What is the comparison of efficacy and safety between lecanemab and donanemab as anti-amyloid (Amyloid Beta) therapies for Alzheimer's disease?

Comparison of Lecanemab and Donanemab as Anti-Amyloid Therapies

Direct Recommendation

Both lecanemab and donanemab demonstrate comparable clinical efficacy with approximately 30% slowing of cognitive decline in early Alzheimer's disease, but donanemab offers a potential advantage through treatment cessation once amyloid clearance is achieved, while lecanemab requires ongoing therapy. 1, 2, 3

Efficacy Comparison

Amyloid Clearance Profiles

• Donanemab achieves more rapid amyloid reduction, with reductions of 60-85 Centiloid (CL) units reported in Phase III trials, compared to lecanemab's similar but potentially slower trajectory 1
• After 18 months (Week 79), 67% of lecanemab-treated patients achieved amyloid levels below 30 CL, the threshold for amyloid negativity 4
• Donanemab's unique feature is treatment cessation once amyloid clearance is achieved (below 24.1 CL), whereas lecanemab requires continuous therapy 1, 2
• Both agents demonstrate time-dependent amyloid reduction starting at Week 12-24 and continuing through Week 76-79 4, 2

Clinical Outcomes

• Both agents slow cognitive decline by approximately 30%, which is clinically meaningful for extending cognitive integrity and delaying severe dementia phases 3
• Donanemab shows reduced clinical benefit in patients with high tau burden, making patient stratification based on tau PET crucial for optimal outcomes 1, 5
• Lecanemab demonstrates consistent efficacy across the early AD population without the same tau-burden stratification requirement 4, 6

Biomarker Effects

• Both agents reduce plasma p-tau217 levels, indicating effects on tau pathophysiology beyond amyloid clearance 5, 4, 2
• Lecanemab increases plasma Aβ42/40 ratio and CSF Aβ[1-42] compared to placebo 4
• Donanemab similarly demonstrates reductions in plasma p-tau217 with statistical significance (p<0.0001) 2

Safety Comparison

ARIA Incidence

• Lecanemab: ARIA-E occurs in 13.6% of patients (Core + OLE), with 34.5% incidence in APOE ε4 homozygotes 6
• Lecanemab: ARIA-H microhemorrhages occur in 16.0% of patients 6
• Donanemab: ARIA risk is approximately 4 times higher in APOE ε4 carriers compared to non-carriers by 24 weeks, regardless of serum exposure 5
• Both agents show ARIA-E typically occurring within 3-6 months of treatment initiation 6
• ARIA is largely radiographically mild-to-moderate with both agents, though serious cases including rare fatalities have occurred 6

Infusion-Related Reactions

• Lecanemab: Infusion reactions occur in 26% of patients (Core study) and 24.5% (Core + OLE) 4, 6
• Approximately 10% of donanemab-treated patients who develop anti-drug antibodies experience infusion reactions 2
• Both agents require monitoring protocols for infusion reactions 4, 2

Serious Adverse Events

• Lecanemab: 3 deaths due to intracerebral hemorrhage in Core + OLE (1 on tissue plasminogen activator, 1 on anticoagulant therapy) 6
• Both agents are contraindicated with concurrent anticoagulation due to increased hemorrhage risk 7
• Atrial fibrillation occurred in 3% of lecanemab patients versus 2% on placebo 4
• Donanemab reported intestinal obstruction (0.4%) and perforation (0.2%) as serious adverse reactions 2

Monitoring Requirements

MRI Surveillance

• Lecanemab requires MRI before 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) 8, 4
• Donanemab requires MRI before 5th, 7th, and 14th infusions with identical timing 8
• Baseline brain MRI is mandatory for both agents to assess contraindications 5

Dosing Schedules

• Lecanemab: 10 mg/kg IV every 2 weeks continuously, with potential transition to every 4 weeks after 18 months to maintain amyloid reduction 4
• Donanemab: 700 mg IV every 4 weeks × 3 doses, then 1400 mg every 4 weeks until amyloid clearance achieved 8, 2
• Donanemab's treatment cessation option reduces long-term infusion burden and cumulative ARIA risk 1, 2

Patient Selection Considerations

Optimal Candidates

• Both agents are FDA-approved only for mild cognitive impairment or mild dementia due to AD with confirmed amyloid pathology 1, 8, 5
• Donanemab demonstrates optimal efficacy in patients with low-medium tau burden, making tau PET valuable for patient selection 5
• Lecanemab does not require tau stratification for treatment decisions 4, 6

Risk Stratification

• APOE ε4 genotyping is recommended before treatment with either agent to assess ARIA risk and inform benefit-risk discussions 9, 7
• Patients with baseline microhemorrhages, superficial siderosis, or cardiovascular risk factors have increased ARIA risk with both agents 9
• APOE ε4 homozygotes face 34.5% ARIA-E risk with lecanemab, requiring careful counseling 6

Practical Implementation

Treatment Duration

• Lecanemab requires indefinite continuation to maintain amyloid reduction, as off-treatment data shows amyloid increases at 2.6 CL/year 4
• Donanemab allows treatment cessation once amyloid clearance achieved (below 24.1 CL), with off-treatment increases of 2.80 CL/year 1, 2
• This represents a significant practical advantage for donanemab in terms of patient burden and healthcare resource utilization 1

Infrastructure Requirements

• Both agents require multidisciplinary teams with specialized training in ARIA management 8, 5
• Hub-and-spoke care models are being developed to address specialist shortages for both therapies 1
• CMS registry enrollment is required for reimbursement of both agents 8

Critical Caveats

• Neither agent should be used with concurrent anticoagulation until more safety data are available 7
• Both agents are inappropriate for cognitively unimpaired individuals, even with positive biomarkers 8
• Treatment cessation decisions for donanemab require amyloid PET quantification between 11-25 CL, where measurement reliability becomes crucial 1
• Brain volume loss occurs with both agents, though clinical significance remains ill-understood 3