carrier, no overt CAA on MRI before lecanemab, and no other comorbid condition) who received three infusions of lecanemab (biweekly regimen) and developed sudden aphasia and left gaze deviation. The CT scan performed shortly after the onset of these symptoms revealed hypodensity of the left temporal lobe and occlusion of the distal left middle cerebral artery. The patient received t-PA and she worsened a few minutes later, with a CT scan revealing multiple and diffuse parenchymal hemorrhages (beyond the supposed territory of infarction territory). The patient eventually died a few days later. Beyond AD neuropathologic changes, the autopsy revealed extensive multifocal intraparenchymal hemorrhages (CAA) and diffuse histiocytic vasculitis with necrotizing vasculopathy involving amyloid deposition within (but not outside) the blood vessel walls. Histiocytic vasculitis was present in all lobes of the cerebral cortex in parallel with the distribution of CAA. A necrotizing component (fibrinoid degeneration of the blood vessel wall) was noted in the temporal, parietal, and occipital lobes, bilaterally, and was generally found adjacent to the areas of acute hemorrhage. No infarct was noted in the autopsy report.
The vasculitis description in this case report is compatible with previous reports of amyloid β-related angiitis (ABRA).9 ABRA is part of the inflammatory CAA spectrum with CAA-related inflammation, a perivascular inflammatory reaction surrounding amyloid-laden vessels, without angio-destructive features.10 ABRA can also be responsible for multiple diffuse fatal hemorrhages following t-PA therapy.8 Considering the pre-lecanemab normal MRI, it appears reasonable to consider this case as a lecanemab-induced ABRA. Additional arguments are: there is a strong assumption of a common pathogenesis between CAA with inflammation and ARIA; the patient is at high risk of ARIA (APOE4 homozygous); ARIA with lecanemab generally occurs within the first 6 months of treatment (maximum in the first 3 months); and normal pre-lecanemab MRI does not rule out CAA measured with pathology since no susceptibility weighted imaging (SWI) but T2 gradient echo was used for microbleed detection in this case, and since any MRI sequence can be normal in cases of CAA without a microvascular complication.11
For clinical practice, this article delivers several messages:
Any patient on AAMAs should be considered at risk for ARIA, especially within the first 6 months of treatment and especially APOE4 carriers. ARIA can, as illustrated in this case, eventually be an ABRA-like phenomenon and be responsible for death in the case of t-PA use. MRI is the gold standard method for ARIA detection.12 Any stroke, or suspected stroke, in these patients, should trigger an emergency MRI, as far as possible, to rule out concomitant ARIA. If not available, the lack of any recent MRI (<2 weeks) should discourage the use of any thrombolytic. Any identified ARIA should be considered a strict contraindication to any thrombolytic therapy pending additional data. It should also raise the likelihood of a differential diagnosis since ARIA-E can manifest as a partial status epilepticus. In the case of a confirmed brain infarct, alternative therapy, such as mechanical thrombectomy, if indicated, could still be considered.
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