Clinical, Biomarker, and Safety Update fromthe Lecanemab Phase 2 Study
Lecanemab: An Assessment of the Clinical Effects, the Correlation of Plasma Aβ42/40 Ratio WithChanges in Brain Amyloid PET SUVr, and Safety from the Core and Open Label Extension of the Phase
2 Proof-of-Concept Study, BAN2401-G000-201, in Subjects With Early Alzheimer’s Disease

Chad J. Swanson,1 Shobha Dhadda,1 Michael Irizarry,1 Michio Kanekiyo,1 David Li,1Akihiko Koyama,1 Larisa Reyderman,1 Robert Gordon,2 Lynn D. Kramer,1 Christopher H. vanDyck,3 Randall Bateman,4 and Jeffrey Cummings5
1.

5.

Eisai Inc., Woodcliff Lake, NJ, USA
2. Eisai Ltd., Hatfield, UK
3. Alzheimer's Disease Research Unit; Yale School of Medicine, New Haven, CT, USA
4. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University ofNevada Las Vegas; Las Vegas, NV
2021 CTAD Annual Meeting | November 9-12, 2021| Boston

Presenter Disclosures2•Dr Swanson is an employee of Eisai.

•Dr Cummings provided consultation to the following pharmaceutical companies: Acadia, Accera, Actinogen, ADAMAS,Alkahest, Allergan, Alzheon, Avanir, Axovant, Axsome, BiOasis Technologies, Biogen, Eisai, Genentech, Grifols, Kyowa, Lilly,Lundbeck, Merck, Nutricia, Otsuka, QR Pharma, Resverlogix, Roche, Samus, Servier, Suven, Takeda, Toyoma, and United
Neuroscience companies.

•Dr Bateman is a co-founders of C2N Diagnostics. Washington University has equity ownership interest in C2N Diagnostics.
Dr. Bateman is a co-inventor of the stable isotope labeling kinetics, blood plasma assay, and methods of diagnosing AD withphosphorylation changes technologies licensed by Washington University to C2N Diagnostics. Through these relationships,
Washington University and Dr. Bateman, are entitled to receive royalties and/or equity from the license agreement with C2N.
Dr. Bateman receives income from C2N Diagnostics for serving on the scientific advisory board. Invited Speaker (12 months):Novartis. Advisory Board (12 months): Roche. DIAN-TU Pharma Consortium: (Active: Biogen, Eisai, Eli Lilly & Co., Janssen,
Roche/Genentech. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience).
DIAN-TU Trial Industry Partners: Eli Lilly and Co., Roche, Janssen, Avid, Eisai, Cerveau.

•Dr van Dyck has served as a consultant or scientific advisor for Roche, Eisai, and Kyowa Kirin and received grant support forclinical trials from Roche, Genentech, Eisai, Biogen, Eli Lilly, Novartis, Merck, Biohaven, and Janssen.

Presentation Overview on Study 201 Core and OLE• The early time course and extent of amyloid clearance produced bylecanemab in the Core and OLE• The clinical effects of lecanemab in the Core study and their correlation
with amyloid reduction• The clinical profile of subjects treated with lecanemab compared toplacebo subjects over a Gap period of time off drug following the Corestudy• The longitudinal plasma Aβ42/40 ratio and plasma p-tau181 & theirrelationship to longitudinal amyloid PET in the Core study, Gap period,and OLE• The consistency of ARIA-E rates from Core and OLE
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Lecanemab: Anti-Aβ Protofibril Monoclonal Antibody
Selectively Targets Aβ Protofibrils•

Humanized immunoglobulin G1(IgG1) monoclonal antibody•

Selectively binds to soluble Aβ
aggregate species– >1000-fold selectivity for
protofibrils over Aβ monomers(low affinity for Aβ monomer1)– Preferential activity for Aβ
protofibrils over fibrils (>10x) 2-54

1. Tucker S, et al. J Alzheimers Dis. 2015;43(2):575-88. 2. Lord A, et al. Neurobiol Dis. 2009;36:425–
34. 3. Sehlin D, et al. PLoS One. 2012;7:e32014. 4. Sehlin D, et al. Neurodegener Dis. 2011;8:117–
23. 5. Logovinsky V, et al. Alzheimer's Research & Therapy. 2016;8:14.

Lecanemab (BAN2401) Phase 2b Trial Design

A Global, Placebo-controlled, Double-blind, Parallel-group, Randomized Trial with Open-label Extension
Core Randomization PhaseN = 856• Subject eligibility criteria for Core study included
CDR global 0.5 (MCI) and 0.5-1.0 (mild AD)

Subjects with Early
Alzheimer’s disease:
MCI due to AD or mild
Alzheimer's dementia

Lecanemab (IV infusion)
2.5 mg/kg biweekly
5 mg/kg monthly
5 mg/kg biweekly
10 mg/kg monthly
10 mg/kg biweekly

Select Key Secondary Endpoints:
Amyloid PET at 18 months
ADCOMS at 18 months
CDR-SB at 18 months
ADAS-cog at 18 months
Fluid biomarkers at 18 months

Gap PeriodNo
treatment

Randomization

Core Primary Endpoint (Bayesian):
ADCOMS at 12 months

5†

Placebo biweekly(IV infusion)(18 months)

Extension Phase(OLE)

10 mg/kg
biweekly(IV infusion)(average 24 months) (up to 60 months)*
9-59 months
OLE Primary Endpoint:
Long-term Safety & Tolerability
Select Secondary/Exploratory Endpoints:
Amyloid PET
ADCOMS
CDR-SB
ADAS-cog
Fluid biomarkers

AD=Alzheimer’s disease; IV= intravenous; MCI=mild cognitive impairment; OLE=open label extension.
*Any subject who completed study treatment (Visit 42 [Week 79] of the Core Study) and fulfilled the Extension Phase eligibility criteria had the option to participate in the Extension Phase. Subjects who previously completed the Core Study (through theFollow-Up Visit, Visit 43) at any time before implementation of the Extension Phase and/or fulfilled the Extension Phase eligibility criteria were eligible to participate. Any subject who had discontinued the Core Study but fulfilled the Extension Phase
eligibility criteria were eligible to participate in the Extension Phase. All subjects not continuing into the Extension Phase had a Follow-Up Visit 3 months after the last dose of study drug in the Randomization Phase.
Eisai Inc. Data on file. 2019. †Randomization assignment was determined by Bayesian Adaptive Design methodology.

Lecanemab Cleared Amyloid Plaques andSlowed Cognitive Decline in Core Study
Slowing of Cognitive Decline

Significant Amyloid Reduction

Amyloid PET SUVrADCOMS

Plasma Aβ42/40 Ratio

Similar results for CDR-SB and ADAS-cog

81%

81% amyloid negative per
Visual Read by 18 months****
81% Visual Read*********p<0.0001

6NBL

12m

18m

NBL

12m

18m

NBL6m

12m

18m

Placebo989688

Placebo888266

Placebo238216

187

160

10BW

44

43

3710BW43

393310BW

152

1309379

10BW = 10 mg/kg biweekly lecanemab. Each analysis population: All randomized subjects with the relevant endpoint at Core baseline and at least one post-baseline visit in Core Study
Adjusted mean was based on a mixed model for repeated measures (MMRM) with treatment group, visit, clinical subgroup, the presence or absence of ongoing AD treatment, APOE4 status, region, treatment group-by-visit interaction as factors, andbaseline value as covariate. Y-axis was inverted for plasma Aβ42/40 Ratio. Increase in plasma Aβ42/40 Rati reflects decrease in brain amyloid levels for this inverted figure.

Amyloid Reduction (PET SUVr) Correlates withClinical Benefit in Core Study
ADCOMS vs. PET SUVr

ADCOMS vs. PET SUVr

Corr. Coeff=0.832, p-value=0.080

Slope=0.199, p=0.036

Population Correlation

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Subject Level Correlation

Adjusted mean was based on the MMRM with treatment group, visit, clinical subgroup, the presence or absence of ongoing AD treatment, APOE4 status, region, treatment group-by-visit interaction as factors, and baseline value as covariate. Analysis population: Subjects
with PET SUVr and ADCOMS at 12 or 18 months were included in the MMRM analysis. Data shown in right figure are for subjects with PET SUVr and ADCOMS at 18 months in 10 mg/kg biweekly and Placebo. CFB = change from baseline.
Adapted from Swanson et. al, 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018 and Swanson et al. Alzheimers Res Ther. 2021;13(1):80.

Amyloid Reduction (Plasma Aβ42/40 Ratio) Correlateswith Clinical Benefit in Core Study
ADCOMS vs. Plasma Aβ42/40 Ratio
Population Correlation

Corr. Coeff=-0.306, p-value NS8ADCOMS vs. Plasma Aβ42/40 Ratio
Subject Level Correlation
Slope= -3.957, p=0.050

Adjusted mean was based on MMRM with treatment group, visit, clinical subgroup, the presence or absence of ongoing AD treatment, APOE4 status, region, treatment group-by-visit interaction as factors, and baseline value as covariate. Analysis population: Subjects
with plasma Aβ42/40 ratio and ADCOMS at 12 or 18 months were included in the MMRM analysis. Data shown in right figure are for subjects with plasma Aβ42/40 ratio and ADCOMS at 18 months in 10 mg/kg biweekly and Placebo. CFB: Change from baseline.
Adapted from Swanson et. al, 11th Clinical Trials on Alzheimer's Disease (CTAD) Conference October 24-27, 2018 and Swanson et al. Alzheimers Res Ther. 2021;13(1):80.

Biomarker and Clinical Progression Profiles After Drug
Discontinuation Suggest Potential Disease Modification*Plasma Aβ42/40 Ratio

ADCOMS

Observed Mean Change (±SE) from Core Baseline
In Plasma Aβ42/40 Ratio

PET SUVr

10*Gap period is off-treatment (on average 24 months, with min 9 & max 59 months).
9PET SUVr: Predicted PET SUVR change from Core baseline was based on piecewise regression for the OLE enrolled subjects with Core baseline and post-baseline in PET sub study in Core Study and OLE phase. Plasma Aβ42/40 ratio: Observed mean change without any
statistical model for the OLE enrolled subjects with Core baseline and at least one post-baseline. ADCOMS: MMRM includes treatment group, visit, clinical subgroup, the presence or absence of ongoing AD treatment, APOE4 status, region, treatment group-by-visit interaction asfactors, and baseline value as covariate for the OLE enrolled subjects. Subjects progressed beyond early AD (global CDR>1 at OLE baseline) are not included.

Amyloid Trajectory Across 5 Years

Plasma Aβ42/40 Corresponds to PET SUVr Changes• Rapid reduction in brain amyloid as early as 3 months in OLE with 43% conversion* to amyloid negative by visual read
• In OLE >80% converted to amyloid negative by 12 months by visual read consistent with Core results• In Core, Plasma Aβ42/40 ratio correlated with PET SUVr (population corr. Coeff=-0.790, p=0.112; subject level
correlation coeff#=-0.411, p<0.017)• Plasma Aβ42/40 ratio may be more sensitive indicator of amyloid change vs PET SUVr
Plasma Aβ42/40

10Less AmyloidLess Amyloid

PET SUVr*n=7 at 3 months and n=12 at 12 months PET sub-study in OLE. # population level corr includes all treatment arms. Subject level only includes 10 BW and placebo.
Each analysis population: All OLE enrolled subjects with the relevant endpoint at Core baseline and at least one post-baseline visit.

p-Tau181 Corresponds to PET SUVr Changes
p-tau181 Correlates with PET SUVr and Plasma Aβ42/40 Ratio

PET SUVr vs p-Tau181, Corr. Coeff: 0.474, p<0.001

Observed Mean Change (±SE) from Core Baseline
In Plasma p-Tau181

Less Amyloid

p-Tau181

Placebo: 39
10 Biweekly: 30

11p-Tau181 vs Aβ42/40 Ratio, Corr. Coeff: -0.359, p=0.001

3.6934263530

272026182720Analysis population: All OLE enrolled subjects with the plasma p-tau181 at Core baseline and at
least one postbaseline visit (left figure). Subjects with plasma p-tau181 and PET SUVr at 18months in Core Study (right upper figure). Subjects with plasma p-tau181 and plasma Aβ42/40
ratio at 18 months in Core Study (right lower figure).

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ARIA Risk in OLE is Similar to ARIA Risk in Core StudyAll Subjects Received 10 mg/kg Biweekly in OLE• ARIA-E rate Core study 10 mg/kg biweekly (9.9%)• Observed cases OLE: 14/180 (7.8%)

Kaplan-Meier Estimate for ARIA-E in OLEAll Subjects• Core placebo-treated subjects: 4/45 (8.9%)• Kaplan-Meier estimate for Core placebotreated subjects (black line) ~10.0%• ~2% symptomatic rate Core & OLE• Most ARIA-E occurs within first 3 months• Most ARIA-E resolves within 4-12 weeks• 6/14 OLE cases have been dosed through(mild or moderate in radiologic severity)

12Core Treatment Assignment
10 mg/kg group: 10 mg/kg biweekly, 10 mg/kg monthly
Low dose: 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly
Adapted from Swanson et al. CTAD 2020

Summary and Conclusions
Rapid and Thorough Amyloid Reduction Correlates with Clinical Benefit• Lecanemab treatment can be initiated without titration• Amyloid reduction achieved within 3 months of treatment and clinical efficacy within 6 months of treatment• >80% amyloid negative (by visual read) by 12 - 18 months
Potential Disease Modifying Effects•

Clinical treatment difference in Early AD subjects is maintained after discontinued dosing over the 24-month
Gap period, suggesting potential disease modifying effects

Potential to use Plasma Biomarkers to Monitor for Lecanemab Treatment Effects•

Correlations between amyloid PET SUVr, clinical cognition endpoints, and plasma biomarker (Aβ42/40 ratioand p-tau181) following treatment with lecanemab•Monitoring of treatment effects using plasma biomarkers may allow simple dose modification following rapidand thorough amyloid removal (e.g., less frequent and/or lower dose)

Low Incidence of ARIA-E (<10%) and Symptomatic ARIA Rate (<2%) in Core and OLE
13These data are hypothesis generating and will be further evaluated in Clarity AD

AcknowledgmentsWe thank the participants, their families and study
partners, and the sites and staff participating in thisstudy for their significant contributions
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

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