Featured Research Session (FRS)

Beyond Amyloid Removal with Lecanemab
Treatment: Update on Long-Term Imaging and Fluid
Biomarkers
July 30, 2024

Alzheimer's Association International Conference (AAIC) 2024
July 28 - August 1, 2024 / Philadelphia, PA, USA + Online

Opening Remarks• Alzheimer’s disease (AD), like other chronic progressive diseases, requires a longterm therapeutic strategy• Long-term treatment should target different pathophysiological processes some ofwhich are more/less important at different stages of the disease– Lecanemab dual mechanism of action removes protofibrils that continue to form and drive AD pathophysiology evenafter amyloid is cleared• Multiple lines of evidence support the need for ongoing treatment:– Stopping treatment results in re-accumulation of biomarkers and reversion to placebo rate of decline– Ongoing treatment results in continued benefit even after amyloid is cleared– After reducing the amyloid source of protofibrils, less frequent maintenance dosing can remove newly
formed protofibrils

2

Beyond Amyloid Removal with Lecanemab Treatment: Update on
Long-Term Imaging and Fluid Biomarkers
Topic

Presenter

Amyloid Plaque Reduction as a Biomarker of Efficacy: Correlation Analysis of Amyloid
PET and Change in CDR-SB Utilizing Semi-Mechanistic Model

Brian Willis

Lecanemab Slows Tau PET Accumulation

Arnaud Charil"Paradoxical” Cerebral Volume Changes in Anti-Amyloid Immunotherapy Trials

Nick Fox

Long-Term Effects of Lecanemab on Biomarkers of Neurodegeneration in Plasma

Charlotte Teunissen

Panel Discussion / Q&A

3AllAmyloid Plaque Reduction as a
Biomarker of Efficacy:
Assessment of Amyloid PET and Change in
CDR-SB Utilizing Semi-Mechanistic Model

July 30, 2024

Brian A. Willis
Eisai Inc. Nutley, NJ. USA.

Disclosures and Acknowledgements
Brian Willis – Disclosures:• BW is an employee of Eisai
Authors:
Brian A. Willis, Pratik Bhagunde, Robert Bell, Natasha Penner, Arnaud Charil,
Michael C. Irizarry, Steven Hersch, and Larisa Reyderman
Eisai Inc. Nutley, NJ. USA.

5

Overview• Exposure response modeling was used to show
– Relationship between amyloid clearance and efficacy– Beneficial effect of early and ongoing treatment– Selecting maintenance dosing regimen

6

Acceleration of AD Pathophysiology in Later Stages Increasingly Driven by
Amyloid Independent Processes
Highlights Importance of Early and Ongoing Treatment Targeting Protofibrils and Plaques

Amyloid hypothesis: synaptic dysfunction and neurodegeneration in Alzheimer’s
disease are caused by the accumulation of toxic amyloid species (oligomers, protofibrils, plaques)• Biomarker changes are starting decades before the clinicalsymptom onset and start with amyloid accumulation• AD progression over time is non-linear, driven by amyloid
and non-amyloid pathways
Amyloid pathway

Non-amyloid pathway

Rapid progression defined by tau
accumulation and neurodegeneration

CDR-SB

Slow progression
defined by amyloid accumulation

Predicted Disease Month

Front. Big Data, 12 August 2020Sec. Medicine and Public HealthVolume 3 - 2020 | https://doi.org/10.3389/fdata.2020.00024

7Aβ, amyloid beta. AD, Alzheimer’s disease. ADD, Alzheimer's disease dementia. AMCI, amnestic mild cognitive impairment. CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes. MCI, mild cognitive impairment.
Jack et al. Brain. 2010;133:3336-48. Jack et al. Lancet Neurol. 2013;12:207-16.

Exposure Response Model for AD Progression and Treatment EffectModel takes into account key factors that
confound crude correlations between amyloid
clearance and clinical outcome:Pharmacokinetics

Efficacy

Amyloid PET

1. Contribution of non-amyloid driven progression
increases with disease severity
2. Greater progression with higher baseline amyloid
levels3. Greater progression with worse cognitive status /disease severity
4. Greater amyloid clearance with greater baselineamyloid levels
Technical details for the model areprovided in Poster, Abstract ID 89308

Diseaseslowing8Models included data for up to 110 months in Study 201 Core and
OLE and up to 54 months of continuous lecanemab biweekly dosing in
Clarity AD Core and open-label extension• Amyloid PET: 4575 observations• CDR-SB: 8456 observations
CDR-SB, Clinical Dementia Rating Scale-Sum of Boxes. CL, clearance. kin=zero-order rate for production of amyloid plaque. kout, first-order rate of degradation of amyloid plaque. PET,
positron emission tomography. PK, pharmacokinetics. PD, pharmacodynamics. Q, intercompartmental clearance. V1, central volume of distribution. V2, peripheral volume of distribution.

Model Takes Into Account Relationship Between Greater
Clinical Progression with Higher Baseline Amyloid Levels
CFB in CDR-SB at 24 Months vs PET SUVR Baseline
for ADNI MCI Participants
Amyloid Positive Participants Only
CFB in CDR-SB at 24 Months

PET = 1.6

Predicted
CDR-SB CFB• Analyses using ADNI data
have suggested thatcognitive decline (increase in
CDR-SB) increases withincreasing amyloid load to an
amyloid PET SUVr of 1.6(131 Centiloid)

Baseline PET SUVR

Dhadda et al, Alzheimer’s Association International Conference (AAIC), Chicago, IL, July 22-26, 2018

9

ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes. CFB, change from baseline. MCI, mild cognitive impairment. PET, positron emission
tomography. SUVr, standardized uptake value ratio.

Modeling Impact of Baseline Amyloid Levels on
Disease Progression• Individual disease progression rates were estimated by fitting Richard’s function to CDR-SB data from Study 201 and Clarity AD• Pattern of increasing disease progression rate with increasing baseline amyloid PET observed using ADNI data wasrecapitulated using data from lecanemab studies• Relationship between rate of disease progression and amyloid PET was modeled using a piecewise function

10

ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes. PET, positron emission tomography.

Model Accurately Predicts Observed 18-Month Data
Lecanemab Effect Increases with Continued Treatment• Separation from placebo group continues to increase with extended lecanemab treatment
CDR-SB
Placebo
93% reductionin amyloid PET
at 48 months

Lecanemab
10 mg/kg

Time (Months)

11

CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes. PET, positron emission tomography.

Primary outcome in Clarity AD was 0.45

CDR-SB
Mean Change from Baseline

Amyloid PET (Centiloid)

Amyloid PET

Lecanemab
10 mg/kg

0.43

1.45

Placebo

Time (Months)

2.15

Simulation Reproduces Greater Amyloid Clearancewith Greater Baseline Amyloid Levels
Amyloid PET
Mild AD(Baseline PET 80 Centiloid)

Amyloid PET (Centiloid)

MCI(Baseline PET 40 Centiloid)

Time (Months)
12AD, Alzheimer’s disease. MCI, mild cognitive impairment. PET, positron emission tomography.

Simulation Outcomes Show Lecanemab Has A Greater
Impact On Cognitive Outcome Earlier In The Disease
MCI

CDR-SB(Baseline PET 40 Centiloid, MMSE 28)

Mild AD(Baseline PET 80 Centiloid, MMSE 23)

CDR-SB
Change from Baseline• Because of greater
contribution of nonamyloid driven
progression as
disease advances, it isimportant to initiate
earlier treatment with atherapeutic targeting
amyloid andprotofibrils
Time (Months)

13

AD, Alzheimer’s disease. MCI, mild cognitive impairment. MMSE, Mini-Mental State Examination. CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes. PET, positron emission tomography.

Monthly Maintenance Dosing Provides Similar Outcomes asContinuous Biweekly Treatment
CDR-SB
Placebo

Continuous
Biweekly Dosing

Initiate Monthly
Dosing at 18 Months

Time (Months)

CDR-SB
Change from Baseline

Amyloid PET (Centiloid)

Amyloid PETContinuous
Biweekly Dosing
Placebo

Initiate Monthly
Dosing at 18 Months

Time (Months)• After reducing amyloid source of protofibrils, less frequent monthly maintenancedosing can remove newly formed protofibrils, and maintain biomarker and clinicaleffect of biweekly dosing
Change in amyloid PET and CDR-SB were simulated for subjects who were treated with placebo, biweekly lecanemab for 48 months, or biweekly lecanemab for 18 months, followed by once-monthly lecanemab

14

Simulations assumed a similar patient population as the Clarity-AD trial.
CDR-SB, Clinical Dementia Rating Scale - Sum of Boxes. PET, positron emission tomography.

Conclusions• Exposure response modeling was used to show
– Relationship between amyloid clearance and efficacy– Beneficial effect of early and ongoing treatment– Selecting maintenance dosing regimen• Results are consistent with disease pathophysiology, mechanismof action, long-term clinical trial data, extensive biomarker
outcomes, and QSP modeling

15

QSP, quantitative systems pharmacology.

Lecanemab Slows Tau PET Accumulation

July 30, 2024

Arnaud Charil
Eisai Inc. Nutley, NJ. USA

Disclosures and Acknowledgements
Arnaud Charil – Disclosures:• AC is an employee of Eisai Inc.
Authors:
Arnaud Charil, Youfang Cao, Brian A. Willis,
Steven Hersch, Michael C. Irizarry, and Larisa Reyderman
Eisai Inc. Nutley, NJ. USA

17

Overview• Previously reported findings suggest that targeting protofibrils in addition toclearing plaque leads to clinical efficacy, slowing of tau progression andimprovement in pathophysiological biomarkers• In Clarity AD, we have described findings in a group of ‘no/low tau’, unlike otherstudies, which support clinical stability or improvement with early initiation oflecanemab• The objective of this analysis was to assess the impact of lecanemab onregional tau SUVR over time and the association with cognition in the tau PET
sub-study of Clarity AD

18

Tau terminology based on latest FDA definitions.
AD, Alzheimer’s disease. PET, positron emission tomography. SUVR, standardized uptake value ratio.

Tau PET Substudy

Lower Tau Indicative of Earlier Alzheimer’s Disease
Averaged Scans from the Tau PET Substudy (n=342)
Baseline stratification• MK6240 PET processed at
Invicro (ref region: ventral
cerebellum)•–

No/Low SUVR <1.06• n=141 (41.2%)–

Intermediate SUVR 1.06-2.91• n=191 (55.8%)–

High SUVR >2.91• n=10 (2.9%)

Intermediate
Tau

5

SUVR

19

Whole cortical gray matter Tau
PET cutoffs derived from
MK6240 scans in theLantheus/Cerveau database[clinical AD, amyloid positive,
mean MMSE (SD): 23.4 (3.5)]

No/Low Tau

0.5

High Tau

Tau terminology based on latest FDA definitions.
AD, Alzheimer’s disease. MMSE, Mini-Mental State Exam. PET, positron emission tomography. SD, standard deviation. SUVR, standardized uptake value ratio.

Anatomical Distribution of Tau PET Signal in No/Low Tau Subgroup
Characterized by Signal in Entorhinal Cortex
Clinical Continuum
Tau Pathology

Mild Cognitive Impairment

No/Low

Mild-Moderate Severe Dementia

IntermediateHigh

Average (n=20)

No/Low Tau
Subgroup

Baseline Tau SUVR

• Not previously
analyzed and/or
reported in otheranti-amyloid
antibody
clinical trials
Entorhinal
Cortex (I)20

Hippocampus
(II)

Early
Limbic (III)Late
Limbic (IV)

Association
Primary
neocortex (V) Neocortex (VI)

Neuroanatomical Region (Braak Stage)Tau terminology based on latest FDA definitions.
SUVR, standardized uptake value ratio.

Analysis• In the tau PET Clarity AD sub-study,
correlation matrices (Spearman’s) weregenerated to explore associations acrossbrain regions (7 composites) between:– Baseline tau SUVR across regions– Baseline tau and amyloid SUVR
– Baseline tau and change in tau SUVR
– Baseline tau and cognition (CDR-SB)
21

CDR-SB, Clinical Dementia Rating-sum of boxes. PET, positron emission tomography. ROI, region of interest. SUVR, Standardized uptake value ratio.

Composite ROIs:
1. Medial Temporal
2. (Lateral) Temporal
3. Meta Temporal
4. Occipital
5. Parietal
6. Cingulate
7. Frontal

Tau Distribution Across Brain Regions

Higher Tau Levels in Early Temporal Brain Regions
Baseline
Frontal Tau SUVR

Baseline Frontal vs Baseline Medial Temporal Tau SUVR

Baseline Medial Temporal Tau SUVR

Baseline
Temporal Tau SUVR

Baseline Temporal vs Baseline Medial Temporal Tau SUVR

22

Composite ROIs:

Baseline Medial Temporal Tau SUVR

ROI, region of interest. SUVR, Standardized uptake value ratio.

1.
2.
3.
4.
5.
6.
7.

Medial TemporalTemporal
Meta Temporal
Occipital
Parietal
Cingulate
FrontalHigher Baseline Amyloid Levels are Associatedwith Higher Baseline Tau Levels Across Brain Regions

Baseline Parietal Tau SUVR

Baseline Parietal Tau SUVR vsBaseline Parietal Amyloid SUVR (Florbetaben)

Composite ROIs:

Baseline Parietal Amyloid SUVR
(Florbetaben)
23

ROI, region of interest. SUVR, Standardized uptake value ratio.

1.
2.
3.
4.
5.
6.
7.

Medial TemporalTemporal
Meta Temporal
Occipital
Parietal
Cingulate
FrontalHigher Baseline Amyloid Levels are Associated with
Higher Baseline Tau Levels Across Brain Regions

Baseline Tau SUVR

Baseline Tau SUVR vs Baseline Amyloid SUVR
in each of the 7 Regions
1.Medial Temporal

2.Temporal

Baseline Tau SUVR

Baseline Amyloid SUVR
(Florbetaben)

4.OccipitalBaseline Amyloid SUVR
(Florbetaben)

5.Parietal

Baseline Amyloid SUVR
(Florbetaben)
24

ROI, region of interest. SUVR, Standardized uptake value ratio.

Baseline Amyloid SUVR
(Florbetaben)

3.Meta-temporal

Baseline Amyloid SUVR
(Florbetaben)

6.Cingulate

Baseline Amyloid SUVR
(Florbetaben)

7.Frontal

Baseline Amyloid SUVR
(Florbetaben)

Placebo

Lecanemab

7
6
5
4
3

1 2

3

4 5 6

13 Months

Composite ROIs:

25

1

2
1

CFB at 13 Months
in Parietal Tau SUVR vsBaseline Medial Temporal Tau SUVR

0.5

7 1 2

3

Medial TemporalTemporal
Meta Temporal
Occipital
Parietal
Cingulate
Frontal

4 5 6

18 Months

CFB Tau SUVR

1.
2.
3.
4.
5.
6.
7.

Rho

7

1 2

3

4 5 6

13 Months

7 1 2

3

4 5 6

18 Months

CFB Tau SUVR

• The higher the tau at baseline,
especially in early regions, the higher
the tau accumulation in other brain
regions with disease progression

7

0

CFB @13mo in Parietal Tau SUVR

Baseline Tau SUVR

Lecanemab Disrupts Tau Accumulation Across Brain Regions• Treatment with lecanemab disrupts tau
accumulation

CFB, change from baseline. Mo, Months. ROI, region of interest. SUVR, Standardized uptake value ratio.

Baseline Medial Temporal
Tau SUVR

Lecanemab Disrupts Tau Accumulation Across Brain Regions
CFB at 13 Months in Tau SUVR in each of the
7 Regions vs Baseline Medial Temporal Tau SUVR

Baseline Medial Temporal Tau SUVR
26

Baseline Medial Temporal Tau SUVR

6.Cingulate

7.Frontal

CFB @13mo in
Cingulate Tau SUVR

5.Parietal

3.Meta-temporal

Baseline Medial Temporal Tau SUVR

CFB, change from baseline. Mo, Months. MTL, medial temporal. SUVR, Standardized uptake value ratio.

CFB @13mo in
Frontal Tau SUVR

4.OccipitalBaseline Medial Temporal Tau SUVR

CFB @13mo in
Parietal Tau SUVR

CFB @13mo in
Occipital Tau SUVR

Baseline Medial Temporal Tau SUVR

2.Temporal

CFB @13mo in
Meta-temporal Tau SUVR

CFB @13mo in
MTL Tau SUVR

CFB @13mo in
Temporal Tau SUVR

1.Medial Temporal

Baseline Medial Temporal Tau SUVR

Baseline Medial Temporal Tau SUVR

For each region, all slopes are statistically differentComparing Tau PET Subgroups*

Lecanemab Slows Tau Spread in Earlier and Later Tau Stages
No/Low: Whole Cortical GM Tau <1.06

Intermediate+High: Whole Cortical GM Tau ≥1.06• Lecanemab impacts medial temporal, earliest tau region• Lecanemab impacts progression more broadly

Change from Baseline (95% CI) in Tau PET*This was a post-hoc analysis with nominal p values and no adjustment for multiplicity

27

Tau terminology based on latest FDA definitions.
Note: Based on modified intention-to-treat analysis population. Adjusted mean change from baseline, SE and p-value are derived using mixed model repeat measures (MMRM) with treatment group, visit, treatment group by visit interaction, clinical subgroup, use of
Alzheimer’s disease symptomatic medication at baseline, ApoE4 carrier status, region, baseline value by visit interaction as fixed effects, and baseline value as covariate.
CI, confidence interval. GM, gray matter. MMRM, mixed models for repeated measures. PET, positron emission tomography. ROI, regions of interest.

Lecanemab Slows Cognitive Decline
Independent of Baseline Tau Levels Across Brain Regions

Composite ROIs:
1.
2.
3.
4.
5.
6.
7.

Medial TemporalTemporal
Meta Temporal
Occipital
Parietal
Cingulate
Frontal• Baseline cognition is not related
to baseline tau levels• Higher cognitive decline isassociated with higher baseline
tau levels

worsening%CFB @18mo in CDR-SB%CFB at 18 Months
in CDR-SB vsBaseline Medial Temporal Tau SUVR

Baseline Medial Temporal Tau SUVR
28

CDR-SB, Clinical Dementia Rating-sum of boxes. CFB, change from baseline. Mo, Months. ROI, region of interest. SUVR, Standardized uptake value ratio.

Lecanemab Slows Cognitive Decline
Independent of Baseline Tau Levels Across Brain Regions%CFB @18mo in CDR-SB

Worsening

CFB at 18 Months in CDR-SB
vs Baseline Tau SUVR in each of the 7 Regions
1.Medial Temporal

2.Temporal

Baseline Temporal Tau SUVR

%CFB @18mo in CDR-SB

Baseline Medial Temporal Tau SUVR

4.OccipitalBaseline Occipital Tau SUVR

29

3.Meta-Temporal

5.Parietal

Baseline Parietal Tau SUVR

Baseline Meta-Temporal Tau SUVR

6.Cingulate

Baseline Cingulate Tau SUVR

CDR-SB, Clinical Dementia Rating-sum of boxes. CFB, change from baseline. Mo, Months. SUVR, Standardized uptake value ratio.

7.Frontal

Baseline Frontal Tau SUVR

For each region, all slopes are notstatistically different, except in Frontal

Tau PET Substudy

Consistent Outcomes for Subgroups
CDR-SB*The longitudinal tau PET substudy was predefined. The subgroups (no/low and intermediate+high tau PET) were a post-hoc analysis with nominal p values and no adjustment for multiplicity
30

CDR-SB, Clinical Dementia Rating-sum of boxes. CI, confidence interval. PET, positron emission tomography.

Neuro-Dynamic QSP Model Supports Continued Treatment
with Lecanemab for Maintained Benefits
Incorporates Key Mechanisms of
Alzheimer’s Disease Pathophysiology

31

Three interlinked modules: Amyloid and Tau pathways
and cognitive impairment to capture the Alzheimer’s
disease pathophysiology and disease progression

QSP Model Describes Medial Temporal Tau PET SUVR

Dr Youfang Cao
Perspectives Session #92093
Tuesday, July 30, 2024: 4:15 PM – 5:45 PM
EDT, Pennsylvania Convention Center, Hall A
Aβ, amyloid beta. ADAS-Cog, Alzheimer's Disease Assessment Scale–Cognitive Subscale. CDR-SB, Clinical Dementia Rating-sum of boxes. CFB, change
from baseline. LEC10-BW, lecanemab 10 mg/kg biweekly. LECA, lecanemab. PET, positron emission tomography. QSP, quantitative systems pharmacology.

Conclusions• Lecanemab treatment impacts tau accumulation across brain regions– In no/low tau group, this impact is seen in earliest regions of MTL while in intermediate/hightau PET group lecanemab impacts progression more broadly across brain regions• Lecanemab slows cognitive decline independent of baseline tau levels across brain regions• Results in early stages of disease (ie, no/low tau) support clinical stability or improvement withearly initiation of lecanemab• Because of greater contribution of non-amyloid driven progression as disease advances, it isimportant to initiate earlier in treatment with a therapeutic targeting amyloid and protofibrils

32

MTL, medial temporal. PET, positron emission tomography. QSP, quantitative systems pharmacology.

"Paradoxical” Cerebral Volume Changes in
Anti-Amyloid Immunotherapy Trials

July 30, 2024

Nick Fox
Dementia Research Centre, Department of Neurodegenerative Disease, and the UK Dementia Research Institute,
UCL Queen Square Institute of Neurology, London
33

Disclosures and Acknowledgements
Nick Fox – Disclosures:• Consultancy / advisory boards: Biogen, Eisai, IONIS, Lilly, Roche & Siemens – all payments to UCL
Authors:
Nick Fox,1 Arnaud Charil,2 Pallavi Sachdev,2 Hongmei Niu,2Michael Irizarry,2 Steven Hersch,2 Shobha Dhadda,2 David Li,2 Amanda Goodwin,2 Mark Hodgkinson,2and Larisa Reyderman2
1. Dementia Research Centre, Department of Neurodegenerative Disease, and the UK Dementia ResearchInstitute, UCL Queen Square Institute of Neurology, London
2. Eisai Inc. Nutley, NJ USA
Acknowledgements:• I would like to acknowledge discussions and contributions from Chris Belder, Jon Schott, Frederik Barkhof,
Delphine Boche, James Nicoll, Zane Jaunmuktane and Henrik Zetterberg
34

First Reported with Aβ Immunization - AN1792• Brain volume loss vs placebo– 3.1 ± 2.0 % vs. 2.0 ± 1.7%
– A “dose/titre-response” relationship• Unchanged by excluding “Encephalitis”
patients• Since seen with many but not all antiamyloid monoclonal antibodies
35

And Seen with Lecanemab: Increased Brain Volume Loss andCortical Thickness Loss, and More Ventricular Enlargement
Whole Brain Volume

Cortical Thickness

Lateral Ventricular Volume
Baseline 43345, 44199
Placebo
Lecanemab

P<0.00001

Baseline 1007564, 1000048
Placebo
Lecanemab

4.1mL greater brain volume
reduction (0.4% of baseline)

P<0.00001

Baseline 2.61, 2.60
Placebo
Lecanemab

0.02mm greater
cortical Tx reduction

1.8mL greater vent volume
increase

Consistent with previous studies of monoclonal antibodies that removed amyloid36* P<0.05; ** P<0.01; *** P<0.001; **** P<0.0001
CI, confidence interval; SE, standard error; vMRI, volumetric magnetic resonance imaging. Bateman et al. 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference. November 29 – December 2, 2022. San Francisco, CA, USA.

However - Reduced Volume Loss of Hippocampi on Lecanemab
Total Hippocampal Volume

P=0.0039
0.02mL lesshippocampal loss

Baseline 6674, 6634
Placebo
Lecanemab* P<0.05; ** P<0.01; *** P<0.001; **** P<0.0001
37

CI, confidence interval; SE, standard error; vMRI, volumetric magnetic resonance imaging. Bateman et al. 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference. November 29 – December 2, 2022. San Francisco, CA, USA.

Possible Explanations• Related to amyloid removal?
– Removal of amyloid plaques– Removal of plaques and associated inflammation• Increased neurodegeneration / toxicity?
– Direct, or via release of oligomers from amyloid plaques– Mediated through ARIA-E• Alterations in fluid dynamics / fluid shifts?
– Alteration in CSF resorption as amyloid is mobilized38

Extensive Amyloid Removal (on PET) Seen with Lecanemab

van Dyck et al. N Engl J Med. 2023;388:9-21.

What Volume is Occupied Amyloid Plaques in AD?
Total Amyloid-β Load in Fusiform
Gyrus of Sporadic AD• In AD ~6-8% of cortex is occupied by amyloid
plaque at autopsy– Bussiere et al 2002 - 6.9% of prefrontal cortex– Josephs et al 2008 – 7% total, 3% by compact Aβ– Clark et al 2012 - 6% of grey matter– Chen et al 2021 - 5-8% by diffuse plaques ; ~1-2% bycompact plaques– Abrahamson et al 2022 - 8.7% of frontal cortex; 6.5% oftemporal cortex• And equate to 2-4% of whole brain• This compares with the ~0.4% excess loss seen
with lecanemab• Amyloid plaques are much more than justamyloid (other proteins, dystrophic neuritesetc.) - they are “space-occupying”
40

Source: UCL Queen Square Brain Bank

AD, Alzheimer's disease.

Does Plaque Accumulation Lead to Volume Increases?
• Increases in cortical thickness are reported in preclinical AD– Montal V et al 2021 - Biphasic cortical macro- and microstructural changes in
ADAD– Vilaplana E et al 2022 - Positive association between astrocytosis PET andcortical thickness in presymptomatic FAD– Salvadó G et al 2022 - Transient higher grey matter volumes at the earliest
stages of AD, associated with CSF YKL-40 and sTREM2

41

AD, Alzheimer's disease. ADAD, autosomal dominant Alzheimer disease. CSF, cerebrospinal fluid. FAD, familial Alzheimer’s disease. PET, positron emission topography.

Autopsy Cases Have Shown Extensive Plaque Clearancewith Immunotherapies

Untreated AD

Pt treated with aducanumab“ ….demonstrating sparse cortical Aβ plaque”
Plowey ED et al. Acta Neuropathol. 2022;144:143-153.

42

Aβ, amyloid beta. AD, Alzheimer's disease. LTE, long-term extension. Pt, patient.

Infrequent Plaques Seen After Lecanemab Treatment
Beta-Amyloid
Untreated AD

Patient treatedwith lecanemab• The lecanemab treated patient showed near absence of diffuse amyloid, and sparse neuritic plaques• Consistent with PET which showed marked reduction of amyloid following lecanemab treatment
43

AD, Alzheimer's disease. PET, positron emission topography.
Honig et al. 2022 Alzheimer’s Association International Conference (AAIC) Annual Meeting. July 31 - August 4, 2022 -- San Diego, CA.

Greater Brain Volume Loss Seen with More Amyloid Removal

Change from Baseline inCentiloids at 18 Months

100

50

0

-50

-100

-150
-40,000-20,000

0

Change from Baseline in Whole Brain Volume (mm3)44Placebo: r=0.186 (P=0.01120)
Lecanemab: r=0.243 (P=0.00069)

Brain Volume – by Baseline Amyloid PET (Centiloids) Quartile
Greater Baseline Amyloid Associated with Greater Excess Volume Loss
1st Quartile

Baseline 1008383, 998524
Placebo
Lecanemab

3rd Quartile

Baseline 999223, 990666
Placebo
Lecanemab

45

2nd Quartile

Baseline 1018330, 1002679
Placebo
Lecanemab

4th Quartile

Baseline 999910, 994282
Placebo
Lecanemab

Amyloid Plaques are Also Associated with Inflammatory Cells

Resolution of thisassociatedinflammatory response
may also contribute tovolume loss following
plaque removal

A. Astrocytes (GFAP+ve) and B. Microglia (IBA1)
surrounding amyloid plaque (green)
46

GFAP, glial fibrillary acidic protein. IBA1, Ionized calcium-binding adaptor molecule 1.

Serrano-Pozo et al. J Neuropathol Exp Neurol. 2013;72:462-71.

GFAP, an Astrocytic Biomarker, Reduced with Lecanemab
Plasma GFAP**** P<0.0001

47

GFAP, glial fibrillary acidic protein. Bateman et al. 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference. November 29 – December 2, 2022. San Francisco, CA, USA.

Neurodegeneration Biomarkers: No Worsening
CSF NfL

Plasma NfL

CSF T-Tau• No difference in CSF NfL which had large variability• Plasma NfL, with larger sample size, trends towards
difference (P=0.06) at 18 months• CSF-total tau increase in placebo and decreased inlecanemab treated group**** P<0.0001

48

van Dyck et al. 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference. San Francisco, CA, USA.
November 29 – December 2, 2022.
CSF, cerebrospinal fluid, NfL, neurofilament light chain. SE, standard error; p-tau, phosphorylated tau; t-tau, total tau.

Brain Volume Change vs Clinical Efficacy Scales• For the same amount of brain volume loss, there is less clinical / cognitive change for lecanemab vs placebo– The normal association of decline with rate of atrophy has been disrupted

49

Lecanemab
Placebo

Change from Baseline ADCS MCI-ADL
at 18 Months

CDR-SB

Worsening

Change from Baseline CDR-SB
at 18 Months

Worsening– i.e. more than one process going on in the treated group

Change from Baseline in Whole Brain Volume (mm3)
CDR-SB, Clinical Dementia Rating-sum of box. ADCS ADL-MCI, Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for mild cognitive impairment (MCI) subjects..

ADCS MCI-ADL

Change from Baseline in Whole Brain Volume (mm3)And What About Relationship of Volume Change to ARIA?
Relative to no ARIA, the group with ARIA had:
• No significant difference in volume loss in whole brain or cortex• Greater lateral ventricular volume loss with ARIA (2.6 mL)• Greater hippocampal volume increase with ARIA (43.4 mm3)50

ARIA, amyloid related imaging abnormalities. ARIA-E, ARIA with edema. ARIA-H, ARIA with hemosiderin deposits.

Consistently Seen with Antibodies that Achieved
Amyloid Removal
Brain volume difference(Rx – PBO)
TRAILBLAZER-ALZ2(donanemab)

Study 201

(lecanemab)

CLARITY-AD

TRAILBLAZER-ALZ(donanemab)(lecanemab)

GRADUATE-II(gantenerumab)

GRADUATE-I
GRADUATE-I

Study 301 (bapineuzumab)
Study 302 (bapineuzumab)(gantenerumab)

ENGAGE(aducanumab)

CREAD(Crenezumab)

EXPEDITION3

EMERGE(aducanumab)(Solanezumab)

51

Belder et al Lancet Neurology in Revision

What About the Brain Volume Loss in Lecanemab-Treated Individuals
Who Achieved Amyloid Reduction to <30 CL by 12 Months?

•
•
•
52

Placebo: all placebo subjects with 12-month amyloid PET
Lecanemab Centiloid 12m < 30: Lec subjects with amyloid PET < 30 at 12 months
Lecanemab Centiloid 12m ≥ 30: Lec subjects with amyloid PET ≥ 30 at 12 months

CL, Centiloids. m, months. PET, positron emission topography.

Analysis models includes baseline amyloid PET as covariate

Conclusions• Increased brain reduction and ventricular enlargement are consistent featuresof immunotherapies that achieve amyloid removal• The excess brain loss is:– compatible with the volume occupied by amyloid plaques in Alzheimer’s disease– is not associated with worse clinical outcomes– is not associated with markers of neurodegeneration• Patient- and group-level analyses support excess brain volume loss is
associated with clinical efficacy• Hippocampal volume was preserved relative to placebo• Need no longer be called “paradoxical”

53• Amyloid-removal related pseudo-atrophy – or ARPA – may be a more
appropriate term while we wait long-term outcomesLong-Term Effects of Lecanemab on
Biomarkers of Neurodegeneration in Plasma
July 30, 2024

Charlotte Teunissen
Amsterdam UMC, Dept. of Laboratory Medicine, Neurochemistry Laboratory,
Department of Clinical Chemistry, Vrije Universiteit Amsterdam.

Disclosures and Acknowledgements
Charlotte Teunissen - Disclosures:

Research Support
European Commission(Marie Curie International Training Network,
grant agreement No 860197 (MIRIADE)) andTAME, and JPND (bPRIDE, CCAD), European
Partnership on Metrology, European Union’s
Horizon Europe Research and Innovation
Programme ((22HLT07 NEuroBioStand), MJ Fox
Foundation, IMI 3TR and EPND projects,
Health~Holland, the Dutch Research Council(ABOARD, TAP-dementia: ZonMW), Alzheimer’s
Drug Discovery Foundation, The Selfridges
Group Foundation, Alzheimers Netherlands,
Alzheimer’s Association

Collaboration Contracts
with commercial entities

Acumen, ADx Neurosciences, AC-Immune,
Alamar, Aribio, Axon Neurosciences, BeckmanCoulter, BioConnect, Bioorchestra, Brainstorm
Therapeutics, Celgene, Cognition Therapeutics,
EIP Pharma, Eisai, Eli Lilly, Fujirebio, InstantNano Biosensors, Novo Nordisk, Olink,
PeopleBio, Quanterix, Roche, Toyama, Vivoryon.
Consultancy contracts for Aribio, Biogen,
Beckman-Coulter, Cognition Therapeutics, Eli
Lilly, Merck, Novo Nordisk, Olink, Roche andVeravas.

Editorial Boards
Editor in Chief: Alzheimer’s Research & Therapy.
Associate editor of
Molecular Neurodegeneration; Neurology:
Neuroimmunology & Neuroinflammation;
Medidact Neurologie; Springer* All contracts concord with European ethical standards and privacy regulations, and are approved by Amsterdam UMC

Dr Teunissen receives no personal compensation from any supports and contracts of the above or others except the Amsterdam UMC.

Authors:
Charlotte Teunissen,1 Brian A. Willis,2 Pratik Bhagunde,2 Robert Bell,2 Natasha Penner,2 Pallavi Sachdev,2 David Li,2 Michio Kanekiyo,2 Larisa Reyderman2
1.

Amsterdam UMC, Dept. of Laboratory Medicine, Neurochemistry Laboratory, Department of Clinical Chemistry, Vrije Universiteit Amsterdam.
2. Eisai Inc. Nutley, NJ USA

Overview• Lecanemab treatment showed robust and continuous impact acrossbiomarkers of Alzheimer’s disease through 24 months• Participants on placebo who started lecanemab at 18 months show
improvement within 3 months with similar trajectory as Core
lecanemab treatment group• Long-term therapy continues to improve biomarkers further, and avoid
re-accumulation of biomarkers and resumption of placebo rate of
decline when anti-amyloid treatment is stopped• Mechanism of action supports continued treatment to remove
protofibrils and oligomers that continue to form after amyloid is cleared56

Alzheimer’s Disease is a Complex, Multifactorial Disease with
Associated Fluid Biomarkers of Underlying Disease Pathophysiology

57

Aβ, amyloid β. NfL, neurofilament light chain. pTau, phosphorylated tau. GFAP, glial fibrillary acidic protein. MMP, matrix metalloproteinase. sAD, sporadic Alzheimer’s disease. fAD, familial Alzheimer’s disease.
Teunissen C, et al. Lancet Neurol. 2022;21:66-77.

Lecanemab Unique Dual-Action Mechanism:

Targets Highly Toxic Protofibrils, Rapidly Clears Amyloid Plaques and Slows Tau Pathology• The unique dual action of lecanemab rapidly clears amyloid plaque and highly toxic protofibrils1-5– Selectively binds to soluble Aβ aggregated species, with preferential activity for Aβ protofibrils over monomers(>1000x) and over fibrils (>10x)1,6-10• Slows tau pathology in temporal lobe (early Braak regions) which is a hallmark of disease progression
Aβ, amyloid-beta; kDa, kilodaltons. Source: Presented at CTAD 2021. Note: Illustration is based on data from Biacore, inhibition ELISA and immunoprecipitation.

58

1. Söderberg L, et al. Neurotherapeutics. 2022 Oct 17. 2. van Dyck CH, et al. N Engl J Med. 2023 Jan 5;388(1):9-21. 3. Lecanemab prescribing information Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s001lbl.pdf Accessed July 24, 2023. 4. Stern AM, et al. Neuron. 2023 Jul 5;111(13):2012-2020.e4. 5. Ono K, Hampel H. Int J Mol Sci. 2020 Jan
31;21(3):952. 6. Tucker S, et al. J Alzheimers Dis. 2015;43(2):575-88. 7. Lord A, et al. Neurobiol Dis. 2009;36:425–34. 8. Sehlin D, et al. PLoS One. 2012;7:e32014. 9. Sehlin D, et al. Neurodegener Dis. 2011;8:117–23.
10. Logovinsky V, et al. Alzheimer’s Research & Therapy. 2016;8:14

Biomarker Assessments in Lecanemab Studies Informed Different
Components of AD Pathology
Amyloid Pathology

Tau Pathology

Neuroinflammation/
Neurodegeneration

Misfolded and AggregatedAβ Species

Misfolded and Aggregated
3R/4R Tau Protein

Neuronal Loss, Axonal
Damage & Neurodegeneration

A+

T+

•
•
•
•

Amyloid PET1Aβ[1-40]2Aβ[1-42]2.
Aβ 42/40 ratio3

•
•
•
•

Tau PET (MK-6240)
MTBR-tau243 (C2N)

pTau1812,5
pTau 2176,7

1florbetaben or florbetapir tracers. 2Fujirebio Lumipulse. 3C2N Precivity AD-Aβ, 4Euroimmun ELISA.
5Quanterix Simoa. 6C2N Precivity AD2. 7ALZPath plasma ptau217

59

N+

•
•
•
•

Glial fibrillary acidic
protein (GFAP)5
t-tau2
NfL5
Neurogranin4

Figures from Nature Review Neurology, 17, 2021

Aβ, amyloid beta. GFAP = glial fibrillary acidic protein. MTBR-tau243, microtubule-binding region (MTBR) of tau containing the residue 243. Nfl, neurofilament light chain.
PET, positron emission tomography. ptau181, phosphorylated tau-181. ptau217, phosphorylated tau-217. t-tau, total tau.

Biomarker of Alzheimer’s Disease (AD) Pathology Across AD
Continuum Reflecting Revised Criteria1,2
Symptom
Onset
Disease Continuum
Early AD pathology

Pathology
Progression

Early

Emergence of
biomarker changes
Aβ42/40
CSF blood

Late AD pathology

Amyloid PET
GFAP2

Tau PET
MTBRtau-2432

pTau181pTau2172

Braak Regions
I/II

Late

Braak Regions
III/IV

Braak Regions
V/VI

Novel biomarker shed from tangles
NfL
T-Tau

Amyloid-induced biomarker of tau
hyperphosphorylation
1. Jack Jr CR, et al. Alzheimer’s Dement. 2018;14:535–562. 2. Jack CR, et al. Nat Med. 2024 Alzheimers Dement. 2024 Jun 27. [Epub ahead of print].

60

Aβ, amyloid beta. AD, Alzheimer's disease. CSF, cerebrospinal fluid. GFAP = glial fibrillary acidic protein. MTBR-tau243, microtubule-binding region (MTBR) of tau containing the residue 243.
Nfl, neurofilament light chain. PET, positron emission tomography. ptau181, phosphorylated tau-181. ptau205, phosphorylated tau-205. ptau217, phosphorylated tau-217. t-tau, total tau.

Clarity AD OLE: Long-Term Treatment Continues to Show
Improvement in Biomarkers of Amyloid Pathology
Amyloid PETCore Study

OLE

Plasma Aβ42/40 Ratio

Core Study

OLE

Less Amyloid

Baseline 0.088, 0.088
Placebo
Lecanemab

Baseline 81.6, 81.5 CL
Placebo
Lecanemab• Lecanemab treated participants continued to benefit during the open label extension• Participants on placebo who started lecanemab at 18 months show improvement in biomarkers within 3months of treatment with similar trajectory as Core lecanemab treatment group61

Aβ, amyloid beta; CHG, change; CL, Centiloids. GFAP, glial fibrillary acidic protein; MMRM, mixed models for repeated measures; PET, positron emission tomography; ptau181, phosphorylated tau-181.

Clarity AD OLE: Long-Term Treatment Continues to Show Improvement in
Biomarkers of Amyloid-Induced Tau Pathology
Plasma pTau1811
OLE

Adjusted Mean Change from Baseline(±SE) in Plasma pTau217 (pg/mL)

Core Study

Plasma pTau2171
Core Study

OLE

Baseline 6.1, 6.2 pg/mL
Placebo
Lecanemab• Lecanemab treatment shows rapid improvement in amyloid-induced tau pathology biomarkers which issustained during the open label extension1• Participants on placebo who started lecanemab at 18 months show improvement within 3 months with similar
trajectory as Core lecanemab treatment group62

Aβ, amyloid beta; CHG, change; GFAP, glial fibrillary acidic protein; MMRM, mixed models for repeated measures; PET, positron emission tomography; ptau181, phosphorylated tau-181.
1Results shown from single batch analysis of all samples available for timepoints through OLE 24 months.

Lecanemab Treatment Slows Progression of CSF MTBR-tau243, and Tau PET
Disrupts Tau Pathology

CSF MTBR-tau243*

Clarity AD

Tau PET

Baseline 549, 499 pg/mL
Placebo
Lecanemab

63*167 subjects (PBO:N=83,LEC:N=84) are included in the MMRM CSFMTBR-tau243; Statistical significance not reached due to limited sample size
Data generated with C2N MTBR-tau (Product Code P0001)
CSF, cerebrospinal fluid. MMRM, mixed models for repeated measures. MTBR-tau243, microtubule-binding region (MTBR) of tau containing the residue 243. ROI, region of interest. SE, standard error.

Interpretation: Robust Reduction of Amyloid-Induced Tau
Pathology Slows Tangle Formation
Effect on Amyloid-induced
pTau181 and pTau217
Plasma pTau181

Core StudyOLE(N) Delayed Start:(N) Early Start:

Adjusted Mean Change from Baseline(±SE) in Plasma pTau217 (pg/mL)
64

AD pathology progression

Effect on Tau-induced
MTBR-tau243 and Tau PETMedial Temporal

CSF MTBR-tau243

Plasma pTau217
Core Study

Clarity AD

OLE

Clarity AD: Improvement in Biomarkers of
Neuroinflammation, Synaptic Injury and Neurodegeneration
Plasma GFAPCore Study

Plasma NFL

OLECore Study

OLE

Baseline 22.2, 21.9 pg/mL
Placebo
Lecanemab

Baseline 361, 356 pg/mL
Placebo
Lecanemab(N) Delayed Start:(N) Early Start:(N) Delayed Start:(N) Early Start:

Core CSF Neurogranin
Baseline 519, 500 pg/mL
Placebo
Lecanemab

65Core CSF T-Tau
Baseline 615, 585 pg/mL
Placebo
Lecanemab

Aβ, amyloid beta; CHG, change. GFAP, glial fibrillary acidic protein. NfL, neurofilament light chain protein. ptau181, phosphorylated tau-181. T-Tau, total tau.

**** P<0.0001

Interrupting Treatment is Associated with Reaccumulation of AD
Pathology
Plasma Aβ42/40 Ratio

Study 201

Plasma pTau181• Rebound in plasma
biomarker levels
observed upontreatment interruption
during the gap periodof Study 201

47% Worsening

Plasma GFAP

30% Reaccumulation

Plasma pTau217

13% Reaccumulation• Ongoing therapy
continues to maintainimprovement inplasma biomarkers ofAD
Gap period is up to 2 years.

66

Aβ, amyloid beta. AD, Alzheimer's disease. GFAP, glial fibrillary acidic protein; PET, positron emission tomography; ptau181, phosphorylated tau-181. ptau217, phosphorylated tau-217.
McDade et al. Alzheimers Res Ther. 2022;14:191. Data on File. Eisai Inc.

PK/PD Models Estimated that Fluid Biomarkers Reaccumulate at Faster
Rate than Amyloid PET When Treatment is Discontinued After 18 Months
PlasmaBiomarker

Reaccumulation t1/2
(year)

Aβ42/400.5

p-tau181

1.6

GFAP

1.7

Amyloid PET

12.1

Reaccumulation for all
biomarkers was estimated via
PK/PD modeling based onclinical data from studies 201
and 301 including OLE• Fluid biomarkers are more sensitive indicators of amyloid and neurodegenerative pathology changes and reaccumulate at a faster rate when treatment is discontinued– For example, half the treatment effect on Aβ42/40 ratio is lost within 6 months while half the treatment
effect on amyloid PET is lost within 12.1 years• Lecanemab mechanism of action supports continued treatment to remove protofibrils and oligomers that
continue to form after amyloid is cleared and sustain changes in plasma biomarkers
67

Aβ, amyloid beta; GFAP, glial fibrillary acidic protein. OLE, open-label extension. ptau181, phosphorylated tau-181. ptau217, phosphorylated tau-217. PET, positron emission tomography. PK, pharmacokinetics. PD, pharmacodynamics.

Summary• Lecanemab treatment showed robust and continuous impact of biomarkers
across measures of amyloid, tau, neurodegeneration, astrocyte andsynaptic pathophysiological measures through 24 months• Alzheimer’s disease pathophysiology biomarkers showed improvement
within 3 months in newly treated participants• Phase 2 Gap period and OLE data show detrimental effect of stopping
treatment, with re-accumulation of biomarkers and resumption of placeborate of decline• Lecanemab mechanism of action supports continued treatment to remove
protofibrils and oligomers that continue to form after amyloid is cleared
68

OLE, open-label extension.

Acknowledgements
Participants & Their Support
We acknowledge with thanks the individuals who enrolled in lecanemab
Study 201 and the Clarity AD Trial as well as their family, caregivers, andfriends who supported them.

Thank you

We also acknowledge the DSMB members, Site Investigators, Study
Coordinators, Raters, contract research organization (CRO), and otherpersonnel whose dedication and hard work in collecting data andproviding care were essential to the completion of this trials.

We thank Clario and Invicro for their ongoing imaging support
Funding for the studies and analyses was provided by Eisai Inc. and Biogen Inc.
Editorial support, funded by Eisai Inc, was provided by
Mayville Medical Communications
Presentations were drafted in accordance with Good Publication Practice (GPP 2022) guidelines

Panel Discussion and Q&A

Beyond Amyloid Removal with Lecanemab Treatment: Update on
Long-Term Imaging and Fluid Biomarkers
Alzheimer's Association International Conference (AAIC) 2024
July 28 - August 1, 2024 / Philadelphia, PA, USA + Online