Lecanemab, marketed as Leqembi, is a new treatment for individuals in the early stages of Alzheimer’s disease. This medication is a monoclonal antibody designed to target and remove amyloid plaques from the brain. Amyloid plaques are abnormal protein deposits, a hallmark of Alzheimer’s disease pathology.
The drug’s mechanism involves binding to soluble aggregated forms of amyloid-beta protein, known as protofibrils, which are toxic in Alzheimer’s progression. Lecanemab aims to reduce the overall amyloid burden in the brain.
Understanding Lecanemab-Associated Fatalities
Reports of fatalities linked to lecanemab treatment are primarily associated with Amyloid-Related Imaging Abnormalities (ARIA). These abnormalities manifest as ARIA-E (brain swelling or fluid leakage, or edema) or ARIA-H (microhemorrhages or superficial siderosis, which are small bleeds in the brain). In rare instances, ARIA can progress to severe complications, including fatal brain hemorrhages.
Fatalities often involve additional risk factors. Some individuals who experienced fatal brain hemorrhages were also taking anticoagulant medications, which increase bleeding risk. Carrying the APOE ε4 gene has also been identified as a factor that can heighten the risk of ARIA, including more serious cases. These occurrences, though rare, highlight the importance of careful patient selection and monitoring during treatment.
Biological Mechanisms Behind Adverse Events
ARIA is directly related to lecanemab’s mechanism of clearing amyloid plaques from the brain. As lecanemab targets and removes amyloid-beta protofibrils and plaques, it can trigger an inflammatory response within the brain’s blood vessels. This inflammation can lead to a temporary disruption of the blood-brain barrier, which normally protects the brain.
Such disruption can result in fluid leaking into the brain tissue, causing edema (ARIA-E), or lead to the fragility of small blood vessels, resulting in microhemorrhages (ARIA-H). Amyloid clearance can affect the integrity of the brain’s vascular system, particularly where amyloid has accumulated around blood vessels.
Identifying and Managing Risks
A significant risk factor for ARIA is the apolipoprotein E ε4 (APOE ε4) gene; individuals with two copies (homozygotes) face a higher incidence of ARIA, including more serious forms. Concurrent use of anticoagulant medications also increases the risk of brain hemorrhage.
Before treatment, comprehensive screening is recommended, including genetic testing for APOE ε4 status and a recent brain MRI scan to check for pre-existing conditions like microhemorrhages or severe white matter disease. During treatment, ongoing monitoring with regular MRI scans is necessary to detect ARIA early, even when asymptomatic. If ARIA is detected or symptoms appear, management involves temporarily suspending or permanently discontinuing the drug, depending on the severity and resolution of the event.
Regulatory Oversight and Patient Guidance
Lecanemab received accelerated approval from the U.S. Food and Drug Administration (FDA) in January 2023, followed by full approval in July 2023. With full approval, the FDA issued a “boxed warning” in the prescribing information to highlight safety risks, particularly concerning ARIA. This warning notes the higher incidence of ARIA in patients homozygous for the APOE ε4 allele, emphasizing the need for genetic testing and clear risk communication.
Regulatory bodies and the drug manufacturer advise caution for patients taking anticoagulants due to an increased risk of intracerebral hemorrhages. Patients and their families should communicate openly with healthcare providers to understand the treatment’s benefits and risks. It is important to report any new or worsening symptoms immediately to the medical team, as prompt action can help manage potential adverse events.