LECANEMAB

IN EARLY
ALZHEIMER’S
DISEASE

Journal Club
Shano Thiyagalingam
October 2, 2023
 OUTLINE
• Background
• Methods
• Results
• Conclusion
• Critical Appraisal
• Practicality
BACKGROUND
• Amyloid β protein may initiate or potential pathological process in Alzheimer’s disease
• How?
• ROS, membrane disruption, synaptic dysregulation, inflammation (microglial activation)
• triggers cascade of phosphorylated tau
• neuroinflammatory response and neuronal death
• protofibrils = most neurotoxic

Drug Discovery News, 2018

Bloom, GS. JAMA Neurol, 2014
Rabinovici, G. JAMA Clinical Reviews, 2023
BACKGROUND
• Anti-amyloid antibody mechanism of action
• binds to amyloid β protofibrils
• body’s immune system identifies and eliminates them

Drug Discovery News, 2018

Van Dyck et al.. NEJM, 2023
Current anti-amyloid drugs
• Aducanumab (positive
and negative trial)
• Lecananemab (positive
trial)
• Donanemab (positive trial)
• Solanezumab (negative
trial)

Chertkow, H. UHN, 2023

WHAT IS THE DRUG
• Lecanumab (brand name: Leqembi)
• IgG1 monoclonal antibody
• Study funded by Esai pharmaceuticals and
Biogen

Park, A. Time, 2023

Van Dyck et al.. NEJM, 2023
CLARITY-AD Phase 3 Trial
 METHODS
• Phase 3 trial, double-blind, placebo-controlled, parallel-group, randomized study,
18 months
• Intervention: Lecanemab monoclonal antibody 10mg/kg biweekly for 18 months
• 235 sites: Canada, USA, Australia, France, Germany, Italy, Japan, Russia, South
Korea, Singapore, Spain, Sweden, UK
• Between 2019 - 2021
• 50-80 years of age
• Early Alzheimer’s disease (MCI or mild dementia)
• Amyloid positive on PET/CSF/blood

Van Dyck et al.. NEJM, 2023

Van Dyck et al.. NEJM, 2023
 Change from baseline at 18 months

• Primary endpoint, change in:

• Clinical Dementia Rating- Sum of Boxes
METHODS • Secondary endpoint, change in:
• Amyloid burden on PET
• ADAS-cog14
• ADCOMS
• ADCS-MCI-ADL

Van Dyck et al.. NEJM, 2023

METHODS
• Validated
measure of
cognition and
function
• Assess six
domains
• Patient and
caregiver
interview

NEJM Quick Time. NEJM, 2023

RESULTS • Disease is progressing in both groups
• Widening between the group with time
Primary endpoint • Narrow confidence intervals

Eisai, 2022
 RESULTS

0.45

Taylor, E. Alz Res UK, 2022

RESULTS Alzheimer’s Disease Cooperative Study MCI ADL
• Functional outcomes (Activities of daily living)
Secondary endpoints • Items of daily activities
• Rated by family/caregiver
• Scored 0-53; lower score is worse functioning
• Baseline score 41
• Difference: 2.0
• 37% slowing
• Narrow confidence intervals

-3.5

-5.5

Van Dyck et al.. NEJM, 2023

RESULTS
Secondary endpoints

3.64 • Centiloids
• Score 0-100;
• > 30 means elevated brain amyloid
• Treatment group: 22
• Difference: 59
• Most robust outcome in study

-55.48

Van Dyck et al.. NEJM, 2023

RESULTS
Statistically significant secondary endpoints

Van Dyck et al.. NEJM, 2023

 R E S U LT S

• Fluid (CSF/Blood) Biomarkers

• Reduction in Alzheimer’s Disease biomarkers

• ie: : A-β, tau

• Reduction in neuroinflammatory biomarkers

• ie: neurogranin, glial fibrillary acidic protein

• Consistent with disease modification treatment effects

Van Dyck et al.. NEJM, 2023

RESULTS
Safety Outcomes
• Antibody targets amyloid in brain but also affects blood vessel amyloid, when cleared causes blood vessels to be leaky
• Amyloid-related imaging abnormalities
• Edema (ARIA-E)
• Hemorrhage (ARIA-H)

Symptomatic: 2.8% 0% Symptomatic: 0.7% 0.2%

Petersen, R. Mayo Clinic, 2023
NEJM Quick Time. NEJM, 2023
RESULTS
Safety Outcomes

• Majority were asymptomatic; most resolve within 4 months of detection (81%)

• Symptoms headache, visual disturbance, confusion, dizziness; seizure, encephalopathy
• Mild: continued treatment, monthly MRIs
• Severe: stop treatment, monthly MRIs; if better then treatment resumed

• HIGHER incidence if ApoE4 homozygous

• ARIA-H (39% in intervention group)
• ARIA-E (33% in intervention group)

Petersen, R. Mayo Clinic, 2023

Van Dyck et al.. NEJM, 2023
RESULTS
Safety Outcomes

• Mostly mild to moderate reactions

• Occurred with first dose (75% of cases)

NEJM Quick Time. NEJM, 2023

 RESULTS
Subgroup analysis

Van Dyck et al.. NEJM, 2023

 RESULTS
Subgroup analysis

Van Dyck et al.. NEJM, 2023

 CONCLUSION
• Lecanumab
• Consistent positive findings in primary and secondary endpoints
• reduced markers of amyloid

• moderately less decline on cognition and function

• Limitations
• Occurrence of ARIA may have led participants and investigators to be aware of trial-group
assignment
• COVID-19 led to missed doses

Van Dyck et al.. NEJM, 2023

CRITICAL APPRAISAL
 Impact on cognition (CDR sum of boxes)
Baseline Adjusted mean change
Both groups Lecanemab group Placebo group Difference
3.2 1.21 1.66 0.45 or 27% slowing in
treatment compared
to placebo

Adverse Events
ARIA-H ARIA-E • RR >1 so treatment increased risk of ARIA
RR 1.92 7.41 • Absolute risk of treatment is a 8-10% increase in ARIA rates
ARI 8.3% 10.9% • Treat 9 patients for 18 months to cause 1 patient to get ARIA

NNH 12 9
 CLINICAL VERSUS STATISTICAL SIGNIFICANCE
• 27% slowing of progression in treatment group versus placebo
• a 0.45-point difference on the CDR-SB, an 18-point scale

Taylor, E. Alz Res UK, 2022

 • 0.45 point difference

• Some US Alzheimer's
Centers of Excellence
will be providing the
drug;
• UHN preparing
protocol; not yet
approved in Canada

WUSL, 2021
MINIMAL CLINICALLY IMPORTANT DIFFERENCE
• “the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in
the absence of troublesome side effects and cost, a change in patient’s management.” – Andrews et al., 2019
• MCID for CDR-SB = 0.98 for MCI and 1.63 for mild AD
• Based on retrospective analysis of a large National Alzheimer’s Coordinating Center Uniform Data Set

• This study found 0.45 point change in CDR-SB for drug vs placebo
• Can MCID be reached if study extended since drug placebo curve were diverging?

Eisai, 2022
Andrews et al. Alzheim Dement, 2019
Lancet Commission on Dementia, 2022
Cummings, J. Alzheim Dement, 2023
PRINCIPLES OF AMYLOID BETA
• Having Amyloid-β plaques doesn’t always lead to Alzheimer’s disease

• Removing all amyloid-β doesn’t seem to lead to resolution of Alzheimer’s disease

• Is amyloid-β a marker of disease or initial disease presentation (ie: in diabetes, glucose

versus HbA1c)

Widera et al. GeriPal Apple Podcast, 2023

Sturchio et al. E Clin Med, 2021
PUTTING LECANEMAB IN PERSPECTIVE
• Donepezil:
• 0.1-1.0 point change on CDR-SB
• with Donepezil over 24 weeks-72 weeks depending on study and confidence interval
• Lecanemab:
• 0.45 point change on CDR-SB
• over 72 weeks

• Lecanemab, new era in Alzheimer’s disease treatment

• Considered a disease modifying drugs
• Doesn’t improve, doesn’t stop or cure the disease
• It does slow the disease course

Rogers, SL., Friedhoff, LT., Euro Neuropsych,1998

Burns et al., Dement Geriatr Cogn Disord, 1999
Petersen, R. Mayo Clinic, 2023
PRACTICALIT Y
• $26,000/year USD for drug alone; additional cost for monitoring and managing side
effects
• Requires MRI
• within 1 year before infusion; five MRI scans during treatment; 1 MRI scan
posttreatment; additional in select pts
• Emergency MRI if acute symptoms
• Neuroradiology training needed to identify ARIA

• Requires PET/blood/CSF to confirm amyloid before infusion eligibility

• Who will stage the dementia to see if patient qualifies?
• Do we have capacity for ApoE4 allele genetic testing?
• What if patient is on anticoagulation?
• What is the age cut-off since drug was more effective in higher age spectrum
PRACTICALIT Y
• Repeat treatment if amyloid returns on PET?
• What is the significance of brain atrophy in treatment group?
• How do we bill for anti-amyloid drug visit evaluation and counselling?
• Donanemab study used amyloid level (specific centiloid cutoff) to stop drug so do we use
biologic or clinical endpoint more important? If monitoring amyloid on PET and and stopping
therapy, do we have PET scan capacity? Can we do blood amyloid levels instead?
• Resume drug if amyloid centiloid reaches a certain threshold?
• Current phase 3 study undergoing extension trial for 4 years
• How long should it be given for? Drug holiday? Are the cognitive effects long lasting?

• Requires infusions for about 1.5 years

• Capacity or infrastructure (ie: “Memory infusion center”)
QUESTIONS AND COMMENTS
REFERENCES
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