What further data on intravenous (IV) lecanemab should future studies address?

Future Research Priorities for Intravenous Lecanemab

Future studies of IV lecanemab should prioritize long-term safety data beyond 18 months, particularly regarding ARIA risk stratification, optimal treatment duration and stopping criteria, effects in diverse populations including underrepresented groups, and the clinical utility of blood-based biomarkers for treatment monitoring.

Long-Term Safety and Efficacy Data

Extended Treatment Duration Studies

• Current evidence is limited to 18-month treatment periods in the pivotal Clarity AD trial, with open-label extension data showing continued benefit but also revealing 4 deaths possibly related to treatment during extended dosing 1
• Studies extending beyond 2-3 years are critically needed to establish whether clinical benefits persist, plateau, or diminish with continued treatment 2, 1
• The gap period analysis from Study 201 showed that clinical treatment differences were maintained after discontinuation over an average of 24 months, but rates of progression eventually paralleled placebo, suggesting potential need for indefinite treatment 3

ARIA Risk Stratification and Management

• While ARIA-E occurs in 12.6% overall and 34.5% in APOE ε4 homozygotes, future studies must identify additional risk factors beyond APOE ε4 status that predict severe or symptomatic ARIA 1
• Research should address whether baseline cardiovascular risk factors, microbleeds, superficial siderosis, or concurrent antithrombotic use can be quantified into a composite risk score to guide treatment decisions 4, 5
• The three deaths due to intracerebral hemorrhage (two on concurrent anticoagulation/thrombolysis) highlight the urgent need for studies defining safe parameters for antithrombotic co-administration 1

Treatment Duration and Discontinuation Criteria

Optimal Stopping Points

• No current data exist on when to discontinue lecanemab after achieving amyloid clearance, with the Centiloid scale showing reductions of 60-85 CL units but uncertainty regarding the clinical significance of residual amyloid between 11-25 CL 4
• Future trials should test whether treatment can be safely stopped after achieving amyloid negativity (below 24.1 CL) versus requiring maintenance dosing 4
• Studies must determine whether plasma p-tau217 normalization or sustained amyloid PET negativity can serve as biomarker-guided stopping criteria 6, 3

Retreatment Strategies

• The gap period data showing gradual return of plasma biomarkers toward baseline suggests potential amyloid reaccumulation, but no studies have examined retreatment protocols 3
• Research should address whether intermittent dosing strategies (e.g., treatment holidays after clearance with retreatment upon biomarker elevation) maintain efficacy while reducing ARIA risk 3

Population-Specific Studies

Underrepresented and Diverse Populations

• Current trial data predominantly reflect non-Hispanic white populations, with insufficient representation of Black, Hispanic, and Asian patients who may have different APOE ε4 allele frequencies and ARIA risk profiles 6
• Studies must specifically enroll diverse populations to establish whether efficacy and safety profiles differ by race, ethnicity, and genetic ancestry 6
• Research in patients with multiple comorbidities (cardiovascular disease, diabetes, chronic kidney disease) is lacking, despite these conditions being common in the target age group 4

Special Clinical Scenarios

• No data exist for lecanemab use in pregnancy, lactation, or patients with significant immunosuppression 4, 5
• Studies are needed in patients with atypical AD presentations (posterior cortical atrophy, logopenic variant primary progressive aphasia) where amyloid distribution may differ 4
• Research should address whether lecanemab is effective in patients with mixed pathology (concurrent vascular dementia, Lewy body disease) 4

Biomarker Development and Validation

Blood-Based Biomarker Monitoring

• While plasma p-tau217 demonstrates high accuracy (AUC 0.92-0.98) for baseline amyloid detection, its role in monitoring treatment response requires validation 6, 7
• Future studies should determine whether serial plasma p-tau217 measurements can replace repeated amyloid PET scans for assessing treatment efficacy and guiding duration decisions 7, 3
• Research must establish whether plasma Aβ42/40 ratio changes correlate with clinical outcomes or merely reflect peripheral pharmacodynamics 3

Tau Biomarker Integration

• The donanemab TRAILBLAZER-ALZ2 study demonstrated that high baseline tau burden predicts reduced clinical benefit, but no comparable tau stratification data exist for lecanemab 6
• Studies should prospectively stratify patients by baseline tau PET burden to identify optimal treatment candidates and establish whether lecanemab effects differ across tau stages 4, 6
• Research is needed on whether plasma p-tau217 reductions during treatment predict better clinical outcomes or represent a mechanistic effect without prognostic value 6, 3

Comparative Effectiveness Research

Head-to-Head Trials

• No direct comparison trials exist between lecanemab and donanemab, the two fully FDA-approved anti-amyloid monoclonal antibodies 6
• Future studies should directly compare efficacy, safety profiles, ARIA rates, and cost-effectiveness between available anti-amyloid therapies 6
• Research should address whether sequential therapy (switching from one anti-amyloid antibody to another after inadequate response) provides additional benefit 4

Combination Therapy Studies

• No data exist on combining lecanemab with other disease-modifying approaches (tau-directed therapies, anti-inflammatory agents, neuroprotective compounds) 6
• Studies should examine whether combining amyloid clearance with tau reduction produces synergistic clinical benefits 6

Patient-Centered Outcome Research

Quality of Life and Functional Outcomes

• While CDR-SB, ADAS-Cog14, and ADCOMS show statistically significant differences, the clinical meaningfulness of these changes for patients and caregivers requires further investigation 8, 2
• Research should prioritize patient-reported outcomes, caregiver burden measures, and time to nursing home placement as primary endpoints 4, 8
• Studies must determine whether the modest cognitive benefits (0.45-point CDR-SB difference at 18 months) translate into meaningful delays in loss of independence 2

Health Economics and Access

• Cost-effectiveness analyses are needed comparing lecanemab's substantial expense (including infusion costs, MRI monitoring, ARIA management) against clinical benefits 6
• Research should address implementation barriers including specialist shortages, infusion center capacity, and MRI availability that limit real-world access 6

Safety Monitoring Optimization

MRI Surveillance Protocols

• Current protocols require MRI before the 5th, 7th, and 14th infusions, but the optimal frequency and duration of ARIA monitoring remain uncertain 6, 5
• Studies should determine whether risk-stratified monitoring (more frequent in APOE ε4 homozygotes, less frequent in non-carriers) maintains safety while reducing costs and patient burden 5, 1
• Research is needed on whether advanced MRI techniques (susceptibility-weighted imaging, arterial spin labeling) provide earlier ARIA detection 4

Infusion Reaction Management

• Infusion-related reactions occur in 26.4% of patients, predominantly with the first infusion, but optimal premedication strategies are undefined 2, 1
• Studies should test whether routine premedication with antihistamines, acetaminophen, or corticosteroids reduces reaction rates without compromising efficacy 9, 1

Mechanistic and Translational Research

Downstream Pathological Effects

• While lecanemab reduces amyloid burden by 59.1 centiloids, its effects on downstream tau pathology, neuroinflammation, and synaptic loss require further characterization 2, 3
• Research should determine whether amyloid clearance slows tau accumulation in longitudinal tau PET studies and whether this mediates clinical benefit 4, 6
• Studies examining effects on neurodegeneration markers (plasma neurofilament light, volumetric MRI) would clarify whether lecanemab provides neuroprotection beyond amyloid removal 3

Microbiome and Systemic Effects

• No studies have examined whether lecanemab affects the gut-brain axis, systemic inflammation, or peripheral amyloid metabolism 4
• Research on cutaneous, cardiovascular, or other systemic effects of prolonged anti-amyloid antibody exposure is lacking 4

Preclinical and Prevention Studies

Presymptomatic Treatment

• The AHEAD study is examining lecanemab in preclinical AD (cognitively normal individuals with elevated amyloid), but results are pending 9
• Future research must determine whether treating asymptomatic amyloid accumulation prevents cognitive decline or merely delays symptom onset without altering disease trajectory 7, 9
• Studies should establish the risk-benefit ratio of exposing cognitively normal individuals to ARIA risk for potential preventive benefit 7