What is the treatment protocol for Leqembi (lecanemab) in patients with early symptomatic Alzheimer's disease?

Leqembi (Lecanemab) Treatment Protocol for Early Alzheimer's Disease

Patient Selection and Eligibility

Lecanemab is indicated exclusively for patients with mild cognitive impairment or mild dementia due to Alzheimer's disease who have confirmed amyloid pathology—treatment should not be initiated in cognitively normal individuals regardless of biomarker status. 1

Required Diagnostic Criteria

• Symptomatic disease confirmation: Patients must have documented objective cognitive impairment with MoCA score ≤25 or comprehensive neuropsychological testing showing impairment in ≥1 cognitive domain 2
• Disease stage: CDR score of 0.5 (MCI) or 1.0 (mild dementia) is required—patients with moderate or severe dementia are excluded 1
• Amyloid confirmation: Presence of amyloid beta pathology must be confirmed prior to treatment initiation through amyloid PET, CSF biomarkers, or blood-based biomarkers (plasma p-tau217) 1, 2

Biomarker Confirmation Options

• Blood-based biomarkers: Positive plasma p-tau217 alone is sufficient to initiate therapy without requiring additional amyloid PET, showing high accuracy (AUC 0.92-0.98) for predicting amyloid status 2
• Amyloid PET: Positive scan using Centiloid scale with values >30 CL corresponding to pathological amyloid burden 3
• CSF biomarkers: Abnormal Aβ42/40 ratio indicating amyloid pathology 2

Pre-Treatment Safety Screening

Mandatory Baseline MRI Requirements

A baseline brain MRI within 12 months of treatment initiation is absolutely mandatory to identify exclusionary findings before the first infusion. 2, 1

Exclusionary MRI Findings (Absolute Contraindications)

• Intraparenchymal macrohemorrhages >10 mm 2, 1
• ≥4 microhemorrhages <10 mm 2, 1
• Superficial siderosis 2, 1
• Vasogenic edema 2, 1
• Significant white matter hyperintensities 2
• Multiple lacunar infarcts 2
• Major vascular territory infarcts 2
• Evidence of cerebral amyloid angiopathy 2

APOE ε4 Genotype Testing

APOE ε4 genotype testing should be performed prior to treatment initiation to inform ARIA risk, as homozygotes (approximately 15% of AD patients) have substantially higher rates of symptomatic and severe ARIA. 1

• APOE ε4 homozygotes experience ARIA-E in 34.5% of cases 4
• APOE ε4 carriers experience ARIA-E in 16.8% of cases 4
• Patients can still receive treatment without genotype testing, but risk stratification cannot be determined 1

Dosing Protocol

Initial Treatment Regimen

Lecanemab 10 mg/kg intravenous infusion every 2 weeks over approximately one hour for 18 months. 1

Maintenance Dosing

• After 18 months, either continue 10 mg/kg every 2 weeks OR transition to maintenance dosing of 10 mg/kg every 4 weeks 1
• Each infusion requires approximately one hour in a facility equipped to manage infusion reactions 2

Missed Dose Management

• If an infusion is missed, administer the next dose as soon as possible 1

Mandatory MRI Monitoring Schedule

MRI monitoring is required prior to the 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) to detect ARIA. 1, 2

Additional MRI Indications

• Obtain MRI immediately if patient develops symptoms suggestive of ARIA (headache, confusion, visual disturbances, altered mental status, seizures) 1
• Consider follow-up MRI 2-4 months after ARIA detection to assess resolution 1

ARIA Management Protocol

ARIA-E (Edema) Incidence and Timing

• ARIA-E occurs in 12.6% of lecanemab-treated patients 4, 5
• Typically manifests within first 3-6 months of treatment 4, 2
• Most cases are radiographically mild-to-moderate and asymptomatic 4

ARIA-E Dosing Interruption Algorithm

Asymptomatic patients with mild ARIA-E on MRI: May continue dosing 1

Asymptomatic patients with moderate or severe ARIA-E on MRI: Suspend dosing until radiographic resolution, then consider resumption based on clinical judgment 1

Symptomatic patients (mild symptoms) with mild ARIA-E: May continue dosing based on clinical judgment 1

Symptomatic patients (mild symptoms) with moderate/severe ARIA-E OR patients with moderate/severe symptoms regardless of MRI severity: Suspend dosing until MRI demonstrates resolution and symptoms resolve 1

ARIA-H (Microhemorrhages/Superficial Siderosis) Management

• ARIA-H occurs in 16.0% of patients 4
• Asymptomatic mild ARIA-H: May continue dosing 1
• Asymptomatic moderate ARIA-H: Suspend dosing until radiographic stabilization 1
• Asymptomatic severe ARIA-H or any symptomatic ARIA-H: Suspend dosing until stabilization and symptom resolution 1

Critical Safety Considerations

Before administering thrombolytic therapy to a lecanemab-treated patient with stroke-like symptoms, clinicians must consider whether symptoms could be due to ARIA-E rather than ischemic stroke. 1

• Three deaths due to intracerebral hemorrhage occurred in clinical trials, including patients on concurrent anticoagulation or tissue plasminogen activator 4
• Serious intracerebral hemorrhages >1 cm, some fatal, have been observed with this class of medications 1

Infusion-Related Reactions

• Infusion-related reactions occur in 26.4% of participants 5 to 24.5% 4
• Most common adverse event requiring monitoring during and after infusion 4
• Facility must be equipped to manage acute infusion reactions 2

Infrastructure and Access Requirements

Multidisciplinary Team Requirements

Treatment requires comprehensive multidisciplinary teams with specialized training in monoclonal antibody therapy and ARIA management, with access to emergency MRI and neurology consultation. 2

CMS Registry Enrollment

• Enrollment in a CMS-approved patient registry is required for Medicare reimbursement 2

Specialist Access Challenges

• Hub-and-spoke care models are being developed to address dementia specialist shortages 3
• Too few dementia specialists are available to meet potential demand, creating access barriers particularly for underserved populations 2

Clinical Efficacy Outcomes

• Lecanemab reduced decline on CDR-SB by 0.45 points at 18 months (27% slowing of decline) compared to placebo 5
• Significant reductions in brain amyloid burden (-59.1 centiloids difference from placebo) 5
• Benefits observed across multiple cognitive and functional measures including ADAS-cog14, ADCOMS, and ADCS-MCI-ADL 5
• Quality of life measures showed 49% less decline on EQ-5D-5L and 56% less decline on QOL-AD at 18 months 6
• Caregiver burden increased 38% less compared to placebo 6

Common Pitfalls to Avoid

• Do not initiate treatment in biomarker-positive individuals with normal cognition—lecanemab is indicated only for symptomatic disease 7, 2
• Do not skip baseline MRI—exclusionary findings must be identified before first infusion 2, 1
• Do not ignore APOE ε4 status—homozygotes require enhanced counseling about ARIA risk 1
• Do not administer to patients on anticoagulation without careful risk-benefit assessment—increased hemorrhage risk 4
• Do not assume stroke symptoms are ischemic—consider ARIA-E before giving thrombolytics 1