What are the concerns regarding the long-term safety of intravenous (IV) lecanemab (generic name)?

Long-Term Safety Concerns with IV Lecanemab

The primary long-term safety concern with IV lecanemab is amyloid-related imaging abnormalities (ARIA), which can be fatal, particularly in patients with genetic risk factors or those on anticoagulation, though most cases are asymptomatic and resolve over time. 1

Major Safety Concerns

ARIA (Amyloid-Related Imaging Abnormalities)

ARIA represents the most significant long-term safety risk and requires ongoing vigilance:

• ARIA-E (edema/effusion) occurred in 12.6% of patients in the CLARITY AD phase 3 trial and 13.6% in the Core + OLE studies, typically manifesting within 3-6 months of treatment initiation 2, 3
• ARIA-H (hemorrhage) with microhemorrhages occurred in 16.0% of patients, with incidence ranging from 15-20% across clinical trials 2, 3
• Fatal outcomes have been documented: 4 deaths were deemed possibly related to lecanemab in the open-label extension, including 2 deaths from intracerebral hemorrhage in patients on concurrent anticoagulant or tissue plasminogen activator therapy 3
• Symptomatic ARIA occurred in 5.7% of patients overall in real-world practice, but this rate increased dramatically to 27% in patients with mild dementia compared to only 1.8% in those with mild cognitive impairment 4

Genetic Risk Stratification

APOE ε4 genotype dramatically increases ARIA risk and must be assessed before treatment:

• APOE ε4 homozygotes experienced ARIA-E in 34.5% of cases, representing the highest risk group 3
• APOE ε4 carriers (heterozygotes and homozygotes combined) had ARIA-E rates of 16.8% 3
• APOE genotyping is mandatory before initiating therapy to inform risk discussions and monitoring intensity 5, 6

Hemorrhagic Complications

Bleeding risks are amplified by concurrent anticoagulation and represent a critical long-term concern:

• Macrohemorrhages (intracerebral hemorrhage >1 cm) have been reported infrequently but can be fatal 1
• Anticoagulant or antithrombotic therapy significantly increases bleeding risk, and current appropriate use recommendations suggest avoiding lecanemab in patients requiring anticoagulation until more safety data are available 5, 6
• Baseline microhemorrhages were present in 23% of patients before starting lecanemab, indicating underlying cerebral amyloid angiopathy that may predispose to further bleeding 4

Infusion-Related Reactions

Infusion reactions are common but typically manageable:

• Incidence of 24.5% in the Core + OLE studies, with most reactions occurring during the first infusion 3
• Symptoms include flu-like symptoms, nausea, vomiting, and blood pressure changes 1
• Most reactions are mild (Grade 1/2) and managed by slowing or temporarily stopping the infusion 7

Long-Term Monitoring Requirements

Mandatory MRI surveillance is essential for detecting ARIA:

• Pre-treatment MRI must be performed within 12 months of initiation 2
• Routine post-treatment MRIs are required before the 5th, 7th, and 14th infusions 2
• Mandatory sequences include DWI, T2 FLAIR, and T2* GRE or SWI to detect both ARIA-E and ARIA-H 2
• Additional MRI should be performed immediately if patients develop symptoms suggestive of ARIA (headache, confusion, dizziness, vision changes, nausea, difficulty walking, seizures) 1

Clinical Management Implications

ARIA detection may require treatment modifications:

• Temporary or permanent cessation of lecanemab may be necessary depending on ARIA severity and symptoms 2
• Corticosteroids or antiepileptic treatment may be required for symptomatic ARIA 2
• Subspecialty care in facilities equipped to manage ARIA complications is essential 2

Unknown Long-Term Risks

Several safety questions remain unanswered:

• Duration of treatment beyond 18 months has limited data, particularly regarding the transition to monthly dosing (10 mg/kg every 4 weeks) after the initial treatment period 1
• Cumulative hemorrhagic risk with extended treatment duration needs better characterization 8
• Long-term cardiovascular effects are not well-studied, though cardiovascular complications are rare with monoclonal antibodies 2
• Effects in patients with more advanced disease remain unclear, as trials excluded patients beyond mild dementia 8

Critical Pitfalls to Avoid

• Never initiate lecanemab without APOE genotyping to properly stratify risk and inform patient discussions 5, 6
• Do not use lecanemab in patients on anticoagulation until more safety data are available, given the documented fatal hemorrhages in this population 5, 6
• Ensure patients carry identification indicating they are receiving lecanemab, as ARIA symptoms can mimic stroke and require different management 1
• Do not rely on clinical symptoms alone to detect ARIA, as most cases are asymptomatic and only detectable on MRI 2, 3