Will biomarker outcomes be key outcome measures in lecanemab (anti-amyloid beta antibody) treatment for Alzheimer's disease?

Biomarkers as Key Outcome Measures in Lecanemab Treatment

Biomarker outcomes are important secondary endpoints in lecanemab treatment, but clinical measures of cognition and function remain the primary outcome measures that determine treatment efficacy and guide clinical decision-making. 1, 2

Primary vs Secondary Outcome Hierarchy

The FDA-approved primary endpoint for lecanemab is the Clinical Dementia Rating-Sum of Boxes (CDR-SB), not biomarker changes. 1 In the pivotal Clarity AD trial, lecanemab demonstrated a statistically significant reduction in clinical decline on CDR-SB at 18 months (difference of -0.45 points, representing 27% less decline versus placebo, P<0.001). 1, 2

Key secondary clinical endpoints that take precedence over biomarkers include:

• ADAS-Cog14 (cognitive assessment): -1.442 point difference (26% less decline, P=0.00065) 1
• ADCS MCI-ADL (functional activities): 2.0 point difference (37% less decline, P<0.0001) 1

Role of Biomarkers in Treatment Monitoring

Biomarker outcomes serve three distinct clinical purposes, but are not the primary measures of treatment success:

1. Pre-Treatment Eligibility Determination

• Biomarker confirmation of amyloid pathology is mandatory before initiating lecanemab, but the specific modality (PET, CSF, or blood-based) is not specified in FDA labeling 3, 1
• Blood-based biomarkers like plasma p-tau217 demonstrate high accuracy (AUC 0.92-0.98) for predicting amyloid status and are sufficient for treatment initiation without requiring amyloid PET 3, 4
• The Global CEO Initiative recommends blood biomarker tests achieve ≥90% sensitivity with ~90% specificity when used as confirmatory tests 3

2. Secondary Efficacy Endpoints

Amyloid reduction on PET imaging was a key secondary endpoint in clinical trials, demonstrating:

• Mean reduction of 59.1 centiloids versus placebo (95% CI: -62.6 to -55.6) at 18 months 2
• Dose-dependent reductions in brain amyloid burden quantified using the Centiloid scale 1, 5

However, these biomarker changes are secondary outcomes that support but do not replace clinical efficacy measures 1, 2

3. Monitoring Treatment Effects

Plasma biomarkers can track treatment response:

• Plasma Aβ42/40 ratio and p-tau181 levels change with lecanemab treatment, showing improvements that correlate with amyloid reduction 5
• These plasma markers return toward pre-treatment levels more quickly than amyloid PET when treatment is discontinued, suggesting utility for monitoring adherence 5

Clinical Decision Framework

The appropriate hierarchy for outcome assessment is:

1. Primary clinical outcomes (CDR-SB, cognition, function) determine treatment efficacy and continuation 6, 1
2. Biomarker outcomes (amyloid PET, plasma markers) serve as:
   • Mandatory entry criteria for treatment eligibility 1
   • Secondary endpoints supporting disease-modifying mechanism 2
   • Potential monitoring tools for treatment effects 5

Important Caveats

• Biomarker improvement alone does not justify treatment in asymptomatic individuals - lecanemab is indicated only for mild cognitive impairment or mild dementia stage disease 1, 7
• The correlation between amyloid reduction and clinical benefit suggests disease-modifying effects, but clinical outcomes remain the definitive measure of treatment success 8, 2
• In the phase 2 study, the 12-month primary endpoint (ADCOMS) was not met despite biomarker changes, underscoring that biomarker reduction does not guarantee clinical benefit 9

Quality of life measures also showed meaningful benefits (49% less decline on EQ-5D-5L, 56% less decline on QOL-AD), representing patient-centered outcomes that complement but do not replace standard clinical assessments 10