Lecanemab for Early Alzheimer’s Disease:Long-Term Outcomes, Predictive Biomarkers andNovel Subcutaneous Administration

Clinical Trials on Alzheimer’s Disease (CTAD)
Boston, MA, USA
October 24 – 27, 2023

Welcome and Introductions

Christopher van Dyck
Yale University School of Medicine

Lecanemab for Early Alzheimer’s Disease: Long-Term Outcomes,
Predictive Biomarkers and Novel Subcutaneous Administration
Topic
Clarity AD: Review of the Mechanism-Based Rationale and Results of the Lecanemab
Phase 3 Trial

Christopher van Dyck

Biomarker Assessments from Clarity AD: Downstream Implications of Targeting
Protofibrils and Tau as a Predictive Biomarker

Keith Johnson

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

Reisa Sperling

Preliminary Update on Lecanemab Safety in Clarity AD Open-Label Extension, Including
Subcutaneous Formulation

Michael Irizarry

Panel Discussion / Q&A
3

Presenter

Christopher van Dyck /AllClarity AD: Review of the Mechanism-Based Rationale
and Results of the Lecanemab Phase 3 Trial

Christopher van Dyck
Yale University 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

5

Janssen Pharmaceuticals
Eisai, Inc
Genentech, Inc
Cerevel Therapeutics

Lecanemab Unique Dual-Action Mechanism:

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

Lecanemab
Targets Protofibrils

Lecanemab
Clears Plaques

Lecanemab
Slows Tau Pathology

INSERT
IMAGE
HERE

•

The unique dual action of lecanemab rapidly clears amyloid plaque and highly toxic protofibrils1-5– Selectively binds to soluble Aβ aggregated species, with preferential activity for Aβ protofibrils over monomers (>1000x)
and over fibrils (>10x)1,6-10•

Slows tau pathology in temporal lobe (early Braak regions) which is a hallmark of disease progression

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

6

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

Lecanemab Preferential Binding to Soluble Aβ Protofibrils
Lecanemab

Aducanumab

Donanemab

Gantenerumab

Results will bepresented
at CTADon Thursday

•
•
•
•

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Small protofibrils, approx. 75-300 kDa,
Large protofibrils, approx. 300-5000 kDa

Lecanemab binds small protofibrils 100x and large protofibrils
25x stronger than aducanumab
Gantenerumab is less selective and binds monomers withsomewhat higher affinity compared to lecanemab andaducanumab

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

Binding to Aβ Monomers and Large Protofibrils
by Inhibition ELISA
Antibody

Monomers
IC50 (nM)

Small Protofibril
IC50 (nM)

Large Protofibril
IC50 (nM)

Lecanemab>25,000

Aducanumab>25,000

0.80 ± 0.10

0.79 ± 0.20

Gantenerumab

2600 ± 130

2.5 ± 0.10

1.3 ± 0.10

>83

22.0 ± 2.0

Clarity AD Study Design

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

8AD, 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 and Tau PET Substudy

Tau PET Substudy Baseline Characteristics Similar to Overall Study Population
All Participants

72.4 (7.8)
92 (55.1)
132 (79.0)
25.6 (2.09)

Lecanemab
10 mg/kg biweekly(N=175)71.8 (7.8)
84 (48.0)
127 (72.6)
25.6 (2.18)

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

71.0 (7.8)
464 (53.0)
706 (80.7)
25.6 (2.23)

Lecanemab
10 mg/kg biweekly(N=859)71.4 (7.9)
443 (51.6)
694 (80.8)
25.5 (2.19)

544 (62.2)
331 (37.8)

528 (61.5)
331 (38.5)

108 (64.7)
59 (35.3)

101 (57.7)
74 (42.3)

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)

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

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)

Placebo(N=875)

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Tau PET Substudy1
Placebo(N=167)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; CDR-SB, Clinical Dementia Rating-sum of boxes; MCI, mild cognitive impairment; MMSE, Mini-Mental State Exam; PET, positron emission tomography; SD, standard deviation.

1Subjects with a baseline tau PET

Clarity AD and Tau PET Substudy: Clinical Outcomes1

Efficacy Results Similar in Tau PET Substudy to Overall Study Population% Less decline = 27%∆ = -.45, p<0.0001

ADAS-Cog14% Less decline = 26%∆ = -1.44, p<0.001

ADCS MCI-ADL% Less decline = 37.9%∆ = -.53, p = 0.033% Less decline = 16%∆ = -1.01, p = 0.34

% Less decline = 39.2%∆ = 1.92, p = 0.042% Less decline = 37%∆ = 2.02, p<0.0001

Tau PET
Substudy

Overall
Clarity AD

CDR-SB

1Subjects

with a baseline
tau PET

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; 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; SE, standard error.

10Summary• Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody with adual mechanism of action– Targets highly toxic protofibrils and rapidly clears amyloid plaques– Selectively binds to soluble Aβ aggregated species, with preferential activity forAβ protofibrils over monomers (>1000x) and over fibrils (>10x)• Clarity AD met all primary and secondary efficacy endpoints (p<0.001)– Consistency of results across scales of cognition and function (27-37% slowing)• Tau PET substudy participants and efficacy results similar to overall population– Keith will next present Tau PET substudy results

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PET, positron emission tomography.

Biomarker Assessments from Clarity AD:
Downstream Implications of Targeting Protofibrils
and Tau as a Predictive Biomarker

Keith Johnson
Massachusetts General Hospital
Brigham and Women’s Hospital
Harvard Medical SchoolKeith Johnson - Disclosures• Consultant: Novartis, Merck• Spouse consultant to: Abbvie, AC Immune, Acumen, Alector, Bristol-Myers-Squibb, Genentech,
Ionis, Janssen, Oligomerix, Prothena, Roche, Shionogi, Vaxxinity• Research funding:– National Institute on Aging:
P01AG036694; R01AG054029; U24AG057437; R01 AG03689;
R01 Alzheimer’s Tau Platform
–
–
–
–
–
–
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Alzheimer’s Association, Fidelity Biosciences
GHR Foundation
Gates Ventures
Eli Lilly
Eisai
Accelerating Medicines Partnership FNIHTau PET Substudy

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

–

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Intermediate Tau

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%)

High Tau

AD, Alzheimer’s disease; MMSE, Mini-Mental State Exam; PET, positron emission tomography; SD, standard deviation; SUVr, standardized uptake value ratio.

5

SUVR

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

Low Tau0.5

Unique Early Population Not Previously Studied or
Analyzed and Reported• Unlike other recently reported studies, there was no tau PET exclusion criteria in
Clarity AD which allowed inclusion of early AD participants with low tau (greymatter PET SUVr <1.06) and confirmed cognitive/functional impairment due to AD– Included all early AD participants (MMSE 22-30, 60% clinically diagnosed with
MCI, 80% global CDR 0.5)
– Elevated amyloid levels confirmed by visual read (no exclusion based on CL
level) or CSF• 40% of Clarity AD tau PET substudy have low tau PET SUVr (<1.06)• Elevated tau in the entorhinal cortex confirmed by MK6240 PET

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AD, Alzheimer’s disease; CDR-SB, Clinical Dementia Rating-sum of boxes; MMSE, Mini-Mental State Exam; PET, positron emission tomography; SD, standard deviation; SUVr, standardized uptake value ratio.

Anatomical Distribution of Tau PET Signal in Low Tau Subgroup
Characterized by Signal in Entorhinal Cortex• Not previously analyzed and/or
reported in previous antiamyloid antibody clinical trials

Baseline Tau SUVR

Average Image of 20 Low Tau Participants
with Entorhinal Uptake

Neuroanatomical Region(Braak Stage)Tau Pathology
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PET, positron emission tomography;
SUVr, standardized uptake value ratio.

Clinical Continuum

Entorhinal
Cortex (I)Hippocampus
(II)

Low

Early
Limbic (III)Late
Limbic (IV)Intermediate

Early Symptomatic Disease

Association
Primary
Neocortex (V) Neocortex (VI)High

Tau PET Substudy Baseline Characteristics

Generally Similar Across Tau Populations with Exception of Amyloid Load

Age, mean (SD), years
Female, n (%)
CaucasianYears since diagnosis
Years since onset of symptoms
CDR Global=0.5
Mild dementia due to AD
MCI
ApoE4 Status
Noncarrier
Carrier
Heterozygous
Homozygous
On AChEIs and/or memantine

Tau PET Substudy
Placebo
Lecanemab(N=167)(N=175)72.4 (7.8)
71.8 (7.8)
92 (55.1)
84 (48.0)
155 (92.8)
163 (93.1)
1.47 (1.949)
1.47 (1.444)
4.21 (3.042)
4.32 (2.443)
132 (79.0)
127 (72.6)
59 (35.3)
74 (42.3)
108 (64.7)
101 (57.7)

Low Tau
Placebo
Lecanemab(N=71)(N=70)
71.8 (8.6)
72.6 (7.6)
36 (50.7)30 (42.9)
64 (90.1)
64 (91.4)
1.48(1.907)
1.68 (1.482)
3.81 (2.027)
4.77 (2.488)
56 (78.9)
47 (67.1)
21 (29.6)
34 (48.6)
50 (70.4)
36 (51.5)

Intermediate/High Tau
Placebo
Lecanemab(N=96)(N=105)72.8 (7.1)
71.2 (7.9)
56 (58.3)
54 (51.4)
91 (94.8)
99 (94.3)
1.45 (1.990)
1.33 (1.409)
4.51 (3.596)
4.01 (2.377)
76 (79.2)
80 (76.2)
38 (39.6)
40 (38.1)
58 (60.4)
65 (61.9)

70 (41.9)
97 (58.1)
84 (50.3)
13 (7.8)
66 (39.5)

36 (50.7)
35 (49.3)
34 (47.9)
1 (1.4)31 (43.7)

34 (35.4)
62 (64.6)
50 (52.1)
12 (12.5)
35 (36.5)

75 (42.9)
100 (57.1)
77 (44.0)
23 (13.1)
71 (40.6)

42 (60.0)28 (40.0)
24 (34.3)
4 (5.7)24 (34.3)

CDR-SB, mean (SD)
Amyloid PET Centiloids, mean (SD)
ADAS-Cog14, mean (SD)ADCOMS, mean (SD)ADCS MCI-ADL, mean (SD)
MMSE, mean (SD)17

33 (31.4)
72 (68.6)
53 (50.5)
19 (18.1)
47 (44.8)

3.31 (1.332)
3.40 (1.307)
3.20 (1.369)
3.44 (1.424)
3.40 (1.304)
3.38 (1.230)
73.84 (41.032) 70.65 (46.844) 50.36 (37.637) 36.35 (35.790) 90.96 (34.536) 93.51 (38.753)
22.88 (6.959) 22.65 (6.723)
20.56 (6.285)
21.39 (6.562)
24.59 (6.968)
23.49 (6.728)
0.39 (0.148)
0.42 (0.141)
0.41 (0.142)
0.40 (0.144)
0.41 (0.145)
0.37 (0.145)
40.68 (6.669) 40.66 (6.919)
40.35 (6.832)
38.81 (6.927)
40.90 (6.581)
41.92 (6.657)
25.65 (2.094) 25.62 (2.178)
25.92 (2.136)
25.46 (2.012)
25.45 (2.051)
25.72 (2.285)¥¥
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.

Lecanemab Effect on Amyloid in Tau PET Substudy

Consistent Amyloid Reductions for Subgroups Across Clinical Assessments

Amyloid PET clearance(% <30 CL) in lecanemab

18

6m
n (%)

12m
n (%)

18m
n (%)

Tau PET Substudy

48 (37.2)

83 (60.1)

79 (71.8)

Intermediate + High Tau PET

17 (20.2)

35 (42.7)

37 (56.9)

Low Tau PET

31 (68.9)

48 (85.7)

42 (93.3)

Observed data.
CL, clearance; m, month; PET, positron emission tomography.

Tau PET Subgroups: Clinical Outcomes1
Stability or Improvement With Early-Stage Treatment
ADAS-Cog14

ADCS MCI-ADL% Less decline = 37.9%∆ = -.53, p = 0.033% Less decline = 16%∆ = -1.01, p = 0.34

% Less decline = 39.2%∆ = 1.92, p = 0.042% Less decline = 549%
∆ = -.59, p = 0.022% Less decline = 52.4%∆ = -1.74, p = 0.20

% Less decline = 88.2%∆ = 3.26, p = 0.009

Low
Baseline Tau

Tau PET
Substudy

CDR-SB

1Subjects with abaseline tau PET

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; 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; SE, standard error.

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Observed Rates for ‘No Decline’ and ‘Improvement’
Improving and Stabilizing in Participants with Low/Baseline Tau
CDR-SB No Decline - Low Tau Population80%70%

P=0.024

60%
50%

55% nodecline at
18 months

40%
30%

60%
50%

30%
20%

10%

10%

(N) Placebo(N) Lecanemab

71
70

6

12

18

67
63

62
57

58
50

P=0.0007

40%

20%

0%
Visit (Month)060%
improvement
at 18 months

70%

Patients (%)

Patients (%)

80%

76% nodecline at
18 months

CDR-SB Improvement - Low Tau Population28%
improvement
at 18 months

0%
Visit (Month)0(N) Placebo(N) Lecanemab

71
70

6

12

18

67
63

62
57

58
50

Observed rates for ‘No Decline’ and ‘Improvement’ at 18 months• ADAS-Cog14: 74% and 68% for lecanemab vs 56% and 32% for placebo• ADCS MCI-ADL: 75% and 70% for lecanemab vs 46% and 46% for placebo
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CDR-SB, Clinical Dementia Rating-sum of boxes; PET, positron emission tomography*This was a post-hoc analysis with nominal p values and no adjustment for multiplicity

Tau PET Substudy

Consistent Outcomes for Subgroups Across Clinical Assessments
ADAS-Cog14

CDR-SBADCS MCI-ADL*The longitudinal tau PET substudy was predefined. The subgroups (low and intermediate+high tau PET) were apost-hoc analysis with nominal p values and no adjustment for multiplicity
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ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS MCI-ADL, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive
Impairment; CDR-SB, Clinical Dementia Rating-sum of boxes; CI, confidence interval; PET, positron emission tomography.

Tau PET Substudy

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

SUVr

Tau PET SUVr

SUVr

Meta Temporal

1Baseline and at least one post-baseline tau PET*Other regions favored lecanemab but were p > 0.05

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Note: Based on modified intention-to-treat analysis population. Adjusted mean change from baseline, SE and p-value are derived using mixed model repeat
measures (MMRM) with treatment group, visit, treatment group by visit interaction, clinical subgroup, use of Alzheimer’s disease symptomatic medication atbaseline, ApoE4 carrier status, region, baseline value by visit interaction as fixed effects, and baseline value as covariate.
CI, confidence interval; PET, positron emission tomography; ROI, regions of interest; SUVr, standardized uptake value ratio.

SUVr

TemporalComparing Low Tau and Intermediate+High Tau PET Groups*
Lecanemab Slows Tau Spread in Earlier and Later Tau Brain Regions
Low: Whole Cortical GM Tau <1.06

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

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

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

Fluid Biomarkers At 18 Months

Improvement in Amyloid, Tau and Inflammation in Early and Late Tau Stages
Aβ42/40

pTau181
Number of Participants

Number of Participants

Low Tau PET

Low Tau PET

GFAP
Number of Participants

Low Tau PET

NfL
Number of Participants

Low Tau PET

The longitudinal tau PET substudy was predefined. The subgroups (low and intermediate+high tau PET) were a post-hoc analysis with nominal p values and no adjustment for multiplicity

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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.
Aβ, amyloid beta; CHG, change; GFAP, glial fibrillary acidic protein; interim, intermediate; MMRM, mixed models for repeated measures; NfL, neurofilament light chain protein; PET, positron emission tomography; ptau181, phosphorylated tau-181; pop, population.

Summary• Findings suggest that targeting protofibrils and clearing plaque leads to clinical efficacy, slowing of
tau progression and improvement in pathophysiological biomarkers– Effects are observed in both early and late tau stages of disease• Results in early stages (ie, low tau) support clinical stability or improvement with early initiation oflecanemab– At 18 months:• 76% no decline; 60% improved on CDR-SB• 74% no decline; 68% improved on ADAS-Cog14• 75% no decline; 70% improved on ADCS MCI-ADL• Lecanemab slows tau spread in different brain regions in low tau and intermediate+high tau PETgroups• Data is supportive of further testing lecanemab in preclinical AD in AHEAD3-45 study
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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; CDR-SB, Clinical Dementia Rating-sum of boxes PET, positron emission tomography.

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

Reisa Sperling
Brigham and Women’s Hospital
Massachusetts General Hospital
Harvard Medical School

Reisa Sperling - Disclosures• RAS Consultant to: AbbVie, AC Immune, Acumen, Alector, Bristol-Myers
Squibb, Genentech, Ionis, Janssen, Oligomerix, Prothena, Roche, Shionogi• KAJ (Spouse) Consultant to: Merck, Novartis• Research Funding:– National Institute on Aging:
P01AG036694; R01AG054029; R01AG061848
U24AG057437; R01 AG03689– Alzheimer’s Association, GHR Foundation– Eli Lilly, Eisai – Public-Private Partnership Trial Funding– Accelerating Medicines Partnership FNIH
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Clarity AD OLE Study Design
Clarity AD OLE is a global, open-label, single-arm study
Extension Phase

Study Population• 1,795 participants with Early AD• MCI due to AD or mild
Alzheimer’s dementia• Amyloid pathology confirmed• MMSE score between 22 and 30
at screening and baseline• WMS-IV LMSII ≥1 SD below ageadjusted mean at screening• Completed the Core Study(except de novo participants)

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Primary Outcome Measures

Extension Phase

Change from Core Study Baseline in
CDR-SB out to 24 months

Lecanemab

Additional Outcome Measures:(open-label)

10 mg/kg biweekly(IV infusion)

Change from Baseline at 24 months:
ADAS-Cog14
ADCS MCI-ADL
Biomarkers

Exploratory analyses with earliest
stage patients based on imaging
estimates of AD pathology

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 OLE: CDR-SB Through 24 Months

Lecanemab-Treated Participants Continued to Benefit Through 24 Months• Separation between early and delayed start maintained between 18 & 24 months when all participants are on lecanemab (p<0.051)• Similar disease trajectory for the early start and delayed start between 18 to 24 months

Core Study

OLE

Note: Early start lecanemab 10 mg/kg biweekly group are those subjects on lecanemab 10 mg/kg biweekly in the Core. Delayed start LEC10-BW group (those subjects that initiate lecanemab 10 mg/kg biweekly in the OLE).

29

1. Based on testing the hypothesis that early start arm maintains at least half of the treatment effect seen at the end of 18 months. Based on modified intention-to-treat analysis population. Adjusted mean change from baseline, SE and p-value are derived using mixed
model repeat measures (MMRM) with 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, andbaseline value as covariate.
ADNI, Alzheimer's Disease Neuroimaging Initiative; CDR-SB, Clinical Dementia Rating-sum of boxes; OLE, open-label extension; SE, standard error.

Clarity AD CDR-SB: OLE in Context of Observational Cohort
Lecanemab-Treated Participants Continued to Benefit Through 24 Months
Core Study

OLE•

These ADNI participants selected tomatch with Clarity AD population– Baseline demographics andclinical characteristics including
randomization strata

ADNI

•

Matched ADNI participants show
similar degree of decline to placebogroup out to 18 months•

Caveats– ADNI is an observational cohort;– Delayed start is Open-label; allparticipants know they arereceiving lecanemab

Note: Early start lecanemab 10 mg/kg biweekly group are those subjects on lecanemab 10 mg/kg biweekly in the Core. Delayed start LEC10-BW group (those subjects that initiate lecanemab 10 mg/kg biweekly in the OLE).

30

Based on testing the hypothesis that early start arm maintains at least half of the treatment effect seen at the end of 18 months. Based on modified intention-to-treat analysis population. Adjusted mean change from baseline, SE and p-value are derived using mixed
model repeat measures (MMRM) with 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, andbaseline value as covariate.
ADNI, Alzheimer's Disease Neuroimaging Initiative; CDR-SB, Clinical Dementia Rating-sum of boxes; OLE, open-label extension; SE, standard error.

ADAS-Cog14 and ADCS MCI-ADL Through 24 Months
Lecanemab-Treated Participants Continued to Show Benefit
ADAS-Cog14

ADCS MCI-ADL•

Separation between the early start and delayed start maintained between • Separation between the early start and delayed start maintained between
18 & 24 months when all participants are on lecanemab (p<0.051)
18 & 24 months when all participants are on lecanemab (p<0.051)•

Parallel disease trajectory for the early start and delayed start between
18 to 24 months• Parallel disease trajectory for the early start and delayed start between
18 to 24 months

Core Study

Core Study

OLE

OLE

Note: Early start lecanemab 10 mg/kg biweekly group are those subjects on lecanemab 10 mg/kg biweekly in the Core. Delayed start LEC10-BW group (those subjects that initiate lecanemab 10 mg/kg biweekly in the OLE).

31

Based on testing the hypothesis that early start arm maintains at least half of the treatment effect seen at the end of 18 months. Based on modified intention-to-treat analysis population. Adjusted mean change from baseline, SE and p-value are derived using mixed
model repeat measures (MMRM) with 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, andbaseline value as covariate.

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; OLE, open-label extension; SE, standard error.

Clarity AD OLE: Biomarker Results Out to 24 Months
Preliminary Subset of Participants
Plasma Aβ42/40 Ratio
Core Study

OLE

Plasma pTau181
Core Study

OLE• Participants with
continuous treatment
continue to show
improvement inbiomarkers in Aβ42/40
and pTau181
Plasma GFAPCore Study

32

Plasma NFL
OLECore Study

OLE• Participants on placebo
who started lecanemab at
18 months show
improvement inbiomarkers within 3months of treatment
Aβ, amyloid beta; CHG, change; GFAP, glial fibrillary acidic
protein; MMRM, mixed models for repeated measures; NfL,
neurofilament light chain protein; PET, positron emission
tomography; ptau181, phosphorylated tau-181.

Clinical Outcomes Through 24 Months Low Tau Subgroup*

Lecanemab-Treated Low Tau Participants Maintain Cognitive Function Through 24 Months
ADAS-Cog14

Core Study

CDR-SBOLE

Low baseline Tau

Core Study

Note: Early start lecanemab 10 mg/kg biweekly group are those subjects on lecanemab 10 mg/kg biweekly in the Core. Delayed start LEC10-BW group (those subjects
that initiate lecanemab 10 mg/kg biweekly in the OLE).
Based on testing the hypothesis that early start arm maintains at least half of the treatment effect seen at the end of 18 months. Based on modified intention-to-treat
analysis population. Adjusted mean change from baseline, SE and p-value are derived using mixed model repeat measures (MMRM) with 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.

33

OLE

*This was a post-hoc analysis with nominal p values and no adjustment for multiplicity
ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS MCI-ADL, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale forMild Cognitive Impairment; CDR-SB, Clinical Dementia Rating-sum of boxes; OLE, open-label extension; SE, standard error.

ADCS MCI-ADL
Core Study

OLE

Observed ‘No Decline’ and ‘Improvement’ Rates in Low Tau

Early-Stage Participants Continue to Benefit from Lecanemab Through 24 Months
CDR-SB No Decline - Low Tau Population

70%

50%

62%
no decline at
24 months

55%
no decline at
18 months

40%
30%

60%

P=0.0007

40%
30%

28%
improvement
at 18 months

10%

10%
0%
Visit (Month)
0
71
70

6

12

18

67
63

62
57

58
50

24
42

0%
Visit (Month)0(N) Placebo(N) Lecanemab

7170*This was a post-hoc analysis with nominal p values and no adjustment for multiplicity

40%
improvement
at 24 months

6

12

18

24

67
63

62
57

58
50

42

Observed rates for ‘No Decline’ and ‘Improvement’ at 24 months• ADAS-Cog14: 67% and 62% for lecanemab• ADCS MCI-ADL: 67% and 62% for lecanemab
34

50%
improvement
at 24 months

50%

20%

20%

(N) Placebo(N) Lecanemab

60%
improvement
at 18 months

70%

P=0.024

60%

80%

Patients (%)

80%

Patients (%)

79%
no decline at
24 months

76%
no decline at
18 months

90%

CDR-SB Improvement - Low Tau Population

CDR-SB, Clinical Dementia Rating-sum of boxes; PET, positron emission tomography

Clinical Outcomes in Low Tau Subgroup Through 30 Months (Preliminary)
Lecanemab-Treated Low Tau Participants

ADAS-Cog14
Core Study

CDR-SB
Core Study

OLE

OLE

ADCS MCI-ADL
Core Study
30
29
25

35

ADAS-Cog14, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCS MCI-ADL, Alzheimer's
Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment; CDR-SB, Clinical
Dementia Rating-sum of boxes; OLE, open-label extension; PET, positron emission tomography

OLE

Low Tau Associated with Lower Levels of Amyloid

Early-Stage Participants Can Also be Identified by Amyloid PET <60 CL
Histogram of Amyloid PET (Tau PET Substudy)• Due to relatively small sample
size in tau PET substudy, we
estimated a similar early stageof disease based on amyloid
PET to apply to overall Clarity
AD population• Amyloid PET threshold <60 CL
used to enrich for low tau
population
60

36

Observed data
ApoE4, apolipoprotein E4; CDR-SB, Clinical Dementia Rating-sum of boxes;
GM, gray matter; PET, positron emission tomography.

Clinical Outcomes Through 24 Months (Overall and Baseline <60 CL)
Early-Stage Participants Continue to Benefit from Lecanemab Through 24 Months

Overall Population

CDR-SB

Core Study

Baseline < 60 CL

Core Study

27%

51%

Core Study

Core Study

OLE

37%

less decline
at 18 months

OLE

less decline
at 18 months

OLE

ADCS MCI-ADL

26%

less decline
at 18 months

Core Study

37

OLE

ADAS-Cog14

less decline
at 18 months

OLE

69%

less decline
at 18 months

60 CL is optimal cutoff to define low tau PETCore Study

OLE

72%

less decline
at 18 months

Summary• Maintenance of treatment difference with ongoing lecanemab treatment through24 months, relative to the newly treated lecanemab participants, is consistent
with a disease-modifying effect• Pathological biomarkers improved at 3 months in newly treated participants andmaintained at 24 months with continuous treatment• Delayed start and lower pathology group results support early initiation oftreatment with lecanemab• These results support testing of lecanemab in an even earlier population as in the
AHEAD3-45 Study

38

Preliminary Update on Lecanemab Safety in Clarity AD
Open-Label Extension, Including Subcutaneous
Formulation

Michael Irizarry
Eisai Inc.

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

40

Clarity AD Study Design
SC Substudy• PK/PD models demonstrate that 720 mg SC
fixed weekly dose will provide similar exposure
to 10 mg/kg biweekly IV administration,
regardless of body weight41

AD, Alzheimer’s disease; 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;PD, pharmacodynamic; PK, pharmacokinetic; SC, subcutaneous; SD, standard deviation; TEAEs, treatment emergent adverse events; WMS-IV LMSII, Wechsler Memory Scale IV-Logical Memory (subscale) II.

Lecanemab Subcutaneous Formulation: Patient Disposition

AI, autoinjector; SC subcutaneous; IV, intravenous; PD, pharmacodynamic.
42

SC Substudy

Baseline Characteristics Generally Similar

Age, mean (SD), years

SC(N=394)n(%)
70.9 (7.80)

SC Lecanemab Naïve
(N=72)
n(%)
73.3 (7.74)

Female, n (%)

209 (53.0)

37 (51.4)

CDR Global=0.5332 (84.5)

61 (85.9)

MMSE, mean (SD)25.90 (2.185)

26.52 (2.235)

114 (28.9)

15 (20.8)

Noncarrier

132 (33.5)

26 (36.1)

Heterozygous

210 (53.3)

35 (48.6)

Homozygous

47 (11.9)

6 (8.3)

CDR-SB, mean (SD)
Amyloid PET Centiloids, mean (SD)3.04 (1.246)
76.58 (42.243)

2.98 (1.359)
77.42 (38.792)

ADAS-Cog14, mean (SD)21.77 (6.658)

19.18 (7.343)

ADCS MCI-ADL, mean (SD)41.95 (6.399)

42.80 (5.886)

Mild dementia due to AD
ApoE4 Status

43

Pharmacokinetics of SC are Comparable to IV• 90% CI for SC vs IV is within BE (Bioequivalence) limits of 80 to 125%,with lower limit much higher than 80%
Parameter

Units

Geometric mean ratio of
SC/IV for AUC(0-2 weeks)

AUC(ss,2weeks)

h*ug/mL

111%

Model: ANOVA with covariate= treatment• Note: AUC is 11% higher on SC vs IV

44

AUC, area under the curve; CI, confidence intervals; CL clearance; IV, intravenous; PK, pharmacokinetic; SC, subcutaneous; SS, steady state.

90% CI for geometricmean ratio(99%, 124%)

Pharmacodynamic Comparability (Amyloid PET Centiloids)
SC Administration Results in 14% Greater Amyloid Removal• 90% CI for SC vs IV meets PD comparability with lower bound much higher than 80%– In addition, PD comparability was confirmed by population PK/PD modeling• Results of the preliminary PD comparability analysis suggest that SC administration is similar in removing
amyloid compared to IV administration at 6 months of treatment
IV(N=354)All subjects
All subjects, baselineamyloid PET ≥ 30 CL

SC denovo(N=71)

Ratio(SC/IV)

Lower Bound of
90% CI for ratio(SC/IV)

Mean

SE

Mean

SE

-35.4

1.14

-40.3

2.27

114%

102%

-41.4

1.35

-45.8

2.68

111%

99%

Model: ANCOVA with covariates= treatment, baseline Centiloids, age

Note:• Only significant covariates (baseline amyloid and age) included in the model• At 6 months, n=275 for IV and n=69 for SC
45

AUC, area under the curve; CI, confidence intervals; CL clearance; IV, intravenous; PET, positron emission tomography; PD, pharmacodynamic; SC, subcutaneous; SE, standard error.

Safety of Subcutaneous Lecanemab

Very Low Incidence of Systemic Injection-Related Reactions

33 (8.4)

SC
Lecanemab
Naïve(N=72)n(%)
11 (15.3)

Local injection site reactions

32 (8.1)

11 (15.3)

Systemic injection reactions

2 (0.5)0Skin rash0

0

Other hypersensitivity

0

0

SC
(N=394)n(%)
Injection-Related reactions

46

SC, subcutaneous.

• Systemic injection/infusion
reactions are uncommon with
SC administration• There was a low rate of local
injection site reactions– Most mild and moderate inseverity consisting ofredness, irritation, or
swelling– No skin rash or otherhypersensitivity reactions
reported

Timing, Frequency and Severity (Clinical and Radiographic)of ARIA Similar SC to IV• Confidence intervals for ARIA-E in the SC group are broad due to the sample size and low event rate
Rate of ARIA-E on Lecanemab Naïve SC vs IV
LecanemabNaïve SCN (%)

LecanemabIV
N (%)

ARIA-E

12 (16.7%)

113 (12.6%)

ARIA-H

16 (22.2%)

155 (17.3%)

Isolated
ARIA-H

6 (8.3%)80 (8.9%)

Shading 95% CI for SC and IV• There was no intracerebral
hemorrhage on SC
Note: PET scan is prior to injection/infusion indicated by the blue arrows
47

ARIA-E, amyloid related imaging abnormalities - edema; IV, intravenous; PET, positron emission tomography; SC, subcutaneous.

•

AUC strongly predicted amyloid lowering•

Exposure-safety analyses based on IV in our Phase 2 and 3
trials (red line) found that lecanemab exposure (as Cmax,ss,
AUCss, Cmin,ss) was correlated with ARIA-E•

Of these predictors, Cmax,ss was strongest predictor of
ARIA-E incidence following IV administration•

SC lecanemab results in minimal fluctuations between Cmax,ss
and Cmin,ss, which is further influenced by more frequent dosing(weekly) compared to IV (biweekly)•

Thus, following SC administration, AUCss, a more
representative exposure parameter of a flat PK profile,
may be a better predictor of incidence of ARIA-E

Serum Lecanemab Concentration (ug/mL)

Effect of PK Profile on Incidence of ARIA-E

Days Post-Dose, Steady-StateIV SC

Based on PK modeling48

ARIA-E, amyloid related imaging abnormalities - edema; AUCss, area under the curve at steady state; Cmax,ss, maximum concentration at steady state; Cmin,ss, minimum concentration at steady state; IV, intravenous;
PET, positron emission tomography; SC, subcutaneous.

Overall Adverse Event Summary

Safety in Open-Label Extension (OLE) Consistent with Core Study

Deaths*Serious adverse event (SAE)
SAE with ARIA-E
SAE with ARIA-H
SAE with infusion-related reactions
SAE without ARIA or infusion-related
reactions
Treatment-emergent AE (TEAE)**
ARIA-E
ARIA-H
ICH
Infusion-related reactions
49

Placebo(n=897)n (%)

Lecanemab(n=898)n (%)

8 (0.9)101 (11.3)
0 (0)1 (0.1)0 (0)7 (0.8)126 (14.0)
7 (0.8)2 (0.2)
11 (1.2)

Lecanemab(Core+OLE)(n=1612)n (%)
16 (1.0)241 (15.0)
18 (1.1)
10 (0.6)
20 (1.2)

101 (11.3)

111 (12.4)

205 (12.7)

15 (1.7)
80 (8.9)
1 (0.1)66 (7.4)

113 (12.6)
152 (16.9)
5 (0.6)237 (26.4)

219 (13.6)
298 (18.5)
8 (0.5)398 (24.7)*Cause of deaths in placebo group: death, acute respiratory failure, myocardial infarction, metastases to bone, hemorrhage intracranial, COVID-19, pancreatic cancer, cardio-respiratory arrest.
Cause of death in lecanemab group: death, cerebrovascular accident, myocardial infarction, respiratory failure, metastases to meninges, COVID-19, diabetic ketoacidosis. No participants died with or from ARIA in Core study.
Cause of death in lecanemab in OLE: myocardial infarction, COVID-19, COVID-19 pneumonia, cerebral hemorrhage (2 subjects), cerebrovascular accident & seizure (1 subject), cerebrovascular accident, road traffic accident, cardiac failure acute**AE rates are similar between placebo and lecanemab when ARIA and infusion-related reactions are excluded.
Data cutoff: 01 Dec 2022
AE, adverse event; ARIA-E, amyloid related imaging abnormalities - edema; ARIA-H, ARIA with hemosiderin deposits; ICH, intracerebral hemorrhage.

Summary• Lecanemab SC may provide substantial benefit for greater patient access, improved
compliance and convenience with overall lower costs to healthcare system• PD comparability by amyloid plaque reduction has been confirmed at 6 months– SC administration resulted in 14% greater amyloid removal• Rates of systemic adverse reactions are significantly lower with SC versus IV– Local injection or infusion site reactions were similar• Timing, frequency and severity of ARIA-E, both clinical and radiographic, are similar
for SC and IV• Safety and immunogenicity in OLE were otherwise consistent with Clarity AD
50

ARIA-E, amyloid-related imaging abnormality-edema; IV, intravenous; OLE, open-label extension; PD, pharmacodynamic; PK, pharmacokinetic; SC, subcutaneous.

Overall Summary• Targeting protofibrils and clearing plaque leads to clinical efficacy, slowing of tau
progression and improvement in pathophysiological biomarkers• Maintenance of treatment effect at 24 months and CDR-SB improvement in the low
tau PET subgroup support early initiation of treatment with lecanemab• The SC formulation has comparable PK and amyloid clearance to IV, providing a
convenient dosing option• These will be further studied in the ongoing Clarity AD OLE and AHEAD3-45 Studyin preclinical AD

51

AD, Alzheimer’s disease; CDR-SB, Clinical Dementia Rating Scale-Sum of Boxes; IV, intravenous; OLE, open-label extension; PET, positron emission tomography; PK, pharmacokinetics; SC, subcutaneous.

Thank you
Clarity AD
Acknowledgements
Participants & Their Support
We acknowledge with thanks the individuals who enrolled in lecanemab Clarity AD Trial as well as
their family, caregivers, and friends who supported them.
We also acknowledge the DSMB members, Site Investigators, Study Coordinators, Raters, contract
research organization (CRO), and other personnel whose dedication and hard work in collecting
data and providing care were essential to the completion of this trial.

Panel Discussion and Q&A

Clarity AD