2022 Clarity AD CTAD Presentations

Clarity AD: A Phase 3 Placebo-Controlled, Double-Blind, Parallel-Group,
18-Month Study Evaluating Lecanemab in Early Alzheimer's Disease
Clinical Trials on Alzheimer’s Disease (CTAD)
San Francisco, CA, USA
November 29 – December 2, 2022

Welcome and Introductions

Takeshi Iwatsubo
University of Tokyo

Clarity AD Topline Results Presentations
CTAD 2022 Clarity AD Session Agenda
TIME
5 min

CTAD 2022 Session Agenda:
Clarity AD: A Phase 3 Placebo-Controlled, Double-Blind, Parallel-Group, 18-Month Study Evaluating Lecanemab in Early Alzheimer's Disease
SESSIONPRESENTERS
Welcome & Introductions
Takeshi Iwatsubo
This introduction will highlight the importance of this first large completed positive phase 3 trial to
The University of Tokyo
patients and their families living with Alzheimer’s disease and scientists in the field.

10 minClarity AD: Clinical Trial Background and Study Design Overview
This session will highlight relevant Alzheimer’s disease background and review the Clarity AD trial study
design.

Michael Irizarry
Eisai

15 min

Lecanemab for the Treatment of Early Alzheimer’s Disease: Topline Efficacy Results from Clarity AD
This session will explore the Clarity AD clinical trial efficacy results: Amyloid PET, Clinical Dementia
Rating-Sum-of-Boxes (CDR-SB; primary endpoint), Alzheimer’s Disease Assessment Scale-Cognitive
Subscale (ADAS-Cog14), Alzheimer’s Disease Composite Score (ADCOMS) and Alzheimer's Disease
Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).

Christopher van Dyck
Yale School of Medicine

10 minSafety Profile of Lecanemab in Early Alzheimer’s Disease
This session will review lecanemab safety results from Clarity AD and overall lecanemab safety profile,including an in-depth review of current evidence related to amyloid related imaging abnormalities(ARIA).

Marwan Sabbagh
Barrow Neurological Institute10 minImaging, Plasma, and CSF Biomarkers Assessments from Clarity AD
This session will highlight the Clarity AD clinical trial biomarker assessment results. Evidence
supporting the optimal dosing regimen and timing will also be presented.

10 minContext of Clarity AD Results
This session will place the efficacy and safety results from the Clarity AD study in context of real-worldpractice, including the lecanemab Phase 2 results.

15 minPanel Discussion and Q&A
Dr. Iwatsubo will moderate this session.
Adjourn

Randall Bateman
Washington University
Sharon Cohen
Toronto Memory ProgramAllClarity AD: Clinical Trial Background and Study Design
Overview
Michael Irizarry
Eisai Inc.

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.
Data Safety Monitoring Board (DSMB), Raters, Investigators, and Study Team Members
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 the completion of this trial.

Disclosure• Dr. Irizarry is an employee of Eisai Inc.

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Lecanemab: Unique Selectivity Towards Toxic Soluble Species of Aβ
Highest Preference for Soluble Protofibrils/Oligomers Versus Monomeric and Fibrillar Forms of Aβ
Neurotoxic forms
Monomers

Oligomers

Protofibrils

Fibrils

9 – 75 kDa>75 – 5000 kDa
SolubleInsoluble

Lecanemab binding profile(Darker color = stronger binding)Strongest binding

Ab pathway in Alzheimer’s Disease

Lecanemab••

Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal
antibody•

Selectively binds to soluble Aβ aggregate species

Aβ dynamically evolves through different conformational states, including:1,2––•

Soluble monomers
Soluble aggregates of increasing size (eg, dimers, trimers, oligomers,
protofibrils)– Protofibrils are defined as large (>75-100kDa), soluble, aggregated Aβfilaments1– Insoluble fibrils and amyloid plaques
Recent studies have garnered considerable interest in the role of protofibrils in
the pathophysiology of Alzheimer’s disease2-4•–>1000-fold selectivity for protofibrils over Aβ monomers (lowaffinity for Aβ monomer5)–

Preferential activity for Aβ protofibrils over fibrils (>10x)6-10

Initiates microglial mediated clearance of protofibrils and plaques

Aβ, amyloid-beta; kDa, kilodaltons. Source: Presented at CTAD 2021. Note: Illustration is based on data from Biacore, inhibition ELISA and immunoprecipitation.

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1. Walsh DM, et al. J Biol Chem. 1997;272:22364-22372. 2. Paranjape GS, et al. ACS Chem Neurosci. 2012;3:302-311. 3. Haass C, Selkoe DJ. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12. 4. Stern AM, et al. bioRxiv 2022.10.18.512754. 5. Tucker S, et al. J Alzheimers Dis. 2015;43(2):575-88. 6. Lord A, et al. Neurobiol
Dis. 2009;36:425–34. 7. Sehlin D, et al. PLoS One. 2012;7:e32014. 8. Sehlin D, et al. Neurodegener Dis. 2011;8:117–23. 9. Logovinsky V, et al. Alzheimer's Research & Therapy. 2016;8:14. Söderberg L, et al. Neurotherapeutics. 2022 Oct 17. Epub ahead of print.

Alzheimer’s Disease Continuum & Lecanemab Clinical Trials
Study 201

A3

AHEAD 3-45 Study
A45

Clarity AD
DIAN-TU

High risk

Preclinical AD

Cognition unimpaired

8

MCI*

Mild AD

Very mild
Symptoms
symptoms.
Interfere with
No interference some everyday
with everyday
activities
activities

Moderate

SevereSymptoms
Interfere withmany everyday
activities

Symptoms
Interfere withmost everyday
activities

Adapted from
Lancet Neurol. 2013 Feb;12(2):207-16.

*MCI due to AD.
Aβ, amyloid-beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PET, positron emission tomography.

Lecanemab Phase 2b Study
Results Enabled Optimization of Design of Clarity AD

Study
DesignStudy 201 (Phase 2b)

Clarity AD (Phase 3)

Bayesian Adaptive Randomization Design and DoseRegimen-finding Study with OLE
854 Randomized

Global, Placebo-Controlled, Double-blind, Randomized
Trial with OLE

MCI due to AD or mild AD dementia (NIA-AA criteria, CDR 0.5-1)• Confirmed amyloid pathology (amyloid PET or CSF)
• MMSE• Memory impairment (WMS-IV LMSII ≥1 SD below age-adjusted mean)
22-30
Selected Exclusions:• Neurological condition that may be contributing to cognitive impairment beyond that caused by AD• Medical conditions which are not adequately controlled, could affect safety or the study assessments

Study
Population

Dose

•
•
•

Lecanemab 2.5, 5, or 10 mg/kg IV q2wk
Lecanemab 5 or 10 mg/kg IV q4wk
Placebo•

ClinicalOutcomes••••

Primary outcome (ADCOMS at 12 mo) not met
ADCOMS at 18 months: 30% less decline
ADAS-Cog14 at 18 months: 47% less decline
CDR-SB at 18 months: 26% less decline• Dose selected had largest treatment effect on
ADCOMS• Clarity AD powered on CDR-SB based on Study 201
results

Biomarker
Outcomes

Safety9• Amyloid PET: Dose & time dependent reduction ofamyloid• Amyloid lowering correlated with clinical outcomes• ARIA-E: 9.9% for LEC10BW; 14.3% in ApoE4+• Treatment discontinued for ARIA-E• Infusion-related reactions: 19.9% Lecanemab 10
mg/kg q2wk, most mild-moderate•

Lecanemab 10 mg/kg IV q2wk dose selected basedon Study 201 clinical and biomarker outcomes

10 mg/kg biweekly
10 mg/kg monthly
Placebo

Dose selected had most rapid and deep amyloid
clearance• No titration based on ARIA-E rates in study 201• Dose through mild asymptomatic ARIA-E; otherwise
pause dosing until resolution

Aβ, amyloid-beta; 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 for Mild Cognitive Impairment; ApoE4, apolipoprotein E4; ARIA-E, amyloid related imaging
abnormalities - edema; CDR-SB, Clinical Dementia Rating-sum of boxes; CSF, cerebrospinal fluid; IV, intravenous;
MCI, mild cognitive impairment; MMSE, Mini-Mental State Exam; MRI, magnetic resonance imaging; NIA-AA, National
Institute on Aging – Alzheimer's Association; OLE, open-label extension; PET, positron emission tomography; q2wk,
every 2 weeks; SE, standard error; WMS-IV LMSII, Wechsler Memory Scale IV-Logical Memory (subscale) II.

Clarity AD Study Design
Clarity AD is a global, placebo-controlled, double-blind, parallel-group, randomized study
Randomization Phase(18 months)

Patient Population•

1,795 patientswith Early AD•

MCI due to AD or mild
Alzheimer’s dementia•

Amyloid pathology
confirmed••

MMSE score between
22 and 30 at screening
and baseline

10 mg/kg biweekly

Key Secondary Outcome Measures:(IV infusion)
R
1:1

WMS-IV LMSII ≥1 SD
below age-adjusted
mean at screening

Randomization Phase
Primary Outcome Measure:
CDR: Change from Baseline at 18 months
CDR-SB:

Lecanemab
Lecanemab
10 mg/kg biweekly(IV infusion)

Placebo
Biweekly

Change from Baseline at 18 months:
Amyloid PET
ADAS-Cog14
ADCOMSADCS MCI-ADL

Extension Phase
Primary Outcome Measures(IV infusion)

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

Randomization stratified according to:Diverse patient population

Optional longitudinal sub-studies• Clinical subgroup (MCI due to AD or mild AD dementia)• Eligibility Criteria• Amyloid burden (amyloid PET; n=716)• Presence or absence of ongoing approved AD treatment(eg, acetylcholinesterase inhibitors, memantine, or both)• Site selection• Brain tau pathology (tau PET; n=257)• Community outreach• CSF biomarkers of neurodegeneration(n=281)• ApoE4 status (ie, carriers or non-carriers)• Geographical region

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Extension Phase(open-label)• Decentralized activities• Subcutaneous formulation (OLE)

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.

Sample Size Calculation & Statistical Testing Hierarchy
Sample Size Determination for CDR-SB

Statistical Testing Hierarchy•

Estimated standard deviation for placebo: 2.031

1.

•

Estimated treatment difference: 0.373 in all subjects•

CDR-SB change from baseline at 18 months–

Increases across any of the six CDR domains scores (which range from 0, 0.5, 1, 2, 3
for a scale range from 0-18, with early Alzheimer’s disease consistent with the 0.5-6

Assumptions based on effect seen in phase 2

portion of the range) represent a clinically notable decline in a primary domain of
Alzheimer’s disease symptomatology.

••

Translates to 25% less decline on treatment

2.

1795 total sample size planned, assuming:

Amyloid PET change from baseline using Centiloids at 18 months
for brain amyloid levels–•

20% dropout rate•

90% power

3.

Quantitative measurement of amyloid-beta deposition

ADAS-Cog14 change from baseline at 18 months–

Cognitive assessment instrument with a scale of 0-90 points with higher scoresindicating increased impairment•

2-sample t-test using 2-sided alpha = 0.05•

Accounts for subjects who missed 3 or moreconsecutive doses due to extenuating
circumstances

4.

ADCOMS change from baseline at 18 months–

Developed to measure outcomes among patients with early Alzheimer’s disease; scaleof 0-1.97, with 1.97 indicating maximum impairment.

5.

ADCS MCI-ADL change from baseline at 18 months–

Scale for evaluating activities of daily living, with scale 0-53, where lower scoreindicates greater level of impairment

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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 for Mild Cognitive Impairment;
CDR-SB, Clinical Dementia Rating-sum of boxes; PET, positron emission tomography.

Study Conduct: Safety•

Safety monitored throughout the study in a blinded manner by
the sponsor and in an unblinded manner by an independent
data safety monitoring committee

Baseline MRI has no exclusion factors

ARIA Management
MRI
Routine or conducted because of symptoms
suggestive of ARIA

– Safety evaluations included monitoring of vital signs,
physical examinations, adverse events, clinical laboratory
parameters, 12-lead electrocardiograms

ARIA-E or ARIA-H detected– ARIA occurrence monitored throughout the study▪ Safety MRI at screening, 9wk, 13wk, 6mo, 12mo, 18mo
▪ Investigators responsible for medical management ofpatients were different from those involved in clinicalassessments▪ Independent medical monitoring team managed ARIA
and infusion-related related reactions firewalled fromclinical team managing the study▪ An independent unblinded DSMB convened at regularintervals to monitor the overall safety of the study andmade recommendations to sponsor as needed
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ARIA-E, amyloid related imaging abnormalities-edema; ARIA-H, ARIA with hemosiderin deposits; DSMB,
Data Safety Monitoring Board; mo, month; MRI, magnetic resonance imaging; wk, week.

Asymptomatic

Symptomatic

Suspend treatment;
Clinical assessment;
Repeat MRI monthly

Severe/moderate ARIA-E
or severe/moderate ARIA-H

Continue treatment with
Lecanemab;
MRIs*

MRI showsresolution of ARIA-E or
stabliziation of ARIA-H;
symptoms resolve; patient
wishes to continue

Resume treatment withlecanemab

Mild ARIA-E
or mild ARIA-H*Asymptomatic ARIA-E havemonthly MRIs until resolution
Asymptomatic ARIA-H continue withregularly scheduled MRIs

Continue treatment;
Discontinue monthly
MRI if ARIA-E resolves or
ARIA-H stablizes

Clarity AD
Subject Disposition and Analyses Populations
Subject Enrolled
N=5967
Subject Randomized
N=1795Treated
N=1795
Placebo N=897
Completed Core Study
Discontinued from Core Study

13757 (84.4%)
140 (15.6%)

Screen Failures N=4172
Did not meet incl./excl. criteria 3555 (59.6%)
Adverse event
11 (0.2%)
Lost to follow-up
17 (0.3%)
Withdrawal of consent
201 (3.4%)
Other
388 (6.5%)

Lecanemab N=898
Completed Core Study
Discontinued from Core Study

729 (81.2%)
169 (18.8%)

Primary reason for discontinuation from study
Adverse event
28 (3.1%)
Subject choice24 (2.7%)
Pregnancy
0 (0%)
Inadequate therapeutic effect
0 (0%)
Lost to follow-up
5 (0.6%)
Withdrawal of consent
67 (7.5%)
Study terminated by sponsor
0 (0%)Other
16 (1.8%)

Primary reason for discontinuation from study
Adverse event
51 (5.7%)
Subject choice
26 (2.9%)
Pregnancy
0 (0%)
Inadequate therapeutic effect
0 (0%)
Lost to follow-up
4 (0.4%)
Withdrawal of consent
69 (7.7%)
Study terminated by sponsor
0 (0%)Other
19 (2.1%)

Placebo
Modified Intent-to-treat population
Safety population
Amyloid PET substudy population

Lecanemab
Modified Intent-to-treat population
Safety population
Amyloid PET substudy population

875
897
344

859
898
354

Clarity AD Baseline Characteristics
Demographic Characteristics
Characteristic

14

Age, median (range), years
Age Group, n (%)<65 years≥65 to <80≥80
Female , n (%)
Region, n (%)
North America
EuropeAsia-PacificRace, n (%)
Asian
Black
Caucasian
Native American
Native Hawaiian or Other PacificIslander
Other
MissingEthnicity, n (%)
Hispanic or Latino
Not Hispanic or Latino
Missing

Combined Total
N=1795

United States
N=948

72 (50, 90)

73(50,90)353 (19.7)
1203 (67.0)
239 (13.3)
938 (52.3)

158 (16.7)
637 (67.2)
153 (16.1)
487 (51.4)

1072 (59.7)
429 (23.9)
294 (16.4)

948 (100)00303 (16.9)
47 (2.6)
1381 (76.9)
2 (<1)

7 (<1)
43 (4.5)
896 (94.5)
1 (<1)

1 (<1)
33 (1.8)
28 (1.6)

1 (<1)
00232 (12.9)
1527 (85.1)
36 (2.0)213 (22.5)
734 (77.4)
1 (<1)

Clarity AD Baseline Characteristics
Comorbidities and Comedications
Combined Total
N=1795

United States
N=948

Hypertension, n (%)

993 (55.3%)

612 (64.6%)

Hyperlipidemia, n (%)

1085 (60.4%)674 (71.1%)

Ischemic Heart Disease, n (%)

291 (16.2%)

189 (19.9%)

Diabetes, n (%)

271 (15.1%)

180 (19.0%)

Obesity, n (%)

298 (16.6%)

229 (24.2%)

At least 2 comorbidities above, n (%)

917 (51.1%)

604 (63.7%)

At least 3 comorbidities above, n (%)

441 (24.6%)

319 (33.6%)

At least 4 comorbidities above, n (%)

139 (7.7%)

111 (11.7%)

At least 5 comorbidities above, n (%)

25 (1.4%)

22 (2.3%)

80 (4.5%)

54 (5.7%)

Characteristic
Comorbidities

Comedications
Anticoagulants

15

Clarity AD Baseline Characteristics
Clinical Characteristics

16

Placebo(N=875)

Lecanemab
10 mg/kg biweekly(N=859)Age, mean (standard deviation), years
Female, n (%)
CaucasianYears since diagnosis
Years since onset of symptoms
CDR Global=0.5
Mild dementia due to Alzheimer’s disease
ApoE4 Status
Noncarrier
Carrier
Heterozygous
Homozygous
On AChEIs and/or memantine

71.0 (7.8)
464 (53.0)
677 (77.4)
1.17 (1.537)
3.98 (2.530)
706 (80.7)
331 (37.8)

71.4 (7.9)
443 (51.6)
655 (76.3)
1.25 (1.506)
3.96 (2.349)
694 (80.8)331 (38.5)275 (31.4)
600 (68.6)
468 (53.5)
132 (15.1)
476 (54.4)

267 (31.1)
592 (68.9)456 (53.1)
136 (15.8)454 (52.9)

CDR-SB, mean (SD)PET Centiloids, mean (SD)
ADAS-Cog14, mean (SD)ADCOMS, mean (SD)
ADCS-ADL-MCI
MMSE, mean (SD)3.22 (1.343)
75.28 (41.85)
24.37 (7.561)
0.400 (0.15)
40.9 (6.89)
25.6 (2.23)

3.17 (1.340)
77.94 (44.78)
24.45 (7.082)
0.398 (0.15)
41.2 (6.61)
25.5 (2.19)

AChEIs, acetylcholinesterase inhibitors; 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 for Mild Cognitive Impairment; ApoE4, apolipoprotein E4; CDR-SB, Clinical Dementia Rating-sum of boxes; MMSE, Mini-Mental State Exam; PET, positron emission tomography; SD, standard deviation.

Summary• The lecanemab phase 2b proof-of-concept study provided a robust
framework to optimally design the confirmatory phase 3 study Clarity AD• Clarity AD is intended to be a definitive Phase 3 study to confirm efficacy
and safety– Simple randomized, double-blind, parallel group design without dose titration– CDR-SB, the gold-standard clinical assessment, utilized as the primary endpoint– Comprehensive assessment of clinical (cognitive, functional, QoL), biomarker (A/T/N/+),and safety outcomes– Efforts to enhance global enrollment of a diverse group of participants (e.g., race,
ethnicity, co-morbidities) and mitigate the impact of COVID
17
A/T/N/+, amyloid/tau/neurodegeneration/other; CDR-SB, Clinical Dementia Rating-sum of boxes; COVID, coronavirus disease; QoL, quality of life.

Acknowledgements
Site Investigators
Australia: Bruce Brew (St Vincent's Hospital - Translational Research Centre); Roger Clarnette (Australian Alzheimer's Research Foundation); Stephen Macfarlane (HammondCare Malvern
Clinical Trials Unit); Ranjeev Chrysanth Pulle (The Prince Charles Hospital/Internal Medicine & Dementia Research Unit); Paul Yates (Austin Health - Medical and Cognitive ResearchUnit); Rosalyn Cora Lai (KaRa Institute of Neurological Diseases); Cathy Short (Central Adelaide Local Health Network, The Queen Elizabeth Hospital and the Royal Adelaide Hospital).
Canada: Jennifer Ingram (Kawartha Centre - Redefining Healthy Aging); Sharon Cohen (Toronto Memory Program (Neurology Research Inc.); Ziad Nasreddine (MoCA Clinic andInstitute/NeuroSearch Developpements Inc.); Eugene Okorie (Okanagan Clinical Trials); Richared Bergeron (Recherches Neuro-Hippocampe Inc. d/b/a Clinique de la Mémoire del'Outaouais); Mark Allan (True North Clinical Research Kentville, Inc.); Paule Royer, (Q&T Research Sherbrooke Inc.); Jennie Wells (St. Joseph's HC- Parkwood Institute); Rodney Brittain (TrueNorth Clinical Research Halifax, Inc.); Kevin Kjernisted (Health Research).
France: Clair Paquet (Centre de Neurologie Cognitive du Pr Paquet); Hélène Mollion (Hôpital neurologique Pierre Wertheimer); Mathieu Ceccaldi (Hopital de la Timone); Pierre-Jean Ousset(Centre de Recherche Clinique du Gérontopôle); Claire Boutoleau-Bretonniere (Hopital Guillaume et RenÃ LaÃnnec); Stéphanie Bombois (Groupe Hospitalier Pitie-Salpetriere); Karim Bennys(Hôpital Gui de Chauliac); Frédéric Blanc (Hôpital de Hautepierre).
Germany: Matthias Boehringer (Neurozentrum Bielefeld Schwerpunktpraxis fuer Neurologie, Psychiatrie und Klinische); Richare Dodel (Geriatrie-Zentrum Haus Berge Klinik für Geriatrie Chefarzt); Matthias Riepe, (Bezirkskrankenhaus Guenzburg); Lutz Frölich, (Central Institute o Mental Health - Department of Psychaitry); Gerd Reifschneider, (Neuro Centrum ScienceGmbH); Timo Grimmer, (Psychiatry of TU Munich); Oliver Peters, (Klinik und Hochschulambulanz für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Berlin, Gedächtnissprechstunde
am ECRC).
Italy: Giancarlo Logroscino, (Ospedale "Card. G. Panico"); Flavio Nobili, (Clinica Neurologica, IRCCS Ospedale Policlinico San Martino, Genova); Gioacchino Tedeschi, (Prima Clinica Neurologica,
Primo Policlinico AOU "L. Vanvitelli"); Carlo Ferrarese, (ASST-Monza, Ospedale San Gerardo); Lucilla Parnetti, (Ospedale S. Maria della Misericordia, S. Andrea delle Fratte); Giuseppe Bruno ,(Universita` Sapienza di Roma - Dipartimento di Neuroscienze Umane); Roberto Ceravolo, (Azienda Ospedaliero Universitaria Pisana); Elio Scarpini, (Fondazione IRCCS CA' Granda Ospedale
Maggiore Policlinico - U.O.S.D. Malattie Neurodegenerative); Camilo Marra, (Fondazione Policlinico Agostino Gemelli - UCSC); Luigi Grimaldi, (Fondazione Istituto G.Giglio di Cefalù); Angelo
Mita, (Ospedale "Vito Fazzi"); Marco Salvatore, (IRCCS SDN); Orazio Schillaci, (UOC Medicina Nucleare Fondazione PTV "Policlinico Tor Vergata").

18

Acknowledgements
Site Investigators
Japan: Sadao Katayama, (Rijikai Medical Corporation Katayama Medical Clinic); Yoshiaki Aihara, (Shinozuka Hospital); Sadahisa Tokuda, (Sapporo Teishinkai Hospital); Akiko Yamazaki, (NIPPONMEDICAL SCHOOL MUSASHI KOSUGI HOSPITAL); Noriko Kawashima, (Kawashima Neurology Clinic); Satoshi Naruse, (General Rehabilitation Center Midori Hospital); Yoshiaki Itoh, (Osaka City
University Hospital); Takao Takeshima, (Tominaga Hospital); Kenichi Shimada, (Hyogo Brain and Heart Center); Riki Matsumoto, (Kobe University Hospital); Kazunori Okahara, (Keimei Memorial
Hospital); Takashi Asada, ( (Memory clinic Ochanomizu); Hamano Tadanori, (University of Fukui Hospital); Yutaka Arahata, (National Center for Geriatrics and Gerontology); Chigusa Watanabe,(National Hospital Organizaton Hiroshima-Nishi Medical Center); Tsutomu Nagamitsu, (Nagamitsu Clinic); Soichiro Shimizu, (Tokyo Medical University Hospital); Haruhiko Akiyama, (Yokohama
Brain and Spine Center); Shizuo Hatashita, (Shonan Atsugi Hospital); Hiroyuki Hatsuta, (Hatsuta Neurology Clinic); Masaharu Amagasa, (Yamagata Tokushukai Hospital); Noeru Shiraki, (Memory
clinic Toride); Yuichi Maruki, (Saitama Neuropsychiatric Institute); Daisuke Ito, (Keio University Hospital); Tatsushi Toda, (The University of Tokyo Hospital); Tomoyuki Kamata, (Japanese Red
Cross Musashino Hospital); Kiyoshi Kanaya, (Tokyo Medical University Hachioji Medeical Center); Sotaro Hieda, (Showa University Hospital East Branch); Osamu Iritani, (Kanazawa Medical
University Hospital); Makoto Urushitani, (Shiga University of Medical Science Hospital); Shinji Tagami, (Osaka University Hospital); Tadashi Kanda, (Yamaguchi University Hospital); Koichi
Kashiwado, (Kashiwado hospital).
Russia: Vladimir Vladimirovich Zakharov, (First Moscow State Medical University n.a. I.M. Sechenov).
South Korea: Seong Hye Choi, (Inha University Hospital); Jae-Hong Lee, (Asan Medical Center); Jun-Young Lee, (Seoul National University Boramae Medical Center); Dong Young Lee, (Seoul
National University Hospital); Kyung Won Park, (Dong-A University Hospital); Hee-Jin Kim, (Hanyang University Seoul Hospital); Sang Won Seo, (Samsung Medical Center); Seol-Heui Han (Konkuk
University Medical Center); Dong Won Yang, (The Catholic University of Korea, Seoul ST. Mary’s Hospital); Ji Won Han, (Seoul National University Bundang Hospital); Sang Yun Kim, (Seoul
National University Bundang Hospital); Byeong-Chae Kim, (Chonnam National University Hospital); Young Ho Sohn, (Severance Hospital, Yonsei University Health System).
Singapore: Christopher Chen, (National University Hospital).
Spain: Félix Viñuela Fernandez, (Hospital Victoria Eugenia - Cruz Roja); Ernest Balaguer Martinez, (Hospital General de Catalunya); Miguel Baquero, (Hospital Universitari i Politècnic LaFe); Gurutz Linazasoro Cristobal, (Policlinica Guipuzkcoa); Eduardo Aguera Morales, (Hospital Universitario Reina Sofía); Manuel Fernandez-Martinez, (Centro CAE Oroitu); Juan Jose Lopez
Lozano, (Complejo Hospitalario Ruber Juan Bravo); Pablo Martinez Lage, (Fundación CITA-alzheimer Findazioa); Raquel Sanchez Valle, (Hospital Clinic i Provincial de Barcelona); Mercé Boada
Rovira, (Fundacion ACE, Barcelona); Angel Montejo Gonzalez, (Hospital de Salamanca); Albert Lleó, (Servicio de Neurologia. Hospital Santa Cruz y San Pablo Calle Sant Antoni Maria Claret 167);
Sweden: Lena Kilander, (Uppsala University Hospital, Uppsala); Anne Börjesson-Hanson, (Karolinska University Hospital); Michael Jonsson, (Psykiatri kognition och äldrepsykiatri); HenrikÖstlund, (Skånes universitetssjukhus).
United Kingdom: Stephen Pearson, (Re:Cognition Health); Petrina Ayertey-Gbeve, (St. Pancras Clinical Research); Brady McFarlane, (Memory Assessment & Research Centre (MARC)); Janet
Hutchison, (Sheffield Memory Service); Nicholas Mannering, (Re:Cognition Health Ltd); Emer MacSweeney, (Re:Cognition Health Ltd); Richard Perry, (Charing Cross Hospital).
19

Acknowledgements
Site Investigators
United States: David Watson, (Alzheimer's Research and Treatment Center); Orlando Maldonado-Robles, (Bradenton Research Center, Inc. ); Jonathan Liss, (Columbus Memory Center); Marshall Nash,(NeuroStudies.net, LLC); Marc Agronin, (Miami Jewish Health Systems); Gregory Jicha, (University of Kentucky Medical Center); John Nardandrea, (Renstar Medical Research); Michael Plopper, (Sharp Mesa
Vista Hospital); Anton Porsteinsson, (AD-CARE, URMC); Sanjiv Sharma, (Advanced Memory Research Institute of NJ, PC); Mary Stedman, (Stedman Clinical Trials, LLC); Michael Badruddoja, (Neurological
Associates of Tucson dba Center for Neurosciences); John Stoukides, (Rhode Island Mood & Memory Research Institute); Victor Faradji, (Visionary Investigators Network); Richard Holub, (Neurological
Associates of Albany, PC); Lee Stein, (Neurology Clinic, P.C. ); Cherian Verghese, (Keystone Clinical Studies, LLC); Julie Schwartzbard, (Visionary Investigators Network); Allan Bernstein, (North Bay
Neuroscience); Mark Goldstein, (JEM Research Institute); Michael Tuchman, (Advanced Research Consultants, Inc. ); David Hart, (Albany Medical College); Scott Losk, (Summit Research Network (OR) Inc.
); William Smith, (Alliance for Multispecialty Research LLC, New Orleans Center for Clinical Research / Volunteer Research Group, an AMR company); John Scott, (National Clinical Research Inc.Richmond); Cynthia Murphy, (DBA The Memory Clinic); Raymond Turner, (Georgetown University Hospital); Seth Gale, (Brigham and Women's Hospital); Mohammad Bolouri, (ANI Neurology, PLLC d/b/a
Alzheimer's Memory Center); Babak Tousi, (Cleveland Clinic); Wendy Bond, (Neuropsychiatric Research Center of Southwest FL); Jose De La Gandara, (Quantum Laboratories Inc. ); Allan Levey, (Emory
University Cognitive Neurology Clinic & ADRC); Tiffany Schwasinger-Schmidt, (KU Wichita Center for Clinical Research); Anthony Ciabarra, (Neurology Center of North Orange County); Stephen Thein, (PacificResearch Network, Inc.); Jared Brosch, (Indiana University School of Medicine); Stephen Salloway, (Butler Hospital - Memory and Aging Program); Paul Mazzeo, (Coastal Neurology, P.A. ); Maryam Beigi ,(University of California - Los Angeles); Paul Solomon, (Boston Center for Memory); Donald Marks, (Donald S. Marks, MD. P.C. ); Barbara Joy Snider, (Knight ADRC Clinical Trials Unit Clinic - Washington
University School of Medicine); Jonathan Drake, (Rhode Island Hospital); Christopher van Dyck, (Yale University School Of Medicine); Adam Boxer, (UCSF Memory and Aging Center); Sharon Sha, (Stanford
University Medical Center); Gil Fernandez-Yera, (Advanced Clinical Research Network); Michael Pfeffer, (Allied Biomedical Research (Clinical Trial)); Jose Gamez, (Galiz Research); Yaneicy Gonzalez Rojas,(Gonzalez MD & Aswad MD Health Services); Darren Gitelman, (Advocate Lutheran General Hospital); Martin Sadowski, (New York University Medical Center PRIME); Aimee Pierce, (Oregon Health &Science University); Melissa Yu, (Baylor College of Medicine AD and Memory Disorders Center); Guido Perez, (BioMed Research Institute); Kimball Johnson, (iResearch Atlanta, LLC); Noah Gilson, (Neurology
Specialists of Monmouth County, PA); Mercedes Ponce De Leon, (Vitae Research Center); Jaron Winston, (Senior Adult Specialty Research); Alex White, (Progressive Medical Research); Lawrence Honig,(Neurological Institute of New York); Ramon Leon, (IMIC, Inc. ); David Greeley, (Kingfisher Cooperative LLC); Ira Goodman, (Synexus Clinical Research US, Inc.); Ayesha Lall, (Synexus ClinicalResearch); Richard Singer, (Infinity Clinical Research, LLC); Murray Grossman, (University of Pennsylvania); Bart Sloan, (Research Center for Clinical Studies, Inc. ); Lilia Ables, (Finlay Medical
Research); Srinath Kadimi, (Yale University, School of Medicine, Department of Neurology); Danielle Goldfarb, (Banner Sun Health Research); David Weidman, (Banner Alzheimer’s Institute- Clinical Trials
Department); Amanda Smith, (USF Suncoast Gerontology Center); Paul Winner, (Premiere Research Institute, West Palm); Allan Bernstein, (St Joseph Heritage Healthcare); Aaron Ritter, (Cleveland Clinic Lou
Ruvo Center for Brain Health); Alexander Smirnoff, (Charter Research); Diana Kerwin, (Kerwin Research Center); Elly Lee, (Irvine Clinical Research); David Russell, (Institute for Neurodegenerative
Disorders); Mitchell Isaac, (PMG Research of Winston Salem); John Duffy, (Apex Research Institute); Michael McCartney, (ActivMed Practices & Research); Bharat Mocherla, (Las Vegas Medical
Research); Douglas Scharre, (Ohio State University); Harvey Schwartz, (Infinity Clinical Research); James Stevens, (Fort Wayne Neurological Center); Brent Forester, (McLean Hospital); Gincy Samuel, (Texas
Neurology, PA); Bradley Robottom, (Raleigh Neurology Associates, P.A. - Research Department); Mark Brody, (Brain Matters Research); Deren Huang, (MDH Research, LLC. ); Michael Mega, (Neural Net
Research, LLC); Francisco Ricart, (CCM Clinical Research Group); Jacobo Mintzer, (Ralph H. Johnson VAMC); Ronald Schwartz, (Hattiesburg Clinic); Ana Acosta, (Advance Medical Research Center); Jeffrey
Burns, (University of Kansas Medical Center Research Institute); Ernesto Diaz, (Linfritz Research Institute, Inc. ); Ryan Drake, (NeuroScience Research Center LLC); Jack Klapper, (Mile High ResearchCenter); Djamchid Lotfi, (Clinical Trial Network); Jeffrey Ross, (Great Lakes Clinical Trials); Ashok Patel, (Bio Behavioral Health); Cynthea Blake, (ImmunoE Research Center); Lourdes Bosch, (Pharmax
Research of South Florida, Inc); Carl Griffin, (Lynn Health Science Institute); Esteban Olivera, (ClinCloud, LLC); Kore Kai Liow, (Hawaii Pacific Neuroscience); David McDonald, (Neurology Associates of OrmondBeach); Liliana Montoya, (Neurostudies, Inc.); Franco Sicuro, (Millenium Psychiatric Associates, LLC); James Sutton, (Pacific Neuroscience Medical Group).
20

Lecanemab for the Treatment of Early Alzheimer’s
Disease: Topline Efficacy Results from Clarity AD

Christopher van Dyck
Yale School of Medicine

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

22

Janssen Pharmaceuticals
Eisai, Inc
Genentech, Inc
Cerevel Therapeutics

Clarity AD: Topline Efficacy Endpoints

Primary Endpoint• Change from baseline at
18 months in CDR-SB

Key Secondary Endpoints
Key secondary endpoints
include change frombaseline at 18 months in:• Amyloid PET• ADAS-Cog14• ADCOMS• ADCS MCI-ADL

23

ADAS-Cog14, Alzheimer’s Disease Assessment Scale–cognitive subscale; ADCOMS, Alzheimer’s Disease Composite Score; ADCS ADL-MCI: Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for mild
cognitive impairment (MCI) subjects; CDR-SB, Clinical Dementia Rating, sum of boxes; PET: positron emission tomography.

Statistically Significant Results for Primary & Key
Secondary Endpoints
Lecanemab vs Placebo
Primary efficacy endpoint
CDR-SB Change from baseline to 18 months
Difference in least square mean
95% CI of the least square mean
P value vs placebo
Key secondary efficacy endpoints
Amyloid PET Centiloids Change from baseline to 18 months
Difference in least square mean
95% CI of the least square mean
P value vs placebo
ADAS-Cog14 Change from baseline to 18 months
Difference in least square mean
95% CI of the least square mean
P value vs placebo
ADCOMS Change from baseline to 18 months
Difference in least square mean
95% CI of the least square mean
P value vs placebo
ADCS MCI-ADL Change from baseline to 18 months
Difference in least square mean
95% CI of the least square mean
P value vs placebo
24-0.451-0.669, -0.233
0.00005-59.12-62.64, -55.60<0.00001-1.442-2.270, -0.613
0.00065-0.050-0.074, -0.027
0.00002
2.016
1.208, 2.823<0.00001

ADAS-Cog14, Alzheimer’s Disease Assessment Scale–cognitive subscale; ADCOMS, Alzheimer’s Disease Composite Score; ADCS ADL-MCI: Alzheimer's Disease Cooperative Study/Activities of Daily Living
scale adapted for mild cognitive impairment (MCI) subjects; CDR-SB, Clinical Dementia Rating, sum of boxes; CI, confidence intervals; PET: positron emission tomography.

Clarity AD Primary Endpoint: CDR-SB

Adjusted Mean Change fromBaseline (±SE) in CDR-SB

Lecanemab Significantly Slowed Disease Progression on CDR-SB by 27% at 18 Months
and at All Time Points Beginning at 6 Months

25

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 groupby 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.
CDR-SB, Clinical Dementia Rating, sum of boxes; LS, least squares; SE, standard error.

Amyloid PET:

Less Amyloid

Lecanemab Significantly Reduced Fibrillar Amyloid Burden at All Time Points Beginningat 3 Months

Mean <30
Centiloids forlecanemab at
18 months*
Baseline 75.0, 77.9

Difference of-59.1 Centiloids
at 18 months*****After 18 months of treatment, the average amyloid level was 23 Centiloids in the lecanemab treatment group in the amyloid PET substudy, which is below the threshold for amyloid positivity of approximately 30 Centiloids above which
participants are considered to have elevated brain amyloid.
** 73 subjects were not included at 18 months (per Statistical analysis plan) since their PET assessments were performed after receiving lecanemab in the extension phase.

26

Note: 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.
PET: positron emission tomography. SE, standard error.

ADAS-Cog14:
Lecanemab Significantly Slowed Disease Progression on ADAS-Cog14 by 26% at 18 Months
and at All Time Points Beginning at 6 Months**

27

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.
ADAS-Cog14, Alzheimer’s Disease Assessment Scale–cognitive subscale; LS, least squares; SE, standard error.

ADCOMS:
Lecanemab Significantly Slowed Disease Progression on ADCOMS by 24% at 18 Months
and at All Time Points Beginning at 6 Months

28

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.
ADCOMS, Alzheimer’s Disease Composite Score; LS, least squares; SE, standard error.

ADCS MCI-ADL:
Lecanemab Significantly Slowed Disease Progression on ADCS MCI-ADL by 37% at 18 Months
and at All Time Points Beginning at 6 Months

29

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.
ADCS ADL-MCI: Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for mild cognitive impairment (MCI) subjects; LS, least squares; SE, standard error.

Results of CDR-SB Sensitivity Analyses
Results are Robust Across Pre-Specified Sensitivity Analyses
Adjusted meanchange frombaseline at 18
months for placebo
group

Adjusted meanchange frombaseline at 18
months forlecanemab group

Treatment
difference at
18 months% Slowing

P-valuePrimary MMRM results(modified ITT)

1.663

1.213

-0.45127<0.001

1) Rank ANCOVA with missing data
imputed via multiple imputation
approach.

NANA-0.456*NA<0.001

2) MMRM repeated on all
randomized subjects (ITT)‡

1.659

1.225

-0.43426<0.001

3) Primary MMRM repeatedcensoring assessments after
occurrence of ARIA-E

1.672

1.169

-0.50330<0.001

4) Primary MMRM repeated toevaluate impact of COVID

1.603

1.208

-0.39425<0.001

Type of Sensitivity Analysis

30*Hodges-Lehmann non-parametric estimate of median difference.
‡Missing values for randomized subjects who are not in ITT analysis set are imputed using placebo mean at each visit.
ANCOVA, Analysis of covariance; ARIA-E, amyloid related imaging abnormalities-edema; CI, Confidence interval; COVID, coronavirus disease; ITT, intention-to-treat; mITT; modified ITT. MMRM, Mixed model for repeated measures;
NA, Not applicable.

Clarity AD Subgroup Analyses: CDR-SB
Consistent Results Across Randomization Strata
No. of Participants(placebo, lecanemab)

Adjusted
Mean
Difference

Percent
Slowing of
Decline (%)

-0.45

27

Favors lecanemab

Overall
875, 859
Use of Symptomatic AD Medication at BaselineYes

468, 447

-0.48

25

No

407, 412

-0.39

28

MCI

544, 528

-0.35

28

Mild AD

331, 331

-0.62

27

Noncarrier

275, 267

-0.75

41

Carrier

600, 592

-0.33

21

North America

516, 514

-0.52

34

Asia

146, 141

-0.33

25

Europe213, 204

-0.33

14

Clinical Subgroup

ApoE4 Status

Region

-1.2

-0.8

-0.4

0

0.4

Adjusted Mean Difference in CDR-SB versus Placebo (95% CI)
31

AD, Alzheimer’s disease; ApoE4, apolipoprotein E4; CDR-SB, Clinical Dementia Rating-sum of boxes; CI, confidence interval; MCI, mild cognitive impairment.

Clarity AD Subgroup Analyses: ADAS-Cog14 & ADCS MCI-ADL
Consistent Results Across Randomization Strata

ADAS-Cog14

ADCS MCI-ADL
Adjusted
Mean
Difference

No. of Participants(placebo, lecanemab)

Percent
Slowing of
Decline (%)

No. of Participants(placebo, lecanemab)

Favors lecanemab
-1.44

26

Use of Symptomatic AD Medication at BaselineYes

466, 445

-2.06

29

No

406, 409

-0.64

16

Clinical Subgroup

Overall
796, 783
Use of Symptomatic AD Medication at Baseline

2.02

37

Yes

423, 404

2.39

37

No

373, 379

1.53

33

Clinical Subgroup

MCI

542, 525

-0.93

23

MCI

499, 492

1.64

38

Mild AD

330, 329

-2.46

30

Mild AD

297, 291

2.71

38

Noncarrier

273, 266

-2.19

35

Noncarrier

245, 234

2.73

47

Carrier

599, 588

-1.11

21

Carrier

551, 549

1.72

33

North America

514, 512

Asia

146, 140

-1.43
-1.38

31
25

North America
Asia

473, 473
130, 121

1.9
1.31

42
23

Europe212, 202

-1.71

22

Europe193, 189

2.76

41

ApoE4 Status

ApoE4 Status

RegionRegion

-4

-2

0

2

Adjusted Mean Difference in ADAS-Cog14 versus Placebo (95% CI)

32

Percent
Slowing of
Decline (%)

Favors lecanemab

872, 854

Overall

Adjusted
Mean
Difference

-2

0

2

4

Adjusted Mean Difference in ADCS MCI-ADL versus Placebo (95% CI)

AD, Alzheimer's disease; 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; ApoE4, apolipoprotein E4;
CI, confidence interval; MCI, mild cognitive impairment.

Clarity AD Subgroup Analyses: CDR-SB
Consistent Results Across Other Subgroups of Interest
Adjusted
Mean
Difference

Percent
Slowing of
Decline (%)

875, 859

-0.45

27

Noncarrier

275, 267

-0.75

41

Heterozygote

468, 456

-0.50

30

Homozygote

132, 136

0.28

-22

Female464, 443

-0.20

12

Male

411, 416

-0.73

43

<65

178, 166

-0.08

6

65-74

381, 368

-0.37

23

≥75

316, 325

-0.72

40

Hispanic

108, 107

-0.50

52

Non-Hispanic

743, 715

-0.46

25

White

677, 655

-0.49

27

Asian

148, 147

-0.35

19

Black

24, 20-0.72

63

Hispanic

99, 100

-0.53

113

Non-Hispanic

356, 354

-0.58

31

White

431, 431

-0.58

36

Black

21, 19-0.55

63

No. of Participants(placebo, lecanemab)
OverallFavors lecanemab

ApoE4 Genotype Status

Sex

Age

Ethnicity - Global

Race - Global

Ethnicity – United States

Race- United States

-2.0

-1.6

-1.2

-0.8

-0.4

0

0.4

0.8

Adjusted Mean Difference in CDR-SB versus Placebo (95% CI)
33

ApoE4, apolipoprotein E4; CDR-SB, Clinical Dementia Rating-sum of boxes; CI, confidence interval.

Clarity AD Subgroup Analyses: ADAS-Cog14 & ADCS MCI-ADL
Consistent Results Across Other Subgroups of Interest
ADAS-Cog14

ADCS MCI-ADL
Adjusted
Mean
Difference

Percent
Slowing of
Decline (%)

872, 854

-1.44

26

Noncarrier

273, 266

-2.19

35

Heterozygote

467, 453

-1.28

23

Homozygote
Sex132, 135

-0.53

13

No. of Participants(placebo, lecanemab)
OverallFavors lecanemab

ApoE4 Genotype Status

Percent
Slowing of
Decline (%)

796, 783

2.02

37

Noncarrier

245, 234

2.73

47

Heterozygote

430, 422

1.97

36

Homozygote

121, 127

1.03

25

OverallFavors lecanemab

ApoE4 Genotype Status

Sex

Female462, 441

-0.98

18

Female416, 399

1.01

19

Male

410, 413

-1.97

34

Male

380, 384

3.17

54

Age

Age

<65

177, 165

-0.92

14

<65

166, 151

1.28

26

65-74

380, 365

-1.47

29

65-74

356, 343

2.02

38

≥75

315, 324

-1.67

30

≥75

274, 289

2.48

40

Ethnicity - Global

Ethnicity - Global

Hispanic

108, 107

-2.06

387

Hispanic

95, 95

2.22

92

Non-Hispanic

740, 711

-1.37

21

Non-Hispanic

677, 653

1.98

33
40

Race - Global

Race - Global

White

674, 652

-1.65

28

White

616, 604

2.20

Asian

148, 146

-1.46

25

Asian

132, 127

1.26

23

Black

24, 20

-1.59

280

Black

22, 171.08

184

Hispanic

99, 100

-2.18

-222

Hispanic

86, 901.92

318

Non-Hispanic

354, 353

-1.34

21

Non-Hispanic

329, 325

2.29

40

Ethnicity – United States

Ethnicity – United States

Race- United States

Race- United StatesWhite

429, 430

-1.65

33

White

392, 395

2.23

45

Black

21, 19

-1.00

209

Black

20, 16

1.5

-221

-6

-4

-2

0

2

4

Adjusted Mean Difference in ADAS-Cog14 versus Placebo (95% CI)
34

Adjusted
Mean
Difference

No. of Participants(placebo, lecanemab)

-4

-2

0

2

4

6

Adjusted Mean Difference in ADCS MCI-ADL versus Placebo (95% CI)

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; ApoE4, apolipoprotein E4; CI, confidence interval.

Summary
Clarity AD Met All Primary and Key Secondary Endpoints• Lecanemab treatment met the primary and secondary end points vs placebo at 18months, with highly significant differences starting at six months (all P<0.001):– CDR-SB: reduced clinical decline by 27% (difference: -0.45; P = 0.00005),– Amyloid PET: reduced brain amyloid burden at 3 months (difference: -59.1 Centiloids)– ADAS-Cog14: slowed cognitive loss by 26%– ADCOMS: slowed progression by 24%– ADCS MCI-ADL: slowed functional decline by 37%• Results were consistent across broad range of endpoints and subgroups
Lecanemab reduced markers of amyloid in early AD and resulted in less decline than placebo on
all measures of cognition and function at 18 months. These differences were observed as earlyas 6 months. These findings encompassed a broad range of endpoints and subgroups.
35

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; CDR-SB, Clinical Dementia Rating-sum of boxes.

Safety Profile of Lecanemab in Clarity AD

Marwan Sabbagh
Barrow Neurological Institute36Disclosures• Dr Sabbagh has the following disclosures:

37–

Ownership interest (Stock or stock options): NeuroTau, Optimal Cognitive Health Company, uMethod
Health, Versanum, Athira, TransDermix, Seq BioMarque, NeuroReserve, Cortexyme/Quince Therapeutics,
Lighthouse Pharmaceuticals, Alzheon–

Consulting: Roche-Genentech, Eisai, Lilly, Synaptogenix, NeuroTherapia, T3D, Signant Health, Novo
Nordisk, Corium, Prothena–

Royalties: Humanix–

Board of Director: EIP Pharma

Clarity AD: Safety Topline Endpoints• Adverse Events• Laboratory Abnormalities• Vital Signs• ARIA-E and H• Infusion-related reactions• Safety was monitored throughout study by the data safety monitoringboard (DSMB) and by an independent medical monitoring team

ARIA-E, amyloid related imaging abnormalities - edema; ARIA-H, ARIA-H, ARIA with hemosiderin deposits; DSMB, Data Safety Monitoring Board.

38

Overall Adverse Event (AE) Summary
Core Study

Deaths*Placebo(n=897)n (%)
7 (0.8)

Lecanemab(n=898)n (%)
6 (0.7)

Serious adverse event (SAE)

101 (11.3)

126 (14.0)

01 (0.1)7 (0.8)5 (0.6)0

11 (1.2)

101 (11.3)

111 (12.4)

735 (81.9)

798 (88.9)

TEAE without ARIA or infusion-related reactions

719 (80.2)

746 (83.1)

TEAE leading to drug withdrawal

26 (2.9)

62 (6.9)24 (2.7)

28 (3.1)

SAE with ARIA-E
SAE with ARIA-H
SAE with infusion-related reactions

SAE without ARIA or infusion-related reactions

Treatment-emergent AE (TEAE)**TEAE leading to drug withdrawal excluding AESI

39

*Cause of deaths in placebo group: death, acute respiratory failure, myocardial infarction, metastases to bone, hemorrhage intracranial, COVID-19, pancreatic cancer.
Cause of death in lecanemab group: death, cerebrovascular accident, myocardial infarction, respiratory failure, metastases to meninges, COVID-19. No participants died with or from ARIA in Core study.
**AE rates are similar between placebo and lecanemab when ARIA and infusion-related reactions are excluded.
AESI, adverse event of special interest; ARIA-E, amyloid related imaging abnormalities - edema; ARIA-H, ARIA-H, ARIA with hemosiderin deposits.

Most Common Adverse Events
Adverse Events Of Special Interest(Pooled preferred terms [PTs])

Infusion-related reaction
ARIA-E
ARIA-H (pooled PTs)
Isolated ARIA-H (pooled PTs)

Other Adverse Events >5%
Headache
Fall
Urinary tract infection
COVID-19
Back pain
Arthralgia
Dizziness
Diarrhea
Anxiety

Placebo(n=897)
%
7.4
1.7
9.0
7.8

Lecanemab(n=898)
%
26.4
12.6
17.3
8.9

Placebo(n=897)
%
8.1
9.6
9.1
6.7
5.8
6.9
5.1
6.5
4.2

Lecanemab(n=898)
%
11.1
10.4
8.7
7.1
6.7
5.9
5.5
5.3
5.0

ARIA-E, amyloid related imaging abnormalities - edema; ARIA-H, ARIA-H, ARIA with hemosiderin deposits; COVID-19, coronavirus disease of 2019, ECG, electrocardiogram.

40• There were no significant
trends in mean changes
over time or shifts frombaseline for any of thelaboratory, ECG or vital
sign parameters and nonotable differences
between groups

Infusion-Related Reactions and Immunogenicity
Infusion-Related Reactions

Placebo(n=897)n (%)

Lecanemab(n=898)n (%)

66 (7.4)

237 (26.4)

Mild

57 (6.4)

163 (18.2)

Moderate

9 (1.0)67 (7.5)

Severe07 (0.8)Infusion-related reactions are limited in impact and do not recur inmost subjects regardless of prophylaxis• Infusion-related reactions were largely mild-to-moderate (grade 1-2:96%) and occurred on the first dose (75%)− Most subjects (65%) only had 1 infusion-related reaction• ~40% of subjects received preventative medications (e.g.
acetaminophen, antihistamine, hydrocortisone) for an infusion after
experiencing the first infusion-related reaction− Recurrence rate ~35% of infusion-related reaction was the same
regardless of receiving preventative medication• 6 of the 7 severe infusion-related reactions (grade 3-4) occurred with
first dose
Immunogenicity

Infusion-related
reactions

Mild (grade 1): Discomfort noticed, but no disruption of normal daily activity
Moderate (grade 2): Discomfort sufficient to reduce or affect normal daily activity
Severe (grade 3-4): Incapacitating, with inability to work or to perform normal daily activity•

Incidence of treatment-emergent positive anti-drug antibody (ADA) was 10.3%, with low titers*•

Incidence of treatment-emergent neutralizing antibody (Nab) positivity was 4.1%, with low titers (≤10)•

There was no impact of immunogenicity on efficacy and safety endpoints or pharmacokinetics

41* Q1-Q3: 16 and 400, with 3 subjects having a titer ≥2000.

ARIA-E

ARIA-E

Placebo(N=897)n/N (%)

Lecanemab(N=898)n/N (%)

15/897 (1.7)

113/898 (12.6)

ApoE4 noncarrier

1/286 (0.3)

15/278 (5.4)

ApoE4 carrier

14/611 (2.3)

98/620 (15.8)

ApoE4 heterozygote

9/478 (1.9)

52/479 (10.9)• In the 2.8% of subjects withsymptomatic ARIA-E, commonly
reported symptoms were
headache, visual disturbance,and confusion

ApoE4 homozygote

5/133 (3.8)

46/141 (32.6)• Recurrent ARIA-E

Symptomatic ARIA-E*

025/898 (2.8)

ApoE4 noncarrier0

4/278 (1.4)

ApoE4 carrier0

21/620 (3.4)

ApoE4 heterozygote

08/479 (1.7)

ApoE4 homozygote

013/141 (9.2)

ARIA-E by ApoE4 genotype

42• ARIA-E events were largely mildto-moderate radiographically(91%) and asymptomatic (78%)*Symptomatic concurrent ARIA-E and ARIA-H were included under ARIA-E.

− Placebo: 1 (0.1%)− Lecanemab: 28 (3.1%)

ApoE4, apolipoprotein E4; ARIA-E, amyloid related imaging abnormalities edema; ARIA-H, ARIA-H, ARIA with hemosiderin deposits.

Time to ARIA-E Events• ARIA-E with lecanemab generally
occurred within the first 3 monthsof treatment (71%) and by 6months (92%)• ARIA-E resolved within 4 monthsof detection (81%), regardless of
ApoE4 carrier status– 60/111 (54%) resolved by
90 days– 90/111 (81%) resolved by
120 days
43

ApoE4, apolipoprotein E4. ARIA-E, amyloid related imaging abnormalities - edema; LEC10-BW, lecanemab 10 mg/kg biweekly.

Lecanemab ARIA-E Events:
Radiographic and Clinical Severity Overall and by APOE4 Genotype• ARIA-E more common in ApoE4+ on treatment and placebo, with highest frequency in homozygotes• Mostly mild to moderate in radiographic and clinical severity, including homozygotes• Most subjects with mild radiographic ARIA-E did not worsen and could continue dosing without drug interruption• Subjects with mild radiographic ARIA-E who continued dosing resolved (3 months) in similar time frame to those who discontinued dosing (3 months)

Radiographic severity(mild/moderate/severe)

Symptomatic Clinical Severity(no symptomatic inplacebo)(mild/moderate/
severe)Placebo(N=897)

Lecanemab(N=898)

Placebo(N=897)

Lecanemab(N=898)

Lecanemab(N=898)

Lecanemab(N=898)

ARIA-E

15/897 (1.7%)

113/898 (12.6%)

9/6/0

37 / 66 / 9

25 (2.8%)

10/12/3

ApoE4+

14/611 (2.3%)

98/620 (15.8%)

9/5/0

31 / 57 / 9

21 (3.4%)

9/9/3

Homozygote

5/133 (3.8%)

46/141 (32.6%)

2/3/0

6 / 33 / 7

13 (9.2%)

5/7/1

Heterozygote

9/478 (1.9%)

52/479 (10.9%)

7/2/0

25 / 24 / 2

8 (1.7%)

4/2/2

1/286 (0.3%)

15/278 (5.4%)

0/1/0

6/9/0

4 (1.4%)

1/3/0

ApoE444

Symptomatic
ARIA-E

ApoE4, apolipoprotein E4; ARIA-E, amyloid related imaging abnormalities – edema.

ARIA-H• Isolated ARIA-H was similar between lecanemab (8.9%) and placebo (7.8%) with low rates of clinically symptomatic ARIA-H• Timing of isolated ARIA-H occurs randomly during treatment course, while ARIA-H that occurs with ARIA-E tended to occur
early in the course of lecanemab treatment

Total

ARIA-H (micro, macro, superficial)
Microhemorrhage
Superficial siderosis
Cerebral macrohemorrhage

Placebo(N=897)n (%)
81 (9.0)68 (7.6)
21 (2.3)
1 (0.1)

Lecanemab(N=898)n (%)
155 (17.3)
126 (14.0)
50 (5.6)
5 (0.6)

Symptomatic ARIA-H

2 (0.2)13 (1.4)

2 (0.2)4 (0.4)

12/286 (4.2)
69/611 (11.3)
41/478 (8.6)
28/133 (21.1)

33/278 (11.9)
122/620 (19.7)
67/479 (14.0)
55/141 (39.0)

11/286 (3.8)
59/611 (9.7)
35/478 (7.3)
24/133 (18.0)

23/278 (8.3)
57/620 (9.2)
40/479 (8.4)
17/141 (12.1)

ARIA-H by ApoE4 genotype
ApoE4 noncarrier, n/N (%)
ApoE4 carrier, n/N (%)
ApoE4 heterozygote, n/N (%)
ApoE4 homozygote, n/N (%)
45

Isolated ARIA-H (no ARIA-E)
Placebo
Lecanemab(N=897)(N=898)n (%)
n (%)
70 (7.8)
80 (8.9)
63 (7.0)60 (6.7)
13 (1.4)
23 (2.6)
1 (0.1)4 (0.4)

ApoE4, apolipoprotein E4; ARIA-E, amyloid related imaging abnormalities - edema; ARIA-H, ARIA-H, ARIA with hemosiderin deposits.

Cerebral Macrohemorrhage in Lecanemab Studies
Data Cutoff October 22, 2022 for Open-Label Extension (OLE; Ongoing)
Total
Study

201 Core Phase
201 OLE301 Core Phase
301 Core + OLE(includes cases in 301 Core above)
301 Core & OLE Deaths withconcurrent macrohemorrhage

Anticoagulant Use

0/245 (0%)

Lecanemab
10 mg/kg q2wk
n/N (%)
1/161 (0.6%)

0/20 (0%)

Lecanemab
10 mg/kg q2wk
n/N (%)
0/11 (0%)

N/A

1/180 (0.6%)

N/A

0/18 (0%)

2/897 (0.2%) 1

6/898 (0.7%) 2

0/74 (0%)

2/83 (2.4%) 2

N/A

10/1608 (0.6%) 2, 3

N/A

5/140 (3.6%) 2, 3

1/897 (0.1%) 4

2/1608 (0.1%) 3

0/74 (0%)

2/140 (1.4%) 3

Placebon/N (%)

Placebon/N (%)

1 Includes one non-treatment emergent case inplacebo (event > 30 days after discontinuing study
medication)
2 Includes one non-treatment emergent case on
anticoagulation (event > 30 days after discontinuing
study medication)
3 1 case of macrohemorrhage in 65F E4 homozygous
after tPA for left MCA occlusion (OLE) and 1 case in
87M E4 non-carrier on apixaban (stopped) thenreceived heparin for MI (OLE, cause of deathcardiopulmonary)
4 In core phase
AD, Alzheimer’s disease; ApoE4, apolipoprotein E4;
MRI, magnetic resonance imaging; NA, Not applicable;
q2wk, every 2 weeks.

Cerebral Macrohemorrhage in AD

Safety Assessment• Lobar macrohemorrhage in AD in the absence of arteriovenous malformation,
hemorrhagic cerebral infarction, or tumor is usually caused by cerebral amyloid
angiopathy (CAA)• There is a low rate of macrohemorrhage with lecanemab therapy (0.6-0.7%),
which is higher than placebo (0.2%)• Risk factors for lobar macrohemorrhage include ApoE4 genotype, presence of
microhemorrhages (which is evidence of CAA), and anticoagulant medications• Rate of macrohemorrhage for subjects on both anticoagulants
and lecanemab was 2.4-3.6%. Background rate of macrohemorrhage in
AD patients on anticoagulation is not known but is expected to be higher than in
non-AD patients due to CAA; therefore, comparative risk is difficult to assess.

• Background rates of macrohemorrhage in placebo arms of prior AD clinical
trials is 0.4% (JAMA Neurol. 2022;79:13-21)• No clear relationship of macrohemorrhage to ApoE4 status, baseline MRI, or
timing of treatment• Subjects allowed to continue on anticoagulation in OLE with informed consent
language regarding increased risk of cerebral hemorrhage with concomitant
anticoagulant use

46Summary
Clarity AD Safety•

Lecanemab was generally well-tolerated– Most common adverse events were infusion-related reactions, ARIA-H, ARIA-E, and headache•

ARIA incidence profile was within expectations, and the symptomatic ARIA rate was low– Incidence of ARIA-E: 12.6% for lecanemab and 1.7% placebo– Symptomatic ARIA-E: lecanemab: 2.8%; placebo: 0.0%
– ARIA-E most commonly occurred within the first 3 months of treatment (71%) and resolved within
4 months of detection (81%)•

The ARIA-H (ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis) rate was 17.3% in
the lecanemab group and 9.0% in the placebo group– Symptomatic ARIA-H: lecanemab: 0.7% and placebo: 0.2%
– There was no imbalance in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) between
lecanemab (8.9%) and placebo (7.8%)•

ARIA-E and ARIA-H were less common in ApoE4 non-carriers versus carriers, with higher frequency in ApoE4 homozygous
carriers vs ApoE4 heterozygous carriers

Infusion-related reaction, ARIA-E, and rare macrohemorrhage are important adverse events
that can be seen with lecanemab treatment. If approved, clinicians, patients, and caregivers
will need to understand the incidence, monitoring, and management of these events
47

ApoE4, apolipoprotein E4; ARIA-E, amyloid related imaging abnormalities - edema; ARIA-H, ARIA-H, ARIA with hemosiderin deposits.

Imaging, Plasma, and CSF Biomarkers Assessmentsfrom Clarity AD

Randall J. Bateman
Washington University School of Medicine

Disclosures• Dr Bateman is the Director of DIAN–TU and Principal Investigator of DIAN–TU-001• He receives research support from the NIA of the NIH, DIAN–TU trial pharmaceuticalpartners (Eli Lilly and Company, F. Hoffman-La Roche Ltd and Avid
Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous
Organization, DIAN–TU Pharma Consortium (active: Biogen, Eisai, Eli Lilly and Company,
Janssen, F. Hoffmann-La Roche Ltd/Genentech; previous: AbbVie, Amgen, AstraZeneca,
Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience)• He has been an invited speaker and consultant for AC Immune, F. Hoffman-La Roche Ltd
and Janssen and a consultant for Amgen and Eisai• Dr. Bateman is a co-founder of C2N Diagnostics. Washington University has equity
ownership interest in C2N Diagnostics. Dr. Bateman is a co-inventor of assay
technologies licensed by Washington University to C2N Diagnostics. Dr. Batemanreceives income from C2N Diagnostics for serving on the scientific advisory board
49

Biomarker Objectives in Lecanemab Development
Biomarkers hierarchy

Assessment

Purpose⚫

Patient Selection

Target Engagement/
Pharmacodynamic

Pathophysiological andClinically Predictive (including
a panel of amyloid, tau andpathophysiologic related
biomarkers)
Clinical Consequence

50

Hypothesis

Amyloid PET
CSF Ab42/40
plasma Ab42/40 (AHEAD 3-45)➢➢

CSF protofibril*
Amyloid PET
CSF or plasma Ab42/40➢➢

Activity against protofibrils
Activity against amyloid
plaques

Amyloid PET
CSF and plasma Aβ[42], Aβ42/40 ratio, ptau181 and NfL
CSF t-tau, neurogranin and GFAP
Tau PET
MRI regional volumes➢➢

Predict clinical benefit for
accelerated approval
Activity against downstream
process in AD (disease
modification)

Early AD: CDR-SB, ADCS MCI-ADL,
ADAS-Cog14, ADCOMS➢

Confirm efficacy

Confirm diagnosis in early AD
Select preclinical AD
population (AHEAD 3-45)⚫

Treatment of early AD prior toadvanced irreversible
neurodegeneration
Preclinical population responsive totailored dose of lecanemab⚫
⚫
⚫

Reduction of free CNS protofibrils
Reduction of amyloid plaques
Reduction of amyloid aggregation
process⚫

Correlation of soluble and aggregatedmeasures of amyloid and tau withclinical effects
Delay in progression of AD
pathophysiological biomarkers⚫

⚫

Slowing of cognitive and functional
decline*Assay in development
Ab, amyloid beta; 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 for Mild Cognitive Impairment; CDR-SB, Clinical Dementia Rating-Sum-of-Boxes; CSF, cerebrospinal fluid, GFAP: glial
fibrillary acidic protein; NfL, neurofilament light chain, MRI, magnetic resonance imaging; PET, positron emission tomography; p-tau, phosphorylated tau; t-tau, total tau.

Clarity AD: Biomarker Assessments
All Prospectively Pre-specified in Statistical Analysis Plan

CSF
•
•
•
•
•
•

Aβ[1-40]1Aβ[1-42]1
t-tau1p-tau1811
Neurogranin2
Neurofilament light chain(NfL)3

PlasmaImaging• Aβ 42/40 ratio4• p-tau1813• Glial fibrillary acidic protein(GFAP)3
• NfL3• Amyloid PET5
• Tau PET (MK-6240)• Volumetric MRI (vMRI;
Whole brain volume,
cortical thickness, and total
hippocampal volume)

1 Fujirebio Lumipulse. 2 Euroimmune ELISA. 3 Quanterix Simoa. 4 C2N Precivity AD-Ab. 5 florbetaben, florbetapir or flutemetamol tracers

51

All analyses of biomarkers report pre-specified nominal p-values without multiple comparison corrections
Ab, amyloid beta; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET, positron emission tomography; p-tau, phosphorylated tau; t-tau, total tau.

Amyloid Biomarkers
CSF and Plasma Aβ42/40 Improves Indicating Early/Sustained Amyloid Reversal Effects
CSF Aβ1-42

CSF Ab42/40

Normalizes (↑) indicating
improvement in Aβ
aggregation process

CSF Aβ1-40

Plasma Ab42/40
Baseline 0.088, 0.088

Not affected52**** P<0.0001

Ab, amyloid beta; CSF, cerebrospinal fluid, SE, standard error.

PET Centiloids and Amyloid PET SUVr Images at Baseline and 18 Months
Highly Significantly Reduced Amyloid Plaque (Centiloids) at All Time Points;
Mean at 18 Months of 23 Centiloids (Below 30 Centiloid Threshold of Positivity)
Baseline

79.45 CL84.44 CL

18 months

Less Amyloid

PlaceboBaseline 75.0, 77.9

Baseline

80.33 CL

*
*
15
24

14
36

15
54

16
68

Lecanemab* 73 subjects were not included at 18 months (per SAP) since their PET assessments were performed
after receiving lecanemab in the extension phase.

53

Note: Based on PD analysis population (PET substudy population). Adjusted mean change from baseline, SE and p-value
are derived using MMRM with treatment group, visit, treatment group by visit interaction, clinical subgroup, use of AD
symptomatic medication at baseline, ApoE4 carrier status, region, baseline value by visit interaction as fixed effects, andbaseline value as covariate.

22.80 CL

18 months% Amyloid Negative (<30 CL)
Placebo
Lecanemab

Florbetaben SUVR

Tau Biomarkers• CSF and plasma p-tau181 continued to increase in placebo group• CSF and plasma p-tau181 decreased in lecanemab group towards normal at all times measured• Indicates removing amyloid improves downstream tau phosphorylation at amyloid responsive 181 site
CSF P-Tau181

54

CSF, cerebrospinal fluid, p-tau, phosphorylated tau; SE, standard error.

Plasma P-Tau181**** P<0.0001

Tau PET
Lecanemab Slows Tau Pathology in Temporal Lobe (Early Braak Regions)*
Medial Temporal
No. of Participants(placebo, lecanemab)

Adjusted
Mean
Difference

P
Value

Favors lecanemab
Medial temporal

122, 135-0.0680.0024

Meta temporal

122, 135-0.071

0.012

Temporal

132, 136-0.065

0.016

Frontal122, 135-0.0230.22

Cingulate132, 135-0.034

0.13

Parietal122, 135-0.0290.25

Occipital

132, 135-0.0030.91

Whole corticalgray matter

122, 443-0.0350.10-0.12 -0.08 -0.04

0

0.04

Adjusted Mean Difference versus Placebo (95% CI)*Other regions favored lecanemab but were p > 0.05
55

CI, confidence interval; PET, positron emission tomography; ROI, regions of interest.

Meta TemporalTemporalNeurodegeneration Biomarkers
CSF NfLCSF T-TauBaseline 615, 585

Plasma NfL• 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 anddecreased in lecanemab treated group56**** P<0.0001
CSF, cerebrospinal fluid, NfL, neurofilament light chain. SE, standard error; p-tau, phosphorylated tau; t-tau, total tau.

Astrocytic and Synaptic Biomarkers• GFAP, a marker of astrocyte activation and neurogranin and marker of synaptic dysfunction, both improved
towards normal

Plasma GFAP

57

CSF, cerebrospinal fluid, GFAP: glial fibrillary acidic protein; SE, standard error.

CSF Neurogranin**** P<0.0001

Volumetric MRI: Increased Atrophy in Whole Brain andCortical Thickness, with Decreased Atrophy in Hippocampi
Whole brain volume

Lateral ventricular volume

Cortical thickness

0

P<0.00001

P<0.00001

Increasing

-1000
-2000
-3000
-4000

P<0.00001

-5000
-6000
-7000

Total hippocampal volume

Left hippocampal volume

Right hippocampal volume

P=0.0039
P=0.0045* P<0.05; ** P<0.01; *** P<0.001; **** P<0.0001

58

CI, confidence interval; SE, standard error; vMRI, volumetric magnetic resonance imaging.

P=0.046

Interpretation
Lecanemab treatment impacted CSF, plasma, and imaging biomarkers across measuresof amyloid, tau, neurodegeneration, astrocyte and synaptic pathophysiological measures.
• Lecanemab had beneficial effects on biomarkers of amyloid, tau, and other pathophysiology
measures• The neurodegeneration markers gave a mixed picture, potentially because these measures
may take time to respond, and will be followed in ongoing studies• The drug directly removed amyloid plaques as measured by soluble & PET measures, andalso had downstream effects on tau pathology by PET, soluble measures of tau, synaptic
dysfunction, and astrocyte activation• These findings indicate biological disease modification, by improving the amount of amyloid
and tau pathology of the disease, while also impacting the pathophysiology of Alzheimer’s
disease1,2• Disease modification is further supported by clinical benefit, with phase 2 data of durable
effect off dosing, and will be further evaluated in the OLE period
59

1. FDA Draft Guidance for Industry. Early Alzheimer's Disease: Developing Drugs for Treatment (2018). 2. CHMP Guideline on the clinical investigation of medicines for the treatmentof Alzheimer's disease. Available online at: CPMP/EWP/553/95 Rev.2 (2018).

Clarity AD: Results in Context

Sharon Cohen, MD FRCPC
Toronto Memory Program

Disclosures• Consultant (no personal fees)– Alnyalm, Biogen, Cogstate, Cognivue, Cassava Sciences, Eisai, Eli Lilly, INmuneBio, Novo
Nordisk, ProMIS Neuroscience, RetiSpec, Roche• Research Grants (paid to institution only)– Agene Bio, Alector, Alnylam, Alzheon, Anavex, Biogen, Cassava Sciences, Eisai, Eli Lilly,
Janssen, Novo Nordisk, RetiSpec, Roche, UCB Biopharma, Vielight61

Alzheimer’s Disease – A Major Unmet Need of Our Time
• A chronic, progressive, disabling, and fatal disease1-7• 6th leading cause of death in seniors3
Personality 3• Accounts forDecreased
60-80% ofCommunication
cases of dementia
judgmentchallenges
changes

Unable toindependently
perform daily
activities• 55 million − rising to 75 million by 2030, and 150 million by 20503• Alzheimer’s disease causes a significant economic burden globally3-4• Severe impact on patients, families, and healthcare systems3-4• Established treatments are insufficient462

1. Dubois B, et al. Lancet Neurol 2010;9:1118–1127. 2. Masters C, et al. Nature Reviews 2015;1:15056. 3. Alzheimer’s Disease International. World Alzheimer Report 2022. 4. Scheltens
P, et al. Alzheimer's disease. Lancet 2021;397:1577-1590. 5. Hampel H, et al. Mol Psychiatry 2021;26:5481-5503. 6. Albert MS, et al. Alzheimers Dement 2011;7(3):270-9. 7. Jack Jr. CA,
et al. Alzheimer’s & Dementia 2011;7;257-62.

Important Treatment Goals in Alzheimer’s Disease• Impact on symptoms• Greater magnitude of improvement• More sustained improvement duration• Slowing of disease• Maintaining or stabilizing abilities for longer periods• Delaying or preventing onset of more disabling andcostly stages of disease• Maintaining/Improving quality of life for patients andfamilies
63

Disease Modification in Alzheimer’s Disease• FDA definition• Persistent effect on disease course• Direct effect on the underlying disease pathophysiology• EMA (CHMP) definition• Persistent delay in the underlying neuropathologicalprocess• Delay of clinical decline64

FDA Draft Guidance for Industry. Early Alzheimer's Disease: Developing Drugs for Treatment (2018).
CHMP Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease. Available online at: CPMP/EWP/553/95 Rev.2 (2018).

Clarity AD Treatment Effect: CDR-SB
Global Measure of Cognition and Function
Clarity AD

No. of Participants(placebo, lecanemab)

CDR-SB

CDR-SB Domains

Adjusted
Mean
Difference%%
Slowing
Improvement

P
Value

Favors lecanemab

Memory875, 859-0.07727.5

0.00117

Orientation

875, 859-0.08128.1

0.00044

Judgement/Problem Solving

875, 859-0.05323.6

0.01008

Community Affairs

875, 859-0.07021.2

0.00524

Home and Hobbies

875, 859-0.09828.8

0.00018

Personal Care

875, 859-0.06729.9

0.01325-0.16 -0.12 -0.08 -0.04

0

0.04

Adjusted Mean Difference versus Placebo (95% CI)

Lecanemab Effect• 27% slowing on CDR-SB• Increased magnitude of separation over time (0.45 at 18 months)• Effect seen across all CDR-SB domains

65

CDR-SB Scale•
Patient and caregiver interview•
Rates 6 cognitive and functional domains•
Each domain scored from 0, 0.5, 1, 2 for range of 0-18•
Mild cognitive impairment and mild AD dementia tend to score 0.5 or 1 in each domain•
Baseline CDR-SB was 3.2

AD, Alzheimer’s disease; CDR-SB, Clinical Dementia Rating-Sum-of-Boxes; CI, confidence interval;
SE, standard error.

Treatment Effect: Consistent Across Comorbidities and Anticoagulant Use
CDR-SB%%
Placebo Difference
Decline Vs Placebo Improvement
Slowing

No. of Participants(placebo, lecanemab)
Favors lecanemab
875, 859

1.66

-0.45

27

Hypertension

486, 471

1.56

-0.47

30

Diabetes

130, 130

1.75

-0.58

33

Heart disease131, 142

1.7

-0.88

52

Hypercholesterolemia

518, 533

1.75

-0.55

32

Obesity136, 145

1.38

-0.53

38

Anticoagulants

72, 80

2.07

-0.74

36

Overall-0.16 -0.12 -0.08 -0.04

0

0.04

Adjusted Mean Difference versus Placebo (95% CI)
66

CDR-SB, Clinical Dementia Rating-Sum-of-Boxes ; CI, confidence interval.

ADAS-Cog14

ADCS MCI-ADL

Treatment Effect: Specific Scales of Cognition and Function• 26% slowing on ADAS-Cog14 at 18 months• 37% slowing on ADCS MCI-ADL at 18 months• Increases in magnitude of separation over time
ADAS-Cog14•
Administered to patient•
Rates 14 domains with score ranging from 0-90 (higher score is worse)•
Baseline ADAS-Cog14 was 24
67

ADCS MCI-ADL•
Rated by family or caregiver•
24 items assessing a range of daily activities with score ranging from 0-53 (lower
score is worse)•
Baseline ADCS ADL-MCI was 41

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; SE, standard error.

Time to Worsening of Global CDR Scores

Rate of Progression to Next Stage

Time to Worsening of Global CDR Scores• Hazard ratio 0.69

• 31% lower risk of convertingto next stage of disease by
global CDR• Individuals remain in earlier
stages of Alzheimer’s
disease for a longer period oftime, even within the
18-month course of the study**

68

Progression was defined as global CDR score progressing from 0.5 [MCI] to 1[mild AD dementia]
or 1 [mild dementia] to 2 [moderate dementia])*KM plot uses actual duration for time to event. Including the number at risk within a 2 week
window, N at 18 months is 497 in placebo and 527 in LEC10-BW

CDR, Clinical Dementia Rating.

Slope Analysis Using CDR-SB
Observed Data and Extrapolation to 2 Years•

32% slowing of slope annually [(95%CI: 18% to 46%), p=0.00001] on lecanemab vs. placebo•

Increasing separation over time between lecanemab & placebo
0

Analysis of Rate of Change Over Time
(Slope Analysis) in CDR-SB•

Projected treatment difference at 25.5 months based on slope showed -0.68 treatment difference

Visit (Month)69

Observed Data

Extrapolated Data

0.4

0.8

1.16
1.2

5.3 M
0.48

1.6

7.5 M

1.64

2

0.68

2.4

2.32
0

3

6

9

12

15

18

• Lecanemab
takes 25.5
months toreach samelevel asplacebo at 18
months

24 25.5

Note: Rate of change over time (mean slope) based on change from baseline in the CDR-SB was analyzed using linear mixed effects (LME) model. LME model included time,treatment by assessment time as covariate with random intercept and slope. CDR-SB, Clinical Dementia Rating-Sum-of-Boxes.

Lifetime Health Outcomes: Trial Data Modeling Simulation
Lecanemab Could Delay AD Progression by Several Years
Modeled early AD patient population1 based on lecanemab Study 201 and ADNI data3
Time to Advance to Mild, Moderate, and Severe AD Longer for Lecanemab
SoC:

SoC + lecanemab:

MCI

Mild ADMCI

Mild AD∆t1

SevereAD

Moderate AD

SevereAD

Moderate AD

∆t2

∆t3

Lecanemab treatment predicted:• Slower rate of disease progression with extended duration of MCI and mild AD stages and shortened
duration of moderate and severe stages• Mean time to mild, moderate, and severe dementia in lecanemab+SoC vs SoC was 2.51, 3.13, and2.34 years respectively• Lower lifetime probability of institutionalization (25% vs. 31%)
• This model will be updated with Clarity AD data which we anticipate consistent results
AD, Alzheimer’s disease; MCI, mild cognitive impairment; SoC, standard of care; t, time.

70

1.
2.
3.

Tahami Monfared AA et al. ”Long-Term Health Outcomes of Lecanemab in Patients with Early Alzheimer’s Disease Using Simulation Modeling”. Neurol Ther. 2022.
Swanson et al. ” A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody”. Alzheimer’s Res Ther. 2021
ADNI (Alzheimer’s Disease Neuroimaging Initiative) studyHealth-Related Quality of Life Measures
Slowing of Health Decline with Lecanemab on Subject and Study Partner Burden
EQ-5D-5L (Subject)

QOL-AD (Subject)

49%
Less Decline

Zarit Burden Interview
38%
Less Decline

****

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•

EQ-5D-5L: European Quality of Life–5 Dimensions (5 Level
version): The descriptive system covers 5 dimensions of health(mobility, self-care, usual activities, pain or discomfort, andanxiety or depression) with 5 levels of severity in each dimension(no problems, slight problems, moderate problems, severe
problems, and unable to perform or extreme problems). The
score being presented is the VAS: Health Today (Visual Analog
Scale subtotal).

•

QOL-AD: Quality of Life in Alzheimer’s Disease: A 13-item
questionnaire designed to provide both a patient and a caregiverreport of the quality of life (QOL) for patients who have been
diagnosed with Alzheimer Disease•

Zarit Burden Interview: The 22-item instrument used indementia caregiving research used to assess the stresses
experienced by study partners of subjects with dementia.

23%
Less Decline

Worsening

Worsening****• Consistent benefits seenin quality of life andcaregiver burden acrossdifferent scales
QOL-AD (Subject by Proxy)

Study Partner Burden (total score)***

56%
Less Decline**

Worsening

Worsening*** P<0.05; ** P<0.01; *** P<0.001; **** P<0.0001*****

SE, standard error.

Summary• The convergence of evidence across multiple measures of cognition, function, diseaseprogression, health-related quality of life, caregiver burden, and biomarkers, demonstratethat lecanemab treatment may offer meaningful benefits to patients, care partners, andsociety– Impact across cognition and function (27-37% slowing) and subgroups (race, ethnicity, comorbidities)– Delay in progression to later stages of disease (HR=0.69)•

Slope analysis suggests continued improvement with longer treatment•

Modeling indicates lecanemab could potentially delay progression by 2.5-3.1 years– Relative preservation of health-related quality of life and caregiver burden (23-56% slowing of decline)– Impact on multiple A/T/N biomarkers demonstrating target engagement and downstream biological impact– Well characterized safety profile with low rates of symptomatic ARIA

The results of Clarity AD:• Support the role for amyloid protofibril-targeted therapy in early AD• Are consistent with FDA and EMA terminology for disease modification• Provide momentum to the broader field of AD drug development• Prompt a paradigm shift towards early diagnosis to achieve disease slowing and to extend
milder stages of disease72

AD, Alzheimer’s disease; ARIA, amyloid related imaging abnormalities; A/T/N/+, amyloid/tau/neurodegeneration/other; EMA, European Medicines Agency; FDA, Food & Drug Administration; HR, hazard ratio.

Panel Discussion and Q&A

Clarity AD

Thank you

Clarity AD