Lecanemab: Amyloid Reduction andEvidence of Downstream
Biomarker Modification

Michael C. Irizarry, MD, MPH
Senior Vice President, Clinical Research, Neurosciences
Deputy Chief Clinical Officer
Alzheimer Disease and Brain Health
Eisai Inc.

2023 Alzheimer Association International Conference (AAIC) Annual Meeting | July 16-20, 2023 | Amsterdam, Netherlands. Plenary #80907. Plenary 4-15-PL.

Disclosures• Author 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

Lecanemab binding profile(Darker color = stronger binding)Oligomers

Protofibrils

9 – 75 kDa>75 – 5000 kDaSoluble

Fibrils

Insoluble

Strongest binding• Lecanemab is a 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 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.

Biomarker Objectives in Lecanemab Development
Biomarkers
Hierarchy
Patient Selection

Target Engagement/
Pharmacodynamic

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

4Assessment

PurposeAmyloid PET
CSF Aβ42/40
Plasma Aβ42/40, p-tau217 (AHEAD 3-45)

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

Amyloid PET
CSF or plasma Aβ42/40
CSF protofibril*Activity against amyloid
plaques
Activity against protofibrils

Amyloid PET
CSF and plasma Aβ[42], Aβ42/40 ratio, ptau181 and NfL
CSF t-tau, neurogranin and GFAP
Tau PET
MRI regional volumes
Early AD: CDR-SB, ADCS MCI-ADL,ADAS-Cog14, ADCOMSAHEAD 3-45: PACC5, CFI

Predict clinical benefit foraccelerated approval
Activity against downstream
process in AD (diseasemodification)

Confirm efficacy

Hypothesis•
•••••
••

Treatment of early AD prior toadvanced irreversible
neurodegeneration
Preclinical population responsive totailored dose of lecanemab
Reduction of amyloid plaques
Reduction of amyloid aggregation
process
Reduction of free CNS protofibrils
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
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; CDR-SB, Clinical Dementia Rating-Sum-of-Boxes; CSF, cerebrospinal fluid; CFI, Cognitive
Function Index; GFAP: glial fibrillary acidic protein; NfL, neurofilament light chain, MRI, magnetic resonance imaging; PACC5, Preclinical Alzheimer Cognitive Composite 5; PET, positronemission tomography; p-tau, phosphorylated tau; t-tau, total tau.

Clarity AD Study DesignDiverse patient population• Eligibility Criteria• Site selection• Community outreach• Decentralized activities
5Optional longitudinal sub-studies• Amyloid burden (amyloid PET)
• Brain tau pathology (tau PET)
• CSF biomarkers of neurodegeneration• 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.

Clarity AD Results• Clarity AD met all primary and secondary efficacy endpoints (p<0.001)• Benefit-risk supported by convergence of comprehensive Clarity AD assessments:– Consistency of results across scales of cognition and function (27-37% slowing) andsubgroups (race, ethnicity, comorbidities)– Delay in progressing to later stages of the disease (HR 0.69)– Preservation relative to placebo of health-related quality of life and caregiver burden(23-56% slowing)– Effects on A/T/N+ biomarkers that provide a biological basis for the treatment effects– Safety profile with important AEs of infusion related reactions (26.4%), ARIA-E (12.6%overall; 2.8% symptomatic) and uncommon intracerebral hemorrhage (0.6%)

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van Dyck CH, et al. N Engl J Med. 2023;388:9-21.
Van Dyck CH, et al. Presented at the 15th Annual CTAD Meeting. November 29 – December 2, 2022. San Francisco, CA

Clarity AD: Biomarker Assessments

All Prospectively Pre-specified in Statistical Analysis PlanCSF
•
•
•
•
•
•

Aβ[1-40]1Aβ[1-42]1t-tau1
p-tau1811
Neurogranin2
Neurofilament light chain(NfL)3

Plasma• Aβ 42/40 ratio4• p-tau1813• Glial fibrillary acidic protein(GFAP)3
• NfL3Imaging• Amyloid PET5
• Tau PET (MK-6240)• Volumetric MRI

1 Fujirebio Lumipulse. 2 Euroimmun ELISA. 3 Quanterix Simoa. 4 C2N Precivity AD-Aβ. 5 florbetaben or florbetapir tracers

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

Amyloid PET

Lecanemab Reduced Amyloid Plaque at All Time Points

Less AmyloidPlacebo**% Amyloid Negative (<30 CL)
Placebo
Lecanemab

15241436

1554

Lecanemab

1668* 73 subjects were not included at 18 months (per SAP) since their PET assessments were performed
after receiving lecanemab in the extension phase.

8Note: 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.

12.5

Amyloid Biomarkers
CSF Aβ1-42Normalizes (↑) indicatingimprovement in Aβaggregation process

9**** P<0.0001

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

Plasma Aβ42/40

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

CSF P-Tau181

10CSF, cerebrospinal fluid, p-tau, phosphorylated tau; SE, standard error.

Plasma P-Tau181**** P<0.0001

Neurodegeneration Biomarkers
CSF NfLCSF T-Tau

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 group
11**** 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

12CSF, cerebrospinal fluid, GFAP: glial fibrillary acidic protein; SE, standard error.

CSF Neurogranin**** P<0.0001

Volumetric MRIGreater Decline in Whole Brain Volume, With Slowing of Volume Loss in Hippocampi
Whole Brain VolumeP<0.00001• Volumetric MRI results were inconsistent—with slowing ofhippocampal atrophy but greater cortical volume loss onlecanemab relative to placebo• Volume loss is not associated with worsening in any
neurodegenerative biomarkers or clinical outcomes• Greater cortical volume loss may be related tomobilization of amyloid and reduced amyloid associateddystrophic neurites and inflammation/gliosis

Total Hippocampal Volume• Not reasonable to conclude that volume loss represents
diffuse neuronal loss
P=0.0039

13* P<0.05; ** P<0.01; *** P<0.001; **** P<0.0001• This is instead pseudo-atrophy and certainly clinicalmeasures indicate a benefit from lecanemab and not adetrimentCI, confidence interval; SE, standard error; vMRI, volumetric magnetic resonance imaging.

Tau PET Substudy
Baseline stratification

Averaged Scans from the Tau PET Substudy (n=342)
MK6240 PET processed at
Invicro (ref region: ventralcerebellum)•Whole cortical gray matter Tau
PET cutoffs derived from
MK6240 scans in theLantheus/Cerveau database[amyloid positive, mean MMSE
(SD): 23.4 (3.5)]–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%)

Low Tau

Intermediate Tau

High Tau

5

SUVR•0.5

Tau PET Substudy
Baseline Characteristics

All Subjects

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Tau PET Substudy 1

Substudy: Low Tau-PET*

Placebo(N=875)

Lecanemab
10 mg/kg biweekly(N=859)Placebo(N=167)

Lecanemab
10 mg/kg biweekly(N=175)

Placebo(N=71)

Lecanemab
10 mg/kg biweekly(N=70)

Age, mean (standard deviation), years

71.0 (7.8)

71.4 (7.9)

72.4 (7.8)

71.8 (7.8)

71.8 (8.6)

72.6 (7.6)

Female, n (%)
CDR Global=0.5MMSE, mean (SD)AD Stage
MCI
Mild dementia
ApoE4 Status
Noncarrier
Heterozygous
Homozygous

464 (53.0)
706 (80.7)
25.6 (2.23)

443 (51.6)
694 (80.8)
25.5 (2.19)

92 (55.1)
132 (79.0)
25.6 (2.09)

84 (48.0)
127 (72.6)
25.6 (2.18)

36 (50.7)
56 (78.9)
25.9 (2.14)

30 (42.9)
47 (67.1)
25.5 (2.01)

544 (62.2)
331 (37.8)

528 (61.5)
331 (38.5)

108 (64.7)
59 (35.3)

101 (57.7)
74 (42.3)

50 (70.4)
21 (29.6)

36 (51.4)
34 (48.6)

275 (31.4)
468 (53.5)
132 (15.1)

267 (31.1)
456 (53.1)
136 (15.8)

70 (41.9)
84 (50.3)
13 (7.8)

75 (42.9)
77 (44.0)
23 (13.1)

36 (50.7)
34 (47.9)
1 (1.4)42 (60.0)
24 (34.3)
4 (5.7)

CDR-SB, mean (SD)PET Centiloids, mean (SD)
ADAS-Cog14, mean (SD)
ADCS-ADL-MCI

3.22 (1.343)
75.28 (41.85)
24.37 (7.561)
40.9 (6.89)

3.17 (1.340)
77.94 (44.78)
24.45 (7.082)
41.2 (6.61)

3.31 (1.332)
73.84 (41.032)
22.88 (6.959)
40.68 (6.669)

3.40 (1.307)
70.65 (46.844)
22.65 (6.723)
40.66 (6.919)

3.20 (1.369)
50.36 (37.637)
20.56 (6.285)
40.35 (6.832)

3.44 (1.424)
36.35 (35.79)
21.39 (6.562)
38.81 (6.927)*Whole cortical gray matter Tau PET cutoffs derived from MK6240 scans in theLantheus/Cerveau database (mean MMSE (SD): 23.4 (3.5))• Low Tau <1.06 (n=141 [41.2%])• Intermediate Tau = 1.06-2.91 (n=191 [55.8%])• High Tau >2.91 (n=10 [2.9%])

1Subjects with a baseline tau PETTau PET

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

Meta TemporalTemporal

16*Other regions favored lecanemab but were p > 0.05
1Baseline and at least one post-baseline tau PET
CI, confidence interval; PET, positron emission tomography; ROI, regions of interest.

Tau PET Substudy: Clinical Outcomes1

Slower Decline Overall and in Low Tau PET Subgroup
CDR-SB

ADAS-Cog14% Less decline = 37.9%∆ = -.53, p = .033

% Less decline = 16%∆ = -1.01, p = .34% Less decline = 549%
∆ = -.59, p = .022

% Less decline = 52.4%∆ = -1.74, p = .20

ADCS MCI-ADL% Less decline = 39.2%∆ = -1.92, p = .042

Overall% Less decline = 88.2%∆ = -3.26, p = .009

LowBaselineTau

1Subjects with a baseline tau PET

Conclusions and Future Considerations
Lecanemab treatment impacted A/T/N+ biomarkers and provides
a framework for assessing biological disease modification• Time course and relationship across biomarkers (“reverse” Jack curves)– Interrelationship of changes among biomarkers• Generalizability of biomarker responses to other therapeutic targets• Application of biomarker outcomes to assess contribution of drugs incombination• Standardization of biomarker measures (e.g. CPAD Tau PET initiative)• Clinical benefits of lecanemab help to validate the biomarker framework18Subcutaneous (SC) Lecanemab is Predicted toAchieve Comparable Efficacy and Improved Safety
Compared to Lecanemab IV in
Early Alzheimer’s Disease (AD)July 17, 2023

Brian A Willis PhD
Clinical Pharmacology and Translational Medicine
Eisai Inc.
2023 Alzheimer Association International Conference (AAIC) Annual Meeting | July 16-20, 2023 | Amsterdam, Netherlands. Developing Topics #82852, Session 2-06-DEV.

Disclosures• Authors are employees of Eisai, Inc.

Brian A Willis PhD, Natasha Penner PhD, Sumit Rawal PhD, Jagadeesh Aluri MS, Larisa Reyderman PhD
Clinical Pharmacology and Translational Medicine
Eisai Inc.

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Background• Lecanemab is a humanized IgG1 monoclonal antibody that binds withhigh affinity to Aβ soluble protofibrils• Lecanemab is currently administered by intravenous infusion at10 mg/kg biweekly• PK/PD modeling demonstrates serum lecanemab Cav,ss is associatedwith plaque lowering and efficacy• Two studies were conducted to explore subcutaneous dosing
alternatives

2Aβ=amyloid beta. Cav,ss=average concentration at steady state. PK=pharmacokinetic. PD=pharmacodynamic.

Bioavailability Data and PK/PD Model Used to
Select Appropriate SC Dose
• Study 004 compared IV (10 mg/kg) vs SC (700 mg)
exposure in healthy subjects– Bioavailability 49.7%

Simulations demonstrate that matching average
steady-state lecanemab concentrations lead tosimilar amyloid PET reductions

Simulations show impact of switching from weightbased dosing to “flat” dosing expected to haveminimal impact on amyloid reduction

3h=hours. IV=intravenous. PET=positron emission tomography. PK=pharmacokinetic. PD=pharmacodynamic. SC=subcutaneous. SD=standard deviation.

Lecanemab 720 mg SC Provides Similar Exposureand Amyloid Reduction as 10 mg/kg IV• Study 005 compared exposures following SC administration using
either an autoinjector or vial/syringe method• Simulations were performed to estimate steady-state exposures andamyloid reduction following SC administration by vial or autoinjector

Projected exposures used with PK/PD model
demonstrates similar reduction in amyloid PETwith either IV or SC administration method– Steady-state exposures projected based on Study 005

Cav,ssSimulated steady-state SC exposures overlappedwith those observed from IV in Studies 201 and 301

4Cav,ss=average concentration at steady state. h=hours. IV=intravenous. PET=positron emission tomography. SC=subcutaneous. SD=standard deviation.

Lower Cmax For Lecanemab SC Administration
Expected to Provide Safety Benefit•

Exposure metrics (Cmax,ss, Cav,ss and Cmin,ss) are all correlated with ARIA-E– Following IV administration in Studies 201/301, Cmax,ss is best predictor of ARIA-E rates•If Cmax,ss continues to predict ARIA-E with SC administration, ARIA-E risk is expected to be less after SCadministration

Projected ARIA-E Rates Following SC or IV Administration

ApoE45SC Vial

AI Device

IVNon-carriers

1.7%

2.0%

5.4%

Homozygotes

10.5%

12.1%

28.0%

Heterozygotes

3.2%

3.7%

9.8%

AI=autoinjector. ARIA-E=amyloid-related imaging abnormalities with edema/effusion. Cav,ss=average concentration at steady state. Cmax,ss=maximum concentration at steady state. Cmin,ss=minimum concentration at steady state. IV=intravenous. SC=subcutaneous.

Conclusions• Lecanemab bioavailability following subcutaneous administration is~50%, as compared to IV administration• PK/PD models demonstrate that 720 mg SC flat dose will provide
similar exposure to 10 mg/kg IV administration, regardless of bodyweight• Lecanemab SC is expected to result in similar amyloid lowering asfollowing IV administration based on comparable exposure (Cav,ss)• SC administration is expected to have a better safety profile relative toIV based on lower incidence of ARIA-E due to lower Cmax
• Safety and amyloid reduction models will be updated based on resultsof SC dosing in the Clarity AD OLE
6ARIA-E=amyloid-related imaging abnormalities with edema/effusion. Cav,ss=average concentration at steady state. Cmax,ss=maximum concentration at steady state. IV=intravenous. SC=subcutaneous.