Perspectives Session

Does the Current Evidence Base Support Lecanemab
Continued Dosing for Early Alzheimer’s Disease?

July 30, 2024

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

Opening Remarks• The pathophysiology of Alzheimer’s disease (AD) involves abnormalities ofamyloid beta (Aβ) and tau processing– Just as in other chronic progressive diseases, AD requires a long-term therapeutic strategy– Specific pathophysiological processes may need to be targeted for optimal long-term treatment
at different stages of AD• Lecanemab dual mechanism of action removes protofibrils that are thought to formand drive AD pathophysiology both before and after amyloid plaque is cleared• In this symposium, we present the latest evidence supporting the need forlecanemab continued dosing in early symptomatic Alzheimer’s disease– Current evidence for mechanism-based rationale– Latest clinical pharmacology data and modeling– Update on clinical and biomarker results from the Clarity AD study, including the latest efficacy
and safety data out to 30-36 months
2

Does the Current Evidence Base Support Lecanemab Continued
Dosing for Early Alzheimer’s Disease?
Topic
Does the Current Evidence for Lecanemab Mechanism Support a Rationale forContinued Lecanemab Dosing?

Dennis Selkoe

How Does the Latest Clinical Pharmacology Data & Modeling Support Continued
Lecanemab Dosing?

Larisa Reyderman

Neuro-Dynamic Quantitative Systems Pharmacology (QSP) Model Supports Continued
Lecanemab Treatment With Maintenance Dosing For Alzheimer’s Disease
Is There Evidence for a Continued Benefit for Long-Term Lecanemab Treatment?
A Benefit/Risk Update from Long-Term Efficacy, Safety and Biomarker Data
Panel Discussion / Q&A

3

Presenter

Youfang Cao
Christopher van Dyck
All

Does the Current Evidence for the Lecanemab
Mechanism Support a Rationale forContinued Lecanemab Dosing?

Dennis Selkoe
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA

Disclosures and Acknowledgments
Dennis Selkoe - Disclosures:• Director and consultant to Prothena Biosciences• Ad hoc consultant to Eisai
Authors:
Dennis Selkoe,1 Shobha Dhadda,2 Michael Irizarry,2 Lynn Kramer2
1. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
2. Eisai Inc. Nutley, NJ USA

5

APPsβGeneration of Amyloid β-Protein (Aβ) Occurs Throughout
Life but can Lead to Aβ Aggregation with Age

β
Aβ

Aβ

2 to ~28 monomers

γ = presenilin

AICD

Oligomers

AβAβ“Protofibrils” (4-8 nm
diffusible aggregates)~~28 – >500 monomers

Amyloid plaques:insoluble amyloid fibrils 8 nm
wide and not readily diffusible
6

Aβ, amyloid beta. APPsβ, amyloid precursor protein sβ.

Haass, Schlossmacher et al. Nature 1992

Aqueously soluble
oligomers/protofibrils
are a minority of Aβ
in AD brain but account forthe major portion of the synaptic
toxicity
and are bound by lecanemab
7Aβ, amyloid beta. AD, Alzheimer’s disease.

Diffusible Aβ Dimers/Oligomers Isolated from AD Brain Inhibit Long Term
Potentiation (LTP) When Floated onto Normal Mouse Hippocampal Slices

8

AD, Alzheimer’s disease. Con, control. D, dimer. fEPSP, field
excitatory postsynaptic potentials. LTP, long-term potentiation.
M, monomer. Min, minutes. MW, molecular weight. TBS, trisbuggered saline. Veh, vehicle.

Shankar et al, Nature Medicine 2008

An Aβ Oligomer-Selective Antibody (71A1) Immuno-purifies
Synaptotoxic Aβ Oligomers from AD Brain Soluble Extracts
71A1 Rescues LTP

9Aβ, amyloid beta. aCSF, artificial cerebrospinal fluid. AD, Alzheimer’s disease. fEPSP, field excitatory postsynaptic potentials.
hBrain, human brain. HFS, high-frequency stimulation. LTP, long-term potentiation.

71A1-purified Oligomers
Directly Inhibit LTP

Liu et al, Alzh Dem 2021

Diffusible Aβ Oligomers from AD Cortex Impair Memory in Healthy Adult Rats
Human Aβ oligomers are infused into the cerebral ventricle of a normal rat

Rat forgets the earlier foot shock
And reenters the dark chamberquickly10Aβ, amyloid beta.

Shankar et al, Nature Medicine 2008

Connecting Aβ Dimers/Oligomers with Tau• Endogenous Aβ monomers and dimers/oligomers can be isolated by SEC from saline extracts of AD cortex

11

Aβ, amyloid beta. AD, Alzheimer’s disease. IP, immunoprecipitate. MW, molecular weight. SEC, size exclusion chromatography.

Jin et al, PNAS 2011

Aβ Dimers/Oligomers from AD Cortex Induce Neurite Dystrophy
After Treatment of Normal Rat or Human Neurons…and οAß increases
pTau levels in neurons

Aβ, amyloid beta.
AD, Alzheimer’s disease.
Con, control.
oAβ, oligomers of Aβ.
TBS, tris-buffered saline.
12

Jin et al, PNAS 2011

Antibodies to the N- but Not the C-terminus of Aβ Prevent
Aβ Oligomer-Induced Neuritic Dystrophy

Aβ, amyloid beta.
AD, Alzheimer’s disease.
Con, control. M, monomer.
TBS, tris-buffered saline.
13

Jin et al, PNAS 2011

A New ELISA (71A1/3D6) Reveals CSF Levels of oAβ Correlate
Directly with CSF Levels of Tau and pTau

Aβ, amyloid beta.
CSF, cerebrospinal fluid.
ELISA, enzyme-linked
immunosorbent assay.
oAβ, oligomers of Aβ.
14

T. Yang, T. Xu, D Selkoe.
unpublished data

Aqueous Soaking Extracts of AD Cortex Contain Diffusible Aβ Fibrils

CryoEM of these diffusible fibrils reveals thesame atomic structure as that of insoluble
amyloid fibrils from plaque-rich cortex

15

Stern, A. et al, Neuron 2023
(Yang, Scheres, Goedert)Lecanemab Binds Both Amyloid Plaque Fibrils in situ and Small
Diffusible Fibrils in Aqueous Extracts of AD Cortex

Aβ, amyloid beta.
AD, Alzheimer’s disease.
RCFav, average relative
centrifugal force.
16

Stern et al, Neuron, 2023

Lecanemab Preferential Binding to Soluble Aβ Protofibrils• Small protofibrils, approx. 75-300 kDa,
• Large protofibrils, approx. 300-5000 kDa• Lecanemab binds small protofibrils 100x and large protofibrils 25x stronger than aducanumab• Gantenerumab is less selective and binds monomers with somewhat higher affinity comparedto lecanemab and aducanumab
17

Aβ, amyloid-beta; kDa, kilodaltons. IC50, half-maximal inhibitory concentration. Söderberg L, et al. Neurotherapeutics. 2023 Jan;20(1):195-206.

Lecanemab Unique Dual-Action Mechanism:

Targets Highly Toxic Protofibrils and Rapidly Clears Amyloid Plaques
Lecanemab
Dual Mechanism

Lecanemab
Targets Protofibrils

Lecanemab
Clears Plaques

Lecanemab
Slows Tau Pathology

INSERT
IMAGE
HERE

•

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•

Lowering Aβ is a crucial step, but AD pathology may still include tau propagation from neuron to neuron
Aβ, amyloid-beta; kDa, kilodaltons. Source: Presented at CTAD 2021. Note: Illustration is based on data from Biacore, inhibition ELISA and immunoprecipitation.

18

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, 2024. 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

Multiple Lines of Evidence Support an Ongoing Pathogenic Role for Soluble Aβ
Oligomers and Diffusible Fibrils (‘Protofibrils’) in Neuronal Dysfunction•

Soluble and diffusible aggregated Aβ species, often called protofibrils, are abundant in AD brain•

These species are toxic and cause:– Synaptic dysfunction– Microglial activation– Tau phosphorylation and neuritic dystrophy– Impaired memory and learning (LTP and in vivo memory)•

Antibodies against these species from typical AD patients prevent neuronal dysfunction•

Lecanemab preferentially binds to soluble aggregated and diffusible species, that continue to be present andproduced after clearance of plaques

The extensive evidence for a dual lecanemab mechanism
supports the rationale for continued dosing as plaquereduction is achieved
19

Aβ, amyloid-beta; AD, Alzheimer’s disease. LTP, long-term potentiation. PET, positron emission topography.

How Does the Latest Clinical Pharmacology Data &Modeling Support Continued Lecanemab Dosing?

Larisa Reyderman
Eisai Inc. Nutley, NJ USA

Disclosures and Acknowledgements
Disclosures:• LR is an employee of Eisai Inc.

Authors:
Larisa Reyderman, Brian Willis, Natasha Penner, Arnaud Charil, Shobha Dhadda,
Steven Hersch, Michael Irizarry, Lynn Kramer
Eisai Inc. Nutley, NJ USA

21

Overview• Alzheimer’s disease (AD), like other chronic progressive diseases, requires a longterm therapeutic strategy• Lecanemab dual mechanism of action removes protofibrils that continue to formand drive AD pathophysiology even after amyloid is cleared• Discontinuation of treatment is associated with reaccumulation of biomarkers andreversion to placebo rate of clinical decline• Modeling and simulation analyses allowed us to define less frequent dosing
regimen to maintain biomarkers and further clinical benefit

22

Alzheimer’s is a Chronic Disease Whose Pathophysiology
Continues Even After Amyloid Plaque Removal• Lecanemab has unique selectivity towards toxic soluble species of Aβ

Protofibrils and oligomers continue to be produced even after plaques are cleared,
providing mechanistic justification for ongoing treatment with lecanemab tomaintain clinical and biomarker efficacy
23

Aβ, amyloid beta.

Clinical Effect is Maintained During Interruption of Lecanemab
Treatment but Reverts to Placebo Rate of Decline (Study 201)
CDR-SB• Initiating

Differences in CDR-SB weremaintained forapproximately 2 years off lecanemab

24

CDR-SB , Clinical Dementia Rating – Sum of Boxes. OLE, open-label extension. McDade et al. Alzheimers Res Ther. 2022;14:191.

lecanemab
treatment in OLE
reduced clinicaldecline in
subjects who
received placebo
and in subjects
who were treatedwith lecanemab
during Study 201
CoreInterrupting Treatment is Associated with Variable Rates of Reaccumulation of
AD Biomarkers: Amyloid PET & Aβ42/40 Ratio (Study 201)
Amyloid PET

Aβ42/40 Ratio

47% Worsening
21% Reaccumulation

Long-term therapy continues to improve biomarkers further, andavoid the reaccumulation of biomarkers when anti-amyloid
treatment is stopped
McDade et al. Alzheimers Res Ther. 2022;14:191.
25

Aβ42/40 = ratio of Aβ42 to Aβ40. OLE = open-label extension. PET= positron emission tomography.

Interrupting Treatment is Associated with Reaccumulation of AD Pathology:
GFAP, pTau181 & pTau217 (Study 201)GFAP

30% Reaccumulation

pTau181

24% Reaccumulation

pTau217

13% Reaccumulation

Long-term therapy continues to improve biomarkers further, andavoid the reaccumulation of biomarkers when anti-amyloid
treatment is stopped
26

GFAP = glial fibrillary acidic protein. pTau181, phosphorylated tau 181. pTau217, phosphorylated tau 217.
McDade et al. Alzheimers Res Ther. 2022;14:191. Data on File. Eisai Inc.

WHAT IS THE IDEAL
MAINTENANCE DOSINGREGIMEN WITH LECANEMABAFTER AMYLOID
CLEARANCE?
27

Defining Maintenance Dose for Longer-Term Clinical Benefit• PK/PD models were used to select maintenance dosing regimen:– Can sustain clinical efficacy (CDR-SB)– Can sustain improvement in plasma biomarkers of amyloid and tau
pathophysiology and neuroinflammation• Simulation analyses were conducted to define optimal time totransition from bi-weekly to maintenance dosing– Initiating maintenance dosing at 18 or 24 months

28

CDR-SB = Clinical Dementia Rating – Sum of Boxes. PD, pharmacodynamic. PK, pharmacokinetics.

Multiple Semi-Mechanistic PK/PD Models Developed Correlating Lecanemab
Exposure With Amyloid PET, Plasma Biomarkers and Clinical Outcome
Pharmacokinetics
Peripheral
V2

Q

CentralV1

Amyloid PETCLkin
Production

Amyloid
Plaquekout
Degradation

Clinical Outcome
Amyloid-driven
progression
Non-Amyloid
driven progression

CDR-SB

Developed Models
1. PK: 32126 serum lecanemab observations from 2295 subjects
2. Amyloid PET: 4575 observations from 1119 subjects
3. CDR-SB: 8456 CDR-SB observations from 1012 subjects
4. Plasma Aβ42/40 ratio: 12468 observations from 1994 subjects
5. pTau181: 7909 observations from 2179 subjects
6. GFAP: 3098 observations from 736 subjects

Models 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 OLE
29

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. pTau181, phosphorylated tau 181. V1=central volume of distribution. V2=peripheral volume of distribution.

PK/PD Models Estimated That Fluid Biomarkers Reaccumulate at a Faster Rate
Than Amyloid PET When Treatment is Discontinued After 18 Months
Plasma Aβ42/40

Amyloid PET

6040
Reaccumulation t1/2=12.1 years

20
0Aβ42/40 Ratio

Amyloid PET (Centiloid)80

Reaccumulation t1/2= 0.5 years0

12 18 24
36
Time (Months)

48

0

12 18 24
Time (Months)

36

48• Changes in fluid biomarkers on treatment discontinuation are more sensitive measures of disease progression• 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• Similar loss of treatment effect observed for pTau181 (t1/2=1.6 years) and GFAP (t1/2=1.7 years)
30

Aβ, amyloid beta. PET, positron emission tomography. pTau181, phosphorylated tau 181. pTau217, phosphorylated tau 217.

Monthly Maintenance Dose Prevents Reaccumulation ofBrain Amyloid and Worsening of Plasma Biomarkers
Plasma Aβ42/40 Ratio

40

Discontinue

20
0

0

Plasma pTau181 (pg/mL)

12

18 24
Time (Months)

36

2.5

LEC10-M

18 24
Time (Months)

0.088

36

48

Discontinue

Aβ cut-off=0.092*

012

Plasma GFAP

312

LEC10-M

0.092

48

Discontinue0

Amyloid
negative

0.096

0.084

LEC10-M

3.5

2Aβ42/40 Ratio

60

Plasma pTau181

31

0.100

80

Plasma GFAP (pg/mL)

Amyloid PET (Centiloid)

Amyloid PET

18
24
Time (Months)

36

48

425

375

Discontinue

325
275
225

LEC10-M
0

12

18
24
Time (Months)

36

48

Aβ, amyloid beta. GFAP, glial fibrillary acidic protein. LEC10-M, lecaneamb 10 mg/kg monthly. PET, positron emission tomography. pTau181, phosphorylated tau 181. *Verbel et al. 14th Annual CTAD Conference. 2021. Boston, MA. USA.

Initiating Monthly Maintenance Dosing at 18 or 24 Months Results in Similar
Effect on CDR-SB & Amyloid PET Compared to Biweekly Dosing for 4 years
CDR-SB
Placebo

No difference in amyloid outcome
when transition to maintenancedose at 18 vs 24 months

0

12

18

24

36

CDR-SB
Change From Baseline

Amyloid PET (Centiloid)

Amyloid PET

48

No difference in clinicaloutcome between biweekly andmaintenance dose regimens

Placebo012(Month)Time (Months)

18

24

36

48

Time
Time (Month)(Month)18 months LEC10-M

24 months LEC10-M

Continuous LEC10-BW

Placebo

Similar effects when initiating monthly maintenance dosing ateither 18 or 24 months
32

CDR-SB = Clinical Dementia Rating scale Sum of Boxes. LEC10-BW = lecanemab 10 mg/kg biweekly. LEC10-M = lecanemab 10 mg/kg monthly. PET = positron emission tomography.

Conclusions• Alzheimer’s disease, like other chronic progressive diseases, requires a long-term
therapeutic strategy• Lecanemab mechanism of action supports long-term therapy that continues toimprove biomarkers further and avoid the reaccumulation of biomarkers when antiamyloid treatment is stopped• Phase 2 and OLE shows detrimental effect of stopping treatment, with
reaccumulation of biomarkers and resumption of placebo rate of decline• Modeling of extensive dose-ranging, placebo-controlled, and OLE data indicate thatmonthly maintenance dosing after 18 or 24 months of biweekly dosing can sustain
efficacy and biomarker benefit of lecanemab

33

OLE = open-label extension.

Neuro-Dynamic Quantitative Systems
Pharmacology (QSP) Model Supports
Continued Lecanemab Treatment With
Maintenance Dosing For Alzheimer’s Disease
July 30, 2024

Youfang Cao
Eisai Inc. Nutley, NJ. USA.

Disclosures and Acknowledgements
Disclosures:• YC is an employee of Eisai• KH is an Eisai-sponsored voluntary research associate professor at Washington University andhas received salary from Eisai• KH may receive income based on technology licensed by Washington University to C2N
Diagnostics
Authors:
Youfang Cao, Brian A. Willis, Pallavi Sachdev, Natasha Penner, Kristin R Wildsmith,Arnaud Charil, Kanta Horie, Akihiko Koyama, and Larisa Reyderman
Eisai Inc. Nutley, NJ. USA.
35

Lecanemab Unique Dual-Action Mechanism:

Targets Highly Toxic Protofibrils and Rapidly Clears Amyloid Plaques
Lecanemab
Dual Mechanism

Lecanemab
Targets Protofibrils

Lecanemab
Clears Plaques

Lecanemab
Slows Tau Pathology

INSERT
IMAGE
HERE

•

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•

Lowering Aβ is a crucial step, but AD pathology may still include tau propagation from neuron to neuron
Aβ, amyloid-beta; kDa, kilodaltons. Source: Presented at CTAD 2021. Note: Illustration is based on data from Biacore, inhibition ELISA and immunoprecipitation.

36

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, 2024. 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

Neuro-Dynamic Quantitative Systems Pharmacology (QSP) Model
Incorporates Key Mechanisms of Alzheimer’s Disease Pathophysiology•

A mechanistic yet parsimonious model for AD
pathophysiology:– 11 equations and 74 parameters•

Built the model on available literature evidence:– Lecanemab binding affinities w/ protofibril vs plaque1– Amyloid monomer clearance rate2– Amyloid aggregation/deaggregation rates3, 4– Kinetics of tau isoforms in human neuron5– Tau pathology progression6– Effects of amyloid and tau in cognitive impairment7•

Informed model parameters using a
6-dimensional dataset (N=4056):– Clarity AD (Study 301)
– Lecanemab Study 201– Alzheimer's Disease Neuroimaging Initiative (ADNI)37

Aβ, amyloid beta. AD, Alzheimer’s disease. ADAS-Cog, Alzheimer's Disease Assessment Scale–Cognitive Subscale. CDR-SB, Clinical Dementia Rating-sum of boxes. PET, positron emission topography. QSP, Quantitative Systems Pharmacology.
1 Söderberg et al., Neurotherapeutics 2023. 2. May et al., J Neurosci 2015. 3. Michaels et al., Nature Chem 2020. 4. Dear et al., PNAS 2020. 5. Sato et al., Neuron. 2018. 6. Roberts et al. Acta Neuropathol Commun 2020.
7. Hanseeuw et al. JAMA Neurol 2019.

Aligning Individual Data on Pathological Time Course
Observed Data Based on Study Time Course

Observed Data Based on Pathological Time Course

Mild AD

Mild AD
Late MCI

Early MCI

PathologicalTime
CourseAdjustment

The GRACE[1] approach was employed to adjust the relative AD
pathological time for all the subjects in the QSP dataset.

Early MCI

Early MCI = Early Mild Cognitive Impairment: ADNI GO/2
Late MCI = Late Mild Cognitive Impairment: ADNI GO/2
Mild AD = Mild Alzheimer’s disease dementia

1. Donohue et al. 2014 Alzheimers Dement.
GRACE: Growth Models via Alternating Conditional Expectations.

38

Late MCI

AD, Alzheimer’s disease. ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating-sum of boxes. MCI, mild cognitive impairment.

QSP ModelMedial Temporal Tau PET SUVR
Core

OLE

Plasma Aβ42/40 Ratio
Core
OLE

CDR-SB Change From BaselineCore

Plasma pTau181
Core

Plasma pTau181 (pg/mL)

Amyloid PET (Centiloid)
Core
OLE

Plasma Aβ42/40 Ratio

Accurately Describes Six Key Outcomes From Clarity AD
OLE

ADAS-Cog Change From Baseline

OLE

Core

OLE

Simulations conducted using a virtual patient population of N=5000 created from the QSP model with matched baseline characteristics of Clarity AD population.
Note: Solid lines and dots represent the mean from simulations and data, respectively. Error bars and shaded areas are 95%ile CI.

39

Aβ, amyloid beta. AD, Alzheimer’s disease. ADNI, Alzheimer's Disease Neuroimaging Initiative. 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. PET, positron emission topography. ptau181, phosphorylated tau-181. QSP, Quantitative Systems Pharmacology. SUVR, standardized uptake value ratio.

QSP Model

Predicts Clinical Outcomes of Anti-Amyloid Treatments
Gantenerumab (GRADUATE I/II)

Donanemab (TRAILBLAZER-ALZ 2)

CDR-SB

Amyloid PET

Aducanumab (EMERGE)

Data source: https://investors.biogen.com/staticfiles/8e58afa4-ba37-4250-9a78-2ecfb63b1dcb

Data source: Bateman et al. N Engl J Med 2023; 389:1862-76.

Data source: Sims et al. JAMA 2023; 330(6):512-527.
(combined population)

Note: Solid lines and shaded areas represent the mean dynamics and 95% confidence intervals from QSP simulations. Dots and error bars represent the mean and 95% confidence intervals from data.

40

•
•
•
•

Drug effect parameters were tuned to capture amyloid PET data for each mAb. Literature binding affinities were used when available
QSP parameters of AD pathophysiology remained unchanged across drugs
Simulations were performed using virtual patient populations mimicking the baseline age, amyloid PET, and CDR-SB of corresponding clinical trials
ApoE4 genotype was used to titrate the dose for aducanumab according to the study design. Simulations followed the dose titration study design of these trials

CDR-SB, Clinical Dementia Rating-sum of boxes. CFB, change from baseline. PET, positron emission topography. QSP, Quantitative Systems Pharmacology.

QSP Model

Describes AD Progression and Links Pathophysiology to Clinical Outcomes
AD Pathological Cascade

QSP Simulated Pathological Cascade
Data supported profiles

Biomarker Abnormality

Model predicted profiles

Time
Jack et al. Lancet Neurol. 2013

All simulated biomarkers are proportionally scaled between 0 and 1 to show their relative dynamics.

• Data informed biomarker profiles and clinical outcome simulated from mechanistic QSP model match literature expectations• Model predicts biomarkers that are not measured clinically: protofibril, tau seed, and neuronal loss
41

Aβ, amyloid beta. AD, Alzheimer’s disease. CDR-SB, Clinical Dementia Rating-sum of boxes. CSF, cerebrospinal fluid. FDG, 18F-fluoro-deoxy-glucose. MRI, magnetic resonance imaging. MCI, mild cognitive impairment. MT, medial temporal region of
the brain. PET, positron emission topography. QSP, Quantitative Systems Pharmacology.

QSP Model Predicts Rapid Clearance of Neurotoxic
Amyloid Protofibrils by Lecanemab
Amyloid Plaque

Amyloid Protofibril
Placebo

70% reduction
by 18 months

Continued LEC10-BW• Model agrees with observed amyloid PET
outcome42

LEC10-BW, Lecanemab 10 mg/kg biweekly. QSP, Quantitative Systems Pharmacology. PET, positron emission topography.

Placebo

94% reduction
by 18 months
Continued LEC10-BW• Predicted impact on protofibrils.
To be confirmed by protofibril assay

Continued Protofibril Suppression Inhibits Tau PET
Accumulation
Amyloid Protofibril
Placebo

Discontinued treatment
30% Re-accumulation

Continued LEC10-BW• Discontinuation: projected 30% protofibril reaccumulation by 48 months vs continued
treatment
43

Medial Temporal Tau PET SUVR
Placebo

Discontinued treatment
23% Accumulation

Continued LEC10-BW• LEC10-BW stabilizes tau PET over 18 months• Discontinuation: projected 23% tau accumulation inmedial temporal region by 48 months vs continued
treatment

LEC10-BW, Lecanemab 10 mg/kg biweekly. CDR-SB, Clinical Dementia Rating-sum of boxes. CFB, change from baseline. LEC10-BW, lecanemab 10 mg/kg biweekly. PET, positron emission topography. SUVR, standardized uptake value ratio..

QSP Model

Supports Lecanemab Monthly Maintenance Dosing
Amyloid PET (Centiloid)

Amyloid Protofibril (% Baseline)

Placebo
Discontinued
Continued LEC10-BW

Monthly
Maintenance*

44

Plasma pTau181
Plasma pTau181(pg/mL)

Plasma Aβ42/40 Ratio

Plasma Aβ42/40 Ratio*Monthly Maintenance: lecanemab 10 mg/kg monthly dosing following 18 months of biweekly initial treatment
LEC10-BW, Lecanemab 10 mg/kg biweekly. Aβ, amyloid beta. CFB, change from baseline. PET, positron emission topography. ptau181, phosphorylated tau-181. QSP, Quantitative Systems Pharmacology.

Conclusions• The neuro-dynamic QSP model was developed to mechanistically describe AD
pathophysiology• Model predicts that lecanemab aggressively clears the toxic amyloid protofibrils,
which slows down tau pathology and disease progression• Simulations showed that discontinued lecanemab treatment may result in rapid
re-accumulation of amyloid protofibrils and rebound of tau pathology measured
by tau PET• Simulations support long-term benefit of monthly maintenance dosing oflecanemab treatment beyond 18 months

45

AD, Alzheimer’s disease. QSP, Quantitative Systems Pharmacology. PET, positron emission topography.

Is There Evidence for a Continued Benefit for Long-Term
Lecanemab Treatment? A Benefit/Risk Update from LongTerm Efficacy, Safety and Biomarker Data

Christopher van Dyck
Yale University School of Medicine, New Haven, CT USA

Disclosures and Acknowledgements
Christopher van Dyck – Disclosures:
Advisor/Consultant for:Roche Pharmaceuticals
Eisai, Inc
Ono Pharmaceuticals
CerevelYale University and Dr. van Dyck receive grant support from:
Eli Lilly
Biogen Idec
Roche Pharmaceuticals
Biohaven Pharmaceuticals
UCB

Janssen Pharmaceuticals
Eisai, Inc
Genentech, Inc
Cerevel Therapeutics

Authors:
Christopher van Dyck,1 Reisa Sperling,2 Shobha Dhadda,3 David Li,3
Steven Hersch,3 Michael Irizarry,3 Lynn Kramer347

1. Yale University School of Medicine, New Haven, CT USA
2. Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston MA, USA
3. Eisai Inc. Nutley, NJ USA

Clarity AD Study Design

Clarity AD Core and Open-Label Extension (OLE) Includes >3 Years of Lecanemab Treatment

Optional longitudinal sub-studies• Amyloid burden (amyloid PET; n=716)• Brain tau pathology (tau PET; n=342)• CSF biomarkers of neurodegeneration (n=281)• Subcutaneous formulation (OLE)

48

Number of Participants with Adverse Events
Change from Core Study Baseline in CDR-SB

Change from Baseline for:
ADAS-Cog14
ADCS MCI-ADL
Biomarkers

AD, Alzheimer’s disease; ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCOMS, Alzheimer’s Disease Composite Score; ADCS MCI-ADL, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale forMild Cognitive Impairment; ApoE4, apolipoprotein E4; CDR-SB, Clinical Dementia Rating-sum of boxes; CSF, cerebrospinal fluid; IV, intravenous; MCI, mild cognitive impairment; MMSE, Mini-Mental State Exam; OLE, open-label extension;
PET, positron emission tomography; SD, standard deviation; TEAEs, treatment emergent adverse events; WMS-IV LMSII, Wechsler Memory Scale IV-Logical Memory (subscale) II. van Dyck CH, et al., N Engl J Med. 2023;388:9-21.

Clarity AD OLE: CDR-SB Efficacy Through 36 Months

Lecanemab-Treated Patients Continue to Accrue Benefit Through 36 Months• Delayed start group does not catch up to early start group, reflecting importance of early treatment initiation• ADAS-Cog14 and ADCS MCI-ADL had similar results as CDR-SB

49

Note: Early start lecanemab 10 mg/kg biweekly group are those subjects on lecanemab 10 mg/kg biweekly in the Core. Delayed start LEC10-BW group (those subjects that initiate lecanemab 10 mg/kg biweekly in the OLE). OLE includes those participants on subcutaneous and intravenous formulations.
Based on testing the hypothesis that early start arm maintains at least half of the treatment effect seen at the end of 18 months. 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 treatmentgroup, 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.
ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating-sum of boxes. OLE, open-label extension. SE, standard error.

Clarity AD OLE: CDR-SB Efficacy Through 36 Months

Lecanemab-Treated Patients Continue to Accrue Benefit Through 36 Months• Treatment effect between lecanemab and ADNI cohort continues to expand from 18 through 36 months• Delayed start group also shows benefit in OLE relative to ADNI cohort• ADNI observational cohort
represents exact
population of those in
Clarity AD study• Matched ADNI participants
show similar degree of
decline to placebo groupout to 18 months

50

Note: Early start lecanemab 10 mg/kg biweekly group are those subjects on lecanemab 10 mg/kg biweekly in the Core. Delayed start LEC10-BW group (those subjects that initiate lecanemab 10 mg/kg biweekly in the OLE). OLE includes those participants on subcutaneous and intravenous formulations.
Based on testing the hypothesis that early start arm maintains at least half of the treatment effect seen at the end of 18 months. 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 treatmentgroup, 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.
ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating-sum of boxes. OLE, open-label extension; SE, standard error.

Lecanemab Meaningfully Delayed Progression to Next AD
Stage Through 36 Months (Responder Analysis)
Time to Worsening on CDR-SB(Shift from MCI to dementia or from mild AD to moderate/severe AD)

CDR-SB Range0

Normal

(95%CI: 0.59, 0.84)

Event Rate

Proportion of Patients that Progress
to Next Stage

0.5 – 4.0

Hazard Ratio = 0.704

30%Reduction

Staging Category

Questionable Cognitive
Impairment

0.5 – 2.5

Questionable Impairment

3.0 – 4.0

Very Mild Dementia

4.5 – 9.0

Mild Dementia

9.5 – 15.5

Moderate Dementia

16.0 – 18.0

Severe Dementia• Progression was defined as CDR-SB Score
progressing from MCI (0.5-4) to mild AD
dementia(4.5-9) or mild dementia to moderatedementia (9.5-15.1) based on dementia staging
on CDR-SB (O’Bryant et al., Arch Neurol 2008)• Given less frequent assessment, "Since
controlled-based imputation was used for missing
data in this analysis, CDR-SB (which has greater
range) was used rather than global CDR for
disease staging"

51

AD, Alzheimer's disease. ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating-sum of boxes. CI, confidence interval. MCI, mild cognitive impairment.

Tau PET Substudy

Lecanemab Slows Tau Spread Especially in Temporal Lobe (Early Braak Regions)1*
Medial Temporal

SUVr

Tau PET SUVr

SUVr

Meta Temporal

1Baseline and at least one post-baseline tau PET*Other regions favored lecanemab but were p > 0.0552

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 atbaseline, ApoE4 carrier status, region, baseline value by visit interaction as fixed effects, and baseline value as covariate.
CI, confidence interval; PET, positron emission tomography; ROI, regions of interest; SUVr, standardized uptake value ratio.

SUVr

Temporal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

53

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• Not previously analyzed and/or
reported in previous antiamyloid antibody clinical trials

Baseline Tau SUVR

Average Image of 20 No/Low Tau
Participants with Entorhinal Uptake

Neuroanatomical Region(Braak Stage)
Slide Courtesy of Keith Johnson

54

Tau terminology based on latest FDA definitions.
PET, positron emission tomography;
SUVr, standardized uptake value ratio.

Tau Pathology
Clinical Continuum

Entorhinal
Cortex (I)Hippocampus(II)

No/Low

Early
Limbic (III)Late
Limbic (IV)Intermediate

Early Symptomatic Disease

Association
Primary
Neocortex (V) Neocortex (VI)High

Clinical Outcomes Through 36 Months

Subjects with No/Low Tau Continued to Benefit Through 36 Months
CDR-SB – Overall Population

CDR-SB – No/Low-Tau Population•

The no/low tau subgroup represents 40% of the overall study population•

Similar results were observed for ADAS-Cog14 and ADCS MCI-ADL

Tau terminology based on latest FDA definitions
OLE includes those participants on subcutaneous and intravenous formulations.

55

ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale. ADCS MCI-ADL, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment. ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating-sum of boxes.
CL, Centiloid. OLE, open-label extension. SE, standard error.

Subjects with No/Low Tau PET: Response Rate

59% Had No Decline and 51% Had Improvement at 36 Months
CDR-SB No Decline – No/Low Tau Population76%
no decline at
18 months

90%
80%

90%

Patients (%)

60%
50%
55%
no decline at
18 months

30%

Lecanemab

20%

Placebo

10%0%Visit (Month): 6
N (Placebo): 63
N (Lecanemab): 67

60%
improvement
at 18 months

80%

59%
no decline at
36 months

70%

40%

100%

70%

Patients (%)

100%

CDR-SB Improvement – No/Low Tau Population

51%
improvement
at 36 months

60%
50%
40%
30%

Lecanemab

28%
improvement
at 18 months

20%

Placebo

10%
12

18

24

30

36

57
62

50
58

45

41

36

0%
Visit (Month): 6
N (Placebo): 63
N (Lecanemab): 67

12

18

24

30

36

57
62

50
58

45

41

36

Observed rates for ‘No Decline’ and ‘Improvement’ at 36 months• ADAS-Cog14: 63% and 61% for lecanemab• ADCS MCI-ADL: 63% and 59% for lecanemab
56

Tau terminology based on latest FDA definitions. Cutoffs for MK Tau PET: No/Low SUVR <1.06; Intermediate SUVR 1.06-2.91; High SUVR >2.91.
ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale. ADCS MCI-ADL, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment. CDR-SB, Clinical Dementia Rating-sum of boxes. PET, positron emission topography.

No/Low Tau Associated with Lower Levels of Amyloid
Early-Stage Participants Can Also be Identified by Amyloid PET <60 CL

Histogram of Amyloid PET (Tau PET Substudy)• Due to relatively small sample
size in tau PET substudy, we
estimated a similar early
pathological stage of disease
based on amyloid PET to apply
to overall Clarity AD population• Amyloid PET threshold <60 CL
used to enrich for low tau
population
60

57

Tau terminology based on latest FDA definitions.
Observed data
CL, Centiloid. GM, gray matter. PET, positron emission tomography.

No/Low Tau PETIntermediate+High Tau PET

Clinical Outcomes Through 36 Months

Subjects with Low Amyloid Continued to Benefit Through 36 Months
CDR-SB – Overall Population

CDR-SB – Baseline < 60 CL

27%less decline
at 18 months

51%

less decline
at 18 months

58

OLE includes those participants on subcutaneous and intravenous formulations.

•

The low amyloid subgroup (<60 Centiloids) represents 54% of theoverall amyloid PET substudy population•

Similar results were observed for ADAS-Cog14 and ADCS MCI-ADL

ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale. ADCS MCI-ADL, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment. ADNI, Alzheimer's Disease Neuroimaging Initiative. CDR-SB, Clinical Dementia Rating-sum of boxes. CL, Centiloid. OLE, open-label extension.
SE, standard error.

Subjects with Low Amyloid PET (<60CL): Response Rate
46% Had No Decline and 33% Had Improvement at 36 Months
CDR-SB No Decline – Low Amyloid Population

CDR-SB Improvement – Low-Amyloid Population

80%

80%

58%
no decline at
18 months

70%
46%
no decline at
36 months

Patients (%)

60%
50%
40%

47%
no decline at
18 months

30%
20%

Lecanemab

10%

Placebo
N: 176 178

0%Visit (Month): 6
N (Placebo): 176
N (Lecanemab): 178

157 164

146 161

132

121

115

12
157
164

18
146
161

24

30

36

132

121

115

Placebo60%

Patients (%)

70%

Lecanemab

37%
improvement
at 18 months

50%

33%
improvement
at 36 months

40%
30%
20%

26%
improvement
at 18 months

10%
N: 176 178

0%Visit (Month): 6
N (Placebo): 176
N (Lecanemab): 178

157 164

146 161

132

121

115

12

18

24

30

36

157
164

146
161

132

121

115

Observed rates for ‘No Decline’ and ‘Improvement’ at 36 months• ADAS-Cog14: 46% and 43% for lecanemab• ADCS MCI-ADL: 51% and 48% for lecanemab
59

ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale. ADCS MCI-ADL, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment. CDR-SB, Clinical Dementia Rating-sum of boxes.
CL, Centiloid. PET, positron emission topography.

Clarity AD OLE: Biomarker Results

Continuous Treatment Results in Minimal Change in Plaque But Greater Aβ42/40 Change• Participants on placebo who started lecanemab at 18 months show improvement in biomarkers within 3 months of treatment• Approximately 70% of subjects were amyloid negative (<30 CL) at the OLE baseline; therefore, ongoing dosing provides benefit
irrespective of OLE amyloid level

Amyloid PETCore Study

Plasma Aβ42/40 Ratio

OLE

Core Study

OLE

Less Amyloid

Baseline 0.088, 0.088
Placebo
Lecanemab

Baseline 81.6, 81.5 CL
Placebo
Lecanemab

Amyloid PET only done every 12 months in OLE (ie, no 36 month). OLE includes those participants on subcutaneous and intravenous formulations.
Aβ, amyloid beta. CL, Centiloid. OLE, open-label extension. PET, positron emission tomography. SE, standard error.

60

Based on pharmacodynamic analysis population (amyloid PET substudy population). Adjusted mean change from baseline, standard error (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

Lecanemab Reduces and Slows the Rate of Tau Pathology
Biomarkers Plasma pTau217 and CSF MTBRtau243
Plasma pTau217

CSF MTBR-tau243*
Baseline 549, 499 pg/mL
Placebo
Lecanemab

61*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. SE, standard error.

Slowingby 44% at
18 months

Summary of TEAE and ARIA (Exposure Adjusted)

Approx Core+OLE Exposure: 3480 Person-Years; Mean 2.2 yrs; >450 With 3 Yearsn

Placebo
N = 897
Exposure%
Adjusted*nAdverse Event (AE)

735

81.9%

59.6

798

Serious Adverse Event (SAE)

101

11.3%

8.2

DeathaDeaths with concurrent
ARIA or ICH irrespective of
ARIA being cause of deathAEs Leading to Study Drug
Withdrawal
ARIA-E
ARIA-H
Isolated ARIA-H
ICHa

8

0.9%

1

62

Lecanemab
N = 898
Exposure%
Adjusted*

Lecanemab(Double-Blind + OLE)
N = 1616
Exposuren%Adjusted*

88.9%

67.8

1480

91.6%

42.5

126

14.0%

10.7

332

20.5%

9.5

0.7

7

0.8%

0.6

24

1.5%

0.7

0.1%

0.1

0

0%

0

3

0.2%

0.1

28

3.1%

2.3

64

7.1%

5.4

160

9.9%

4.6

15
80
69
2

1.7%
8.9%
7.7%
0.2%

1.2
6.5
5.6
0.2

113
152
78
6

12.6%
16.9%
8.7%
0.7%

9.6
12.9
6.6
0.5

238
385
211
11

14.7%
23.8%
13.1%
0.7%

6.8
11.1
6.1
0.3

n, %, exposure-adjusted rate (per subject-year) are presented. OLE is based on IV datasets (as of 31 Mar 2024).
*Exposure adjusted rate (per 100 persons per year)
a: Includes all post-treatment events. Approx, approximate. yrs, years.
ARIA-E, amyloid related imaging abnormalities - edema; ARIA-H, ARIA with hemosiderin deposits; ICH, intracerebral hemorrhage.

No New Clinically Significant Safety Events Identified with
Long-Term Treatment• No increase of known adverse events over time

MedDRA PT

63

Lecanemab(Double-Blind + OLE)
N = 1616<12 months

Lecanemab(Double-Blind + OLE)
N = 1286
12 - <24 months

Lecanemab(Double-Blind + OLE)
N = 872
24 - <36 months

Cough

31

1.9%

27

2.1%

18

2.1%

Headache

131

8.1%

49

3.8%

17

1.9%

Diarrhea

58

3.6%

30

2.3%

12

1.4%

Infusion related reaction

369

22.8%

26

2.0%

11

1.3%

Nausea/Vomiting

62

3.8%

28

2.2%

12

1.4%

Rash

49

3.0%

33

2.6%

14

1.6%

MedDRA PT, Medical Dictionary for Regulatory Activities preferred term. OLE, open-label extension. OLE is based on IV datasets (as of 31 Mar 2024).

Long-Term Safety for Core Lecanemab Patients: ARIA-E• Risk period for ARIA-E is first 6 months based on vascular amyloid clearance
and increased permeability• After 6 months– Few cases of ARIA-E identified incidentally by scheduled MRI– Risk reduced - likely due to vascular remodelling after amyloid clearance

100%
90%
80%
70%
60%
50%

Lecanemab
Homozygous

40%
30%
20%
10%
0%

0

4

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 116 120

MRI evaluations:

Weeks

*

* *

*

LEC Homozygous (N)141 141 116 101 101 100 100 91 89 89 89 89 89 88 86 86 86 85 85 85 81 76 74 73 73 73 73 69 67 66 66

LEC Heterozygous (N)479 479 446 423 415 410 404 395 390 387 386 381 381 374 369 367 365 362 360 358 348 335 332 331 329 327 320 303 298 287 282

LEC Noncarrier (N)278 277 259 255 250 247 245 239 235 231 225 221 220 216 214 211 208 205 205 204 203 195 192 190 188 188 184 173 170 169 168* MRI schedule for placebo patients who transitioned to lecanemab in the OLE to capture ARIA (same MRI schedule as was done in beginning of trial).
64

OLE data as of 30 Nov 2023; based on intravenous dataset.

ARIA-E, amyloid related imaging abnormalities - edema; MRI, magnetic resonance imaging.

Lecanemab
Heterozygous
Lecanemab
Noncarrier

ARIA is Not Associated with Accelerated Long-Term
Progression• Most patients who had ARIA had CDR-SB assessments after event• Sensitivity analyses assessing impact on cognition or function showed no impact from ARIA
• Multiple imputation (plausible and worst-case scenarios)• ARIA as covariate (fixed and time-varying)• No accelerated long-term progression for ARIA versus without ARIA irrespective of threshold

Time to Worsening of CDR-SB by 3.0 points

65

Based on intravenous dataset. ARIA, amyloid related imaging abnormalities. CDR-SB, Clinical Dementia Rating-sum of boxes. OLE, open-label extension.​
Difference in starting KM rate in the OLE is due to not all core Lecanemab subjects from core entering OLE and core placebo converted to Lecanemab in OLE

Summary• OLE results support disease-modifying effect and the importance of continued
long-term lecanemab treatment• Lecanemab-treated participants continued to accrue benefit through 36 months• Early-stage patients (no/low tau or low amyloid) show stability or improvement over 1836 months, supporting early initiation of treatment with lecanemab• Amyloid pathway biomarkers improved at 3 months in newly treated participants andmaintained/improved with continuous treatment• Lecanemab slows rate of increase in plasma pTau217 & CSF MTBR-tau243 in
Clarity AD, a clear demonstration of drug effect on amyloid and tau pathology cascade• No new safety signals are observed with continued lecanemab treatment• After first six months, ARIA rates are low and similar to ARIA rates on placebo• ARIA is not associated with accelerated long-term progression
66

AD, Alzheimer's disease. ARIA, amyloid related imaging abnormalities. CSF, cerebrospinal fluid. MTBR-tau243, microtubule-binding region (MTBR) of tau containing the residue 243. OLE, open-label extension. pTau217, phosphorylated tau-217.

Thank you
Clarity AD
Acknowledgements
Participants & Their Support
We acknowledge with thanks the individuals who enrolled in lecanemab Clarity AD Trial as well as their family, caregivers,
and friends who supported them.
We also acknowledge the DSMB members, Site Investigators, Study Coordinators, Raters, contract research organization(CRO), and other personnel whose dedication and hard work in collecting data and providing care were essential to thecompletion of this trial.
Editorial support, funded by Eisai Inc, was provided by Mayville Medical Communications.
Funding for the studies and analyses was provided by Eisai Inc. and Biogen Inc.

Panel Discussion and Q&A

Does the Current Evidence Base Support Lecanemab Continued
Dosing for Early Alzheimer’s Disease?
Alzheimer's Association International Conference (AAIC) 2024
July 28 - August 1, 2024 / Philadelphia, PA, USA + Online