At the Ready for a New Standard of Alzheimer's Care: Preparing Your Practice for the New Era of Amyloid-Targeting Therapies

Co-Chairs, Gil Rabinovici, MD, and David A. Wolk, MD, FAAN, discuss Alzheimer’s disease in this CME/MOC/NCPD/AAPA activity titled “At the Ready for a New Standard of Alzheimer's Care: Preparing Your Practice for the New Era of Amyloid-Targeting Therapies.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/AAPA information, and to apply for credit, please visit us at https://bit.ly/41D5Vj1. CME/MOC/NCPD/AAPA credit will be available until October 7, 2025.

1. he Ready for a New Standard

of Alzheimer’s Care
Preparing Your Practice for the New Era of
Amyloid-Targeting Therapies

Gil Rabinovici, MD David A. Wolk, MD, FAAN

Edward & Pearl Fein Distinguished Professor Director, Alzheimer's Disease

Director, UCSF Alzheimer's Disease Research Center

Research Center Co-Director, Penn Institute on Aging

Departments of Neurology, Radiology and Co-Director, Penn Memory Center

Biomedical Imaging Division Chief, Cognitive Neurology

University of California, San Francisco Department of Neurology

San Francisco, Califomia University of Pennsylvania
Philadelphia, Pennsylvania

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2. Our Goals for Today

Enhance your understanding of the mechanisms of action
and latest evidence supporting the use of new and emerging
amyloid-targeting therapies (ATTs) for the management of early
symptomatic AD

Increase your ability to identify patients with early symptomatic
AD for whom anti-amyloid therapy would be an appropriate
treatment option

Augment your skills needed to employ principles of shared
decision-making when educating patients and care partners
about the risks, benefits, and goals of treatment with ATTs

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3. The Mechanisms of Action and Latest
Evidence on New and Emerging ATTs for
Early Symptomatic AD

Gil Rabinovici, MD David A. Wolk, MD, FAAN

Edward & Pearl Fein Distinguished Professor Director, Alzheimer’s Disease

Director, UCSF Alzheimer's Disease Research Center

Research Center Co-Director, Penn Institute on Aging

Departments of Neurology, Radiology and Co-Director, Penn Memory Center

Biomedical Imaging a Division Chief, Cognitive Neurology

University of California, San Francisco Department of Neurology

San Francisco, Califomia University of Pennsylvania
Philadelphia, Pennsylvania

Copyright © 2000-2024, PeerView

4. of Action of

Activation of resting microglia by ATTs + The hypothesized mechanism
behind the reduction of AB plaques
for all ATTs involves the activation of
microglia, which then phagocytize
fibrillar AB and facilitate its
degradation via the
endosomal/lysosomal pathway

Resting microglia

‘Activated microgla

1. Cummings Jet al. BaDrugs 2024:385-22 PeerView

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5. AB Aggregation Species Targeted by

Anti-AB Monoclonal Antibodies

The monoclonal antibodies
their preferential selectivity for
fic AB aggregation species,

| Amyloid-B
| Donanemab clumps into
Neuron Binds to plaqu

y, EQ) Prsscrataso Lecanemab
e Binds to protofibrils

a u
,
y Y¥ °Y¥

Solanezumab Gantenerumab Aducanumab
| Stops first phase Blocks fibril Blocks second phase
of aggregation elongation of aggregation

1. Mullard A. Nat Rev Drug Discov. 2023229.

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I- plaques

may translate into differences
in efficacy and safety
Donanemab only binds to highly
toxic pyroglutamate-modified AB
peptides that are only found in
amyloid plaques
Lecanemab preferentially binds to
AB protofibrils
Aducanumab preferentially binds to
AB plaques and oligomers
Gantenerumab binds to several
forms of AB
Solanezumab preferentially binds to
AB monomers

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6. Anti-AB Monoclonal Antibodies: The First

Disease-Modifying Therapies to Be Approved in AD*?

Impact on AD Pathobiology

Can lower amyloid plaques substantially and make many patients “amyloid-negative” within 12-18 months of
treatment

Consistent signals of impact on other AD biomarkers, including some biomarkers of abnormal tau,
neuroinflammation, and possibly neurodegeneration

Impact on Slowing of Clinical Decline

* Consistent evidence for moderate group-level efficacy (slowing of clinical decline for the “average” patient)
when amyloid plaques are sufficiently lowered in the right patients (clinically early-stage AD: mild cognitive
impairment and mild dementia stages of AD)

Treatments provide, “on average,” the equivalent “savings” of about 5-7 months of expected decline
compared to placebo over 18 months

1. AWA. Semin Newel 2018;
Pipe en corsa lg
dt eb OTE NOON Gan tal Pos Ame 20229501542

5 Doody Ret al M Engl Mod. 2014370311321 71am Dyck tl, Eng J te. 2028386921 8. Sms Joa AC 2023 Oral presentan 55
5 Simo etal JA 202830681227 PeerView

27-280, 2. Cummings Jet al. Alzhoimers Ros Ther 2021:13:98. 3. Aduhoim (aducanumab) Prescribing Information.
.geatida dec=label2021/76117801 po. 4. Leqemti (ucanemad) Preserbieg Information

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7. Phase 3 Clarity AD Trial: Lec:

Amyloid Burden’

m
£a
x ©
i She Mean <30
828 Centiloids for
A s<2 lecanemab at
A 523
A 2:5
< sao
un soo
AH Zus
€ |
ca 3: 3
Er
3
E
<a Visit, mo
A Dyck el. Eng Mod. 2008388 921 PeerView

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8. LS mean difference at
18 mo: -0.451

Lecanemab

27% slowing by
lecanemab at 18 mo

©

b

Adjusted Mean Change From
Baseline (+ SE) in CDR-SB
e
8

12
16
0 3 6 9 12 15 18
Visit, mo
Aa joe atl hi Emi Mod. 2023:88:921 PeerView

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9. Clarity AD: Lecanemab Safety!

Events (n, %)

Death

Serious AE

Treatment discontinuation due to
AES

Any AEs

AEs occurring in 25% of
participants in either group

ARIA-H

ARIA-E

Headache

Fall

Infusion-related reaction

1 van Dyck Gt al. N Engl J Med. 2023:388:9-21

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Lecanemab (n

6 (0.7)
126 (14.0)
62 (6.9)

798 (88.9)

155 (17.3)
113 (12.6)
100 (11.1)
93 (10.4)
237 (26.4)

Placebo (n

7 (0.8)

101 (11.3)

26 (2.9)

897)

735 (81.9)

81 (9.0)
15 (1.7)
73 (8.1)
86 (9.6)
66 (7.4)

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10. Adjusted Mean Change (95% Cl) in Amyloid PET

o

Lowimedium tau
ADonanemab
Placebo

Combined

Amyloid PET, Centiloids
8

-100

0 12 24 36 52 64 76
Time After Baseline, wk

+p 00.
4 Sims JR otal, JAMA, 2023:330:512-527.

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Amyloid clearance was
reached in 76.4% of the

combined population of
donanemab-treated
participants at 76 weeks

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11. ly Slowed Disease

29% slowing
by donanemab
at 76 weeks

Donanemab

A0.70

Adjusted Mean Change (SE)

0 12 24 36 52 64 76
Time, wk a
1 Sins ot i JAM, 2023200512507 PeerView

+ p<01.2P< ot

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12. RAILBLAZER-ALZ 2: Donan

1. Sms JR eta

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Events (n, Donanemab (n = 853)
Death 16 (1.9)
Serious AE 148 (17.4)
Treatment discontinuation due to 112 (13.1)
AES
Any AEs 759 (89.0)
AEs occurring in 25% of
participants in either group
ARIAH 168 (19.7)
ARIA-E 205 (24.0)
Headache 119 (14.0)
Fall 114 (13.4)
Infusion-related reaction 74 (8.7)
SAMA, 2029:300512:27.

Placebo (n = 874)

10 (1.1)
138 (15.8)
38 (43)

718 (822)

65 (7.4)
17 (19)
86 (9.8)
110 (12.6)
4 (0.5)

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13. ATT Dosing Schedules and ARIA Monitoring?

Infusion schedule
Infusion time

Dose titration

Dose

Potential for limited duration
of treatment?

MRI monitoring schedules

TRAILBLAZER.

Z 2 (Donanemab)
Every 4 weeks
30 min
Yes
700 mg (infusions 1-3)
1,400 mg (infusions 4+)

Yes; in phase 3 clinical trial, dosing was stopped
after 6, 12, or 18 months of treatment if amyloid
plaque reduced to minimal level on amyloid PET

Safety MRI prior to 2nd, 3rd, 4th, 7th dose

RITY AD (Lecanemab)
Every 2 weeks
60 min

No

10 mgkg

Unknown; in phase 3 clinical trial, all
patients continued dosing indefinitely

Safety MRI prior to 5th, 7th, 14th dose

1. Kiunla (donanemab) Preset Information. tips www ccossdata da govidrugsatida docsabel2024/76124850001 pat

2 Legend decanomab) Prescribing Informati. pnw Scan (o govinugralia_docatabol2023/01250009 16001 pal. PeerView

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14. Limited Duration Treatment Option With Donanemab‘

+ Inthe TRAILBLAZER-ALZ 2 trial, amyloid PET was performed at weeks 24, 52, and 76

+ Donanemab treatment was stopped if patients achieved amyloid plaque clearance based on PET scan

Donanemab-Treated Patients That Cleared Amyloid and Stopped Treatment by Each Timepoint

Week 24 Week 52 Week 76
LOGE % (n/N) % (nN) % (n/N)
Reduction to placebo

oe 17.1 (130/761) 46.6 (313/672) 69.2 (429/620)
Treatment-related amyloid

here 29.7 (2261761) 66.1 (443/670) 76.4 (469/614)

Note: While patients in the TRAILBLAZER-ALZ 2 trial were evaluated for amyloid clearance based on amyloid PET
Centiloid scores, the prescribing label recommends “consider stopping dosing with donanemab based on reduction of
amyloid plaques to minimal levels on amyloid PET imaging,” suggesting that a negative amyloid PET based on the
visual read is sufficient.

+ Reduction to placebo rteria was defined as amylok plaque levels +11 CL at one vis, or <25 CL at wo consecutivo viste, on amyloid PET scan,
* Treatment-elated acid clearance was defined as amylon plaque lovls <24 1 CL on amyloid PET scan, whi is consistent wih a negative visual ad, PeerView
1. his nv fa govimedia/t79167/download

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15. Donanemab Demonstrated Efficacy in Patients Who Switched to
Placebo After Treatment-Related Amyloid Clearance’

CDR-SB
Adjusted Mean Change (SE)

+ P< 0001
1 its: fa govimeda/179167idownload

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05

20

25

Mean time in trial prior to
¡switch to placebo for these
participants:

47 weeks

Time, wk

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16. Future Directions

+ Unanswered questions need to be explored in ongoing studies

— Are the treatment effects in patients with typical AD observed in the trials
generalizable to broader populations?

> Racial/ethnic groups that were under-represented in the trials
> Patients with more medical comorbidities

— Can these therapies slow or prevent cognitive decline if administered to
patients with preclinical AD based on positive biomarkers?

> TRAILBLAZER-ALZ 3
> AHEAD 3-45

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17. enecena Antibades Direct pains Ami
forthe Treatment of Ashelmers Disease CD

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18. Identifying Patients With Early Symptomatic
AD for Whom ATTs Would Be Appropriate

Gil Rabinovici, MD David A. Wolk, MD, FAAN

Edward & Pearl Fein Distinguished Professor Director, Alzheimer's Disease

Director, UCSF Alzheimer's Disease Research Center

Research Center Co-Director, Penn Institute on Aging

Departments of Neurology, Radiology and Co-Director, Penn Memory Center

Biomedical Imaging = Division Chief, Cognitive Neurology

University of California, San Francisco Department of Neurology

San Francisco, Califomia University of Pennsylvania
Philadelphia, Pennsylvania

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19. Key Stages in the Diagnostic Workup for AD!

( Step 2: AssessiDifferentiate |

oF mms Access to biomarkers
Structural imaging 3
Cognitive and 5
functional assessments =

Blood test, neurologic
and physical exams

Patient Presentation

Patient and
family history

Jalists (eg, PCPs)

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1. Porsteinsson AP eta J Prev AL Dis. 2021:3371-386.

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20. p of AD: Testing and Evaluation

+ Initial detection and assessment of cognitive symptoms to identify risk factors for AD and
to rule out non-AD pathologies (should be performed by PCP)

— Don't dismiss mild memory complaints
- Assessments include
> Patient history, including family history
> Care partner perspective
> Medical and disease history
> Medications
> Lifestyle data (smoking, alcohol, exercise)
> Lab tests (B12, TSH, full blood count, BG, liver and renal function tests)
> Physical exam

1. Porstonsson AP et al JPrev Al Di. 2021:3:371-38. PeerView

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21. p of AD: Testing and Evaluati

+ Clinical assessments and structural imaging (typically performed/interpreted by
dementia specialist)

- Neurologic examination (to rule out non-AD pathologies)
— Cognitive assessments: MMSE, MoCA
— Functional assessments: FAQ, A-IADL-Q, FAST
- Behavioral assessments: GDS or NPI-Q
- Brain imaging: MRI
> Rule out other non-AD causes of cognitive impairment

> Look for findings supporting an AD diagnosis

1. Porstonsson AP et al JPrev Al Di. 2021:3:371-38. PeerView

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22. nical Staging for Indivi Is on the AD Continuum

Stage 1: Asymptomatic, biomarker evidence only

Stage 2: Transitional decline: mild detectable change, but minimal
impact on daily function

ATTs are Stage 3: Objective cognitive impairment insufficient to result in
approved for significant functional loss (MCI)
patients in

stages 3 and 4 Stage 4: Mild dementia
Loss of independence with
Stage 5: Moderate dementia progressively greater loss of
function
Stage 6: Severe dementia

Note: Clinical stages 3-4 correspond to

+ MoCA score ~ 18 to 25, or
+ MMSE score ~ 20 to 30

1. deck GR et a. Alzheimer Dement. 2026127. PeerView

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23. Role of MRI in t d AD!

Workup of MCI

+ MRI rules out other non-AD causes of cognitive impairment, including
- Cerebrovascular disease: microangiopathic changes and micro/lacunar infarcts
— Mass lesions: tumors, cysts, abscesses
— Traumatic brain injury: gliosis, hemorrhagic contusions, subdural hematomas
+ MRI identifies changes that are suggestive of AD
- Focal atrophy (ie, hippocampal atrophy, medial temporal lobe atrophy)
- Microbleeds are suggestive of cerebral amyloid angiopathy
+ MRI needed to evaluate patient eligibility for ATT antibody therapy
— Non-contrast MRI
- T1 FLAIR
- T2" GRE or susceptibility weighted imaging
— Diffusion-weighted imaging
- Preferably on a 3T magnet

1. os Jradiologyassistant nineuroradologyféementiaiol-ofmri 2. Dickerson 8. Ati A. Dementia: Comprohensive Principles ond Practices. Oxford, UK:
Sud Unwaray Pros 2014 9 Cummnge 3 Y Prev Alhama Di 200310988377

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24. Revised Criteria for Biomarker-Based Diagnosis of AD!

Biomarker Category

CSF Imaging

Core 1 Biomarkers

A (AB proteinopathy) AB42/AB40 Amyloid PET + Core 1 biomarkers
define the initial stage
T, (phosphorylated tau) P-tau217, P-taut81 of AD that is detectable

in vivo

ABA2IABAO, P-tau217/ A
Lei toi P-tau181/AB42, | non-phosphorylated- + AD can be diagnosed
My T-tau/AB42 tau217 with any Core 1
biomarker
Note: Biomarkers in red boxes are FDA-approved and reimbursed by Medicare
1. deck GR ota. Alzheimer Dome. 2026127. PeerView

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25. Advantages and Limitations of Three Modalities

of AD Biomarkers

Modal

‘Advantage ions.
+ Associated with changes in management of patients
with MCI end dementia + Cost without coverage and stil dificult to get
PET scan's + Long history of use and standardized interpretation reimbursed by Medicare in many locations
‘Amyloid PET, tau PET + Muliple FDA-approved tracers + Limited capacity and availabilty
+ Reflects spatial distribution and amount of pathology « Invasivo (radiation)
+ Medicare wll now cover amyloid PET
+ Widely available . —
à RL be care a Tost characteris vary by mated (eng and
Sen + Long history of use and standardzed interpretation, [pesen mar puncture)
Prauttrapa2 2 AIS FDA seoraved lees + Contraindicaions
+ Can be performed by a radiologist, neurologist, or cerro
advanced practice provider 5
Plasma’ CUA-certfied N
A . + Not yet FDA-approved
he oli ets ao ala Sry nach : Natfemoures ay CMS
Là - Widely accessible + Test performance varies by assay and measurement
cn I Gana ected by ay over la
co + Analicall validated + Relatively new; lacking validation in a general population
{Wong DF tal I Med 201051018000 2, Rabinovs GO etal JAMA AIG FI IE 2 Je CU et al Phamsasucal 20211410,
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26. Commercially Available Biomarkers for AD"

Test Name (Developer) Biomarker Modality
Florbetapir (Lily) ‘Amyloid PET NA FDA-approved
Florbetaben (Life Molecular Imaging) Amyloid PET NA FDA-approved
Flutemetamol (GE Healthcare) ‘Amyloid PET Amyioid plaques: NA FDA-approved
Flortaucipir (Lily) Tau PET Tau aggregates NA FDA approved
Elecsys AD (Roche) CSF ere Elecsys FDA-approved
Lumipulse G (Fujrebio) csr Ap4240 Lumipulse FDA-approved
5 Petau217, paut81, LEIA, :

AD-Detect (Quest Diagnostics) Plasma ‘AB42/40, APOE isoform LO-MSMS CLIA-certified

ú CLIA certified &
ALZpathDx (ALZpath, Quanterix) Plasma P-tau217 Simon FDA Breakthrough
LucentAD (Lucent Diagnostics) Plasma P-tau217 Simoa CLIA-certified
‘Amyloid Plasma Panel (Roche, Lily) Plasma EAST Elecsys Breakthrough device
Phosphorylated Tau 217 (Labcorp) Plasma P-tau217 Lumipuise CLEIA CLIA-certified
Phospho-Tau 217 (Mayo Clinic) Plasma Petau217 CLEIA CLiA-certified
PrecivityAD, PrecivityAD2 (C2N) Plasma AOS IP-LC-MSIMS CLiAbreakthrough

P-tau217/nP-tau217

1. https /Restdirectory.questdiagnostics.comitesttest-guides/TS_AD_Detect_Ptau217Plasmalquest-ad-detect-phosphorylated-tau217-p-tau217-plasma?pstd. 2.

nen gatos confers oferto pala Cosina SOI AM are pur cio rs op:

Sonentglnds 2024/00107 LucentAD.Vhte Paper. hp oor contest AB phosphore au 217 5217 plasma. 8.

tps preci compet hep. 6 Nips agnosis roche comtstnie wetng/2024toce grated ie-breakvough-devce designation pau217-od- .

es support carie aieraimens disease sagas him! 7, hipe! mw mesoucale comen products and senrkesisenrkesieneriau pti? and priei_severs®. PECT View
Breen Det al Praia Nal, 20242327 428. Harpe et a Naurn. 2028.11 2701-2790,

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27. Inclusion/Exclusion Criteria for Phase 3 Trials!*

Lecanemab (Clarity AD) Inclusion Criteria Donanemab (TRAILBLAZER-ALZ 2) Inclusion Criteria

‘Clinical diagnosis of MCI or mild AD dementia
Positive biomarker for brain amyloid pathology
50-90 years of age
MMSE score 22-30 at screening and baseline
Have an identified care partner
Lecanemab (Clarity AD) Exclusion Criteria

‘Any medical, neurologic, or psychiatric condition that may be contributing
to the cognitive impairment or any non-AD MCI or dementia

>4 microhemorrhages
Any superficial siderosi
‘Any macrohemorrhage >1 em
‘Severe white matter changes
‘Cortical infarct involving a major vascular territory
21 lacunar infarct

‘Any immunological disease that is not adequately controlled or which
requires systemic treatment with immunoglobulins, MABS,
immunosuppressants, or plasmapheresis,
Contraindications for MRI

San Dyck Got al N Engl J Mod, 2023:388:9-21. 2. Legembi lecanemab) Presenbing informaron,
hitos www accessdata (da govidrugsatida_docsabal/2023/7612690F9 150011 pa. 3. Kisuna (donanemab) Prosering Information.

Clinical diagnosis of MCI or mild AD dementia
Positive biomarker for brain amyloid pathology
Positive biomarker for brain tau pathology
60-85 years of age
MMSE score 20-28 at screening and baseline
Have an identified care partner
Donanemab (TRAILBLAZER-ALZ 2) Exclusion Criteria

‘Any medical, neurologic, or psychiatric condition that may be contributing
to the cognitive impairment or any non-AD MCI or dementia

>4 microhemorrhages

>1 area of superficial siderosis,
Any macrohemorrhage >1 om
‘Severe white matter changes
Cortical infarct not specified
Lacunar infarct not specified

Current treatment with IVIG therapy

Contraindications for MRI

ps www accessdata fda govdrugsatida_docsfabel2024/76124Bs0COIL pal. 4. Sims J etal. JAMA, 2023:330:512327.

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28. Appropriate Use Recommendations Exclusion

Criteria for Lecanemab?

AUR Exclusion Cri ia for Lecanemab
‘Any medical, neurologic, or psychiatric condition that may be contributing to the cognitive

COMORES) impairment or any non-AD MCI or dementia

>4 microhemorrhages

A single macrohemorrhage

Any superficial siderosis

Vasogenic edema
MRI-based >2 lacunar infarcts or stroke involving a major vascular territory
exclusion criteria

Severe subcortical hyperintensities consistent with a Fazekas score of 3
Evidence of amyloid beta-related angitis

CAA

Other major intracranial pathology that may cause cognitive impairment

Any history of immunologic disease (eg, lupus erythematosus, rheumatoid arthritis, Crohn's
Immune-related disease) or systemic treatment with immunosuppressants, immunoglobulins, or monoclonal
antibodies or their derivatives

Bleeding disorder that is not under adequate control
Bleeding risk Patients on anticoagulants (coumadin, dabigatran, edoxaban, rivaroxaban, apixaban, betrixaban,

or heparin)

1. Cummings Je a. Prov Alzheimer Oi, 2023:10:362:97. PeerView

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29. What Are Amyloid-Related Imaging Abnormalitie

ARIA results from amyloid in cerebral vessels (CAA) and can occur spontaneously in AD
Treatment-related + Risk of ARIA increases with antibodies that clear aggregated amyloid
changes noted on + Two pes of ARIA
i = ARIA-E: brain swelling (vasogenic edema)

neuroimaging: — ARIA-H: microhemorrhage, superficial siderosis, macrohemorrhage
ARIA-E and + ARIA is typically asymptomatic and resolves spontaneously

ARIA-H + When symptoms occur, they are usually mild-moderate (eg, headache, dizziness)

+ However, serious and life-threatening events rarely can occur

ARIA-H
l

1. Speting R ot Alzheimers Dement 2011:7:367-385.2. Cogswell Pot al. AINR Am J Neurone 20228103. rView

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30. APOE ¢4 copy number

Dose and timing of treatment (ARIA is more common with higher
dose and earlier in treatment course)

Presence and severity of underlying cerebral amyloid angiopathy
Presence of extensive ischemic cerebrovascular disease

2011:7:367-385. 2. Cogewell Peta. AINR Am J Neuroradiol, 2022.43 10-636.
Dis. 2023;10:362.977,

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31. + Risk of ARIA-E is related to APOE £4 genotype in a dose-dependent manner
Higher incidence of ARIA

Earlier occurrence of ARIA
Higher rate of recurrent ARIA
More serious outcomes from ARIA

+ An informed discussion with patients and care partners about risks/benefits of treatment
requires knowledge of APOE genotype

Cummins al J Pry Aina D 20231036277
2 Legemb lecanemab) PrescringInlormaton. tips ww accessdataf¢a.govidrugstida.docslabo/2023/76 126900150011 pt
3. Kisuna (doranemab) Presnbing Information. hips ww accessdata ca. govidrogsaée_docsfabel202476 124830000 el.

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32. Timing and Risk of ARIA-E Events Overall and by APOE £4

Genotype for Lecanemab!

Overall By APOE e4 Genotype
035

Lecanemab

Homozygotes for lecanemab
wy 0.125 10 mg/kg biweekly YW os y
< <
E 01 Π02
= Time, wk S 02
5 0075 2 24 48 52 76 °
2 EventRate of 89 116 131 138 139 2B oss Heterozygoles for lecanemab
5 005 ARIA-E, % 3
3 E N for b
3 loncarrier for lecanema
200% 2 005
a
0 0

0 8 16 24 32 40 48 56 64 72 80 88 0 8 16 24 32 40 48 56 64 72 80 88
cd Visit, wk No, at Risk Visit, wk
Locanomab 1.612 1484 1344 1254 11101034 966 870 816 729 155 20 Femenil comunas S67 208 Tas G6 138 oo TB or 109 8 1 2
Placebo — 007 888 870 861 63% 613 795 782 770 757 Noncamierforlecanemad 496 464 443 433 307 360 324 293 269 234 68 11

Picobo $97 888 670 881 833 813 Ts 182 170 757

Note: There is a paper in progress that is examining the timing and risk of ARIA by APOE ¢4 genotype in

TRAILBLAZER-ALZ 2.
1 Honig LS et al Aimer Res Ther 202616108, PeerView

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33. Commonalities Between CAA-ri and ARIA’

While ARIA and CAA-ri are separate entities, they share a number of similarities

Risk Factors

1. Greenberg SM et al Nat Re

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Location

S

Ae
EA

CAA develops to a greater
in cortical and leptomeninge:
sels (the locations where

Syndrome
Resemblance

NV?

Infiltration of inflammatory cells
(microgli
AB-containing multinucleatec
in CAA-ri suggests possible
taneous anti-AB immunization

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34. Infusion Reactions

+ Infusion reactions are typically mild to moderate in severity

— Usually occur during the first two treatments and are seen during the infusion or
up to several hours after the inf

+ Infusion-reaction symptoms typically resolve within 24 hours and can usually be

managed at home

+ Symptoms include fever, chills, headache, rash, nausea, vomiting, abdominal
discomfort, and elevated blood pressure

1 Gummings Jet a. J Prev Alheimers Dis 202310362377. PeerView

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35. AD Prevalence, Early Detecti

and Participation in Clinical Trials?

+ Older Black Americans and Latino and Hispanic Americans are at higher risk than
older White Americans to develop dementia

+ Despite higher prevalence of AD in racial and ethnic minority populations, these
populations are less likely to be diagnosed at a mild stage and receive a less
comprehensive evaluation at an early stage

+ Black Americans, Latino and Hispanic Americans, Asian Americans and Pacific
Islanders, American Indians, and Alaska Natives were also under-represented in
Clinical trials for ATTs, which limits the generalizability of the trial outcomes to
these groups

1. Toy € etal JAMA Nour 202%:78:857-685.2. van Dyck Ca al. Engl J Med. 2023:3880-21. 3. Sims J tal. JAMA, 2023:300:512:827. PeerView

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36. Addressing Barriers to Implementing ATTs in the Clinic

Site-specific protocols need to be developed to facilitate roll-out of ATTs
Every clinic/institution will have unique barriers and challenges to address

Assess biomarker testing capabilities
+ Evaluate radiology/nuclear medicine capacity for performing and interpreting PET
+ Accessibility of CSF biomarker testing and interpretation

Be proactive about patient safety
+ Determine capacity for APOE genotype testing and genetic counseling
+ Educate emergency physicians and PCPs about signs and symptoms of ARIA

Assess financial burden of treatment
+ Determine costs/copays of each component (eg, medication copays, infusion center
fees, amyloid PET scans, APOE tests, CSF tests, recurrent MRIs to monitor for ARIA),
+ Identify local processes and barriers to obtain reimbursement of expenses
= Insurance coverage for ATTs depends upon geographic location and provider
— Pharmaceutical companies have patient support services to assist eligible
patients with the cost of treatment

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37. Employing Shared Decision-Making to
Individualize Patient and Care Partner
Education on ATTs

Gil Rabinovici, MD David A. Wolk, MD, FAAN

Edward & Pearl Fein Distinguished Professor Director, Alzheimer's Disease

Director, UCSF Alzheimer's Disease Research Center

Research Center Co-Director, Penn Institute on Aging

Departments of Neurology, Radiology and Co-Director, Penn Memory Center

Biomedical Imaging = Division Chief, Cognitive Neurology

University of California, San Francisco Department of Neurology

San Francisco, Califomia University of Pennsylvania
Philadelphia, Pennsylvania

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38. n-Making?!
+ Discussions between the patient, care partners, and members of the
healthcare team

+ A collaborative process that provides patients with the autonomy and support
they need and allows healthcare providers to feel confident in the care given

— Healthcare providers, patients, and care partners review the benefits/risks
of options

— Healthcare providers share information about the options and answer
questions

— A decision that reflects the best interests of the patient is made

1. to ww nfomedmedcaldecisonsor/what-s-shred-deesion making PeerView

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39. Guidelines for Structured Discussions

Identify the patient’s goals, values, and preferences

Support active participation of the patient and care partner

Establish realistic expectations

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40. Barriers to Active Provider Pai

Provider barriers
+ Lack of expertise in decision-making
+ May not have all the information needed
Patient barriers
+ Patients may require additional support throughout the process

— May have more questions and may repeat questions

— May have multiple family members involved

— May have trouble remembering what was discussed

> Provide information using a multimedia approach: verbal face-to-face,

printed materials, video links .
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41. Topics to Include in a Shared Decision-Making Discussion With

Patients and Care Partners Regarding ATTs!

AA + Potential slowing of cognitive and functional decline, but symptoms are not expected to improve
treatment + How will effectiveness be measured in individual patients?

+ Risks of ARIA and symptoms to watch out for, such as headache, confusion, dizziness, and visual changes
+ What are possible complications of ARIA?

Risks of ATTs + What is the patient's individualized risk profile, based on their APOE genotype, baseline MRI brain scan,
comorbid medical conditions, and current medications?

Commitment! ‘Significant commitment of time/effort/burden to receive frequent infusions, after the commitment to confirm
burden elevated amyloid via PET or CSF testing, and additional follow-up MRIs to monitor for ARIA

+ How much will treatment cost?
Cost + What are the additional costs associated with treatment (eg, pretreatment evaluations, safety MRIs, etc.)?
+ What is the insurance coverage?

+ Would a clinician consider patients younger or older than the age range selected in the pivotal trials?
Questions + What is the duration of treatment, and when should a patient stop? (This may vary, depending on which
remaining ATT is being considered)

+ Would the option of participating in a clinical research trial studying a different type of DMT, or a trial
studying a drug or intervention to enhance cognition (symptomatic therapy), be more appealing?

1. Day GS et. Neurology. 2022:8:6194891. 2. Ramanan VK ot a. Neuroogy. 202310142652. PeerView

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42. Educating Your Patients and Their Families/Care Partners
About ARIA

What do you need to know about amyloid-targeting therapies so that you can make an informed
decision about whether this treatment option is right for you?

The medication might cause some swelling and/or minor bleeding in your brain. This is called ARIA, and it is a common
side effect of this type of medication.

You will need several MRIs over your treatment course to monitor for ARIA
You are at higher risk for ARIA if you have 1 or 2 copies of the APOE e4 gene
ARIA is usually asymptomatic; however, sometimes ARIA presents with these symptoms

Less frequent Uncommon

6 6 G © (3

Confusion Neuropsychiatric E Gait Visual disturbance!

Ho and dizziness symptoms disturbance blurred vision

Seizure

À Call Your Doctor Immediately if You Experience A
Any of These Symptoms!

43. Provide Patient Wallet Card

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eue uen Guquosesg

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NP Denon ao anne > (EN fe PRO EY
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For Healthcare Professionals:
In Case of Emergency

Name:
Date of Bi
am current being treated with an amylidtargting

insen treatment ed — nn

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44. Assistance Programs

https://www.legembi.comleisai-

patient-support

El:
https: //kisunla.lilly.com/hcp/support- F
resources#supportprogram be

Available resources can assist with

+ Locating infusion centers nearby

* Reducing financial burden of treatment (eg, by conducting benefits investigations,
appealing insurance denials, facilitating reimbursement for treatment, providing savings card
to eligible patients)

+ Providing care coordination (eg, by navigating logistics associated with treatment such as
linking infusion appointments with MRI visits)

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45. at Matters Most to Patients and Care Partners?!

+ Individuals experiencing early symptoms of AD are concerned about
— Memory (80%)
— Dependence (67%)
+ Most desired outcomes of AD treatment are
— Improvement or restoration of memory (67%)
— Stopping (58%) or slowing (33%) AD progression
— Maintaining ability to function, perform ADLs (25%)

+ Patients are also concerned about emotional well-being, a desire to preserve
independence, overall physical and mental health, and safety

1 DiBenegat DB ea Aaneimers Ros Ther 202012602, Haube Bet a Neuro! Ter 202812505 27. N
3 Jessen Fatal J Prev Alzheimer Dis. 2022.9 80-558, 4 Watson Jet al Host Erpoca,2010.22504517. PeerView

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46. comes for Patients

Slowing of fun

Sta ing clinical symptoms
educing risk of advancing to the next clinical stage

Meaningful change to individual patients

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47. Interpreting Treatment Effect Through “Time Saved”!

E
|
|

DMT that slows In TRAILBLAZER-ALZ 2,
clinical decline donanemab treatment slowed
clinical decline by 35%,

based on ¡ADRS

Placebo or natural
clinical decline

>

Expressed as the
clinical between
treatment and placebo
groups or

The time saving approach
presses treatment effect
with treatment

with OMT

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1. Dickson SP eta J Prov Alzheimers Dis. 2023:10:595-599,

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48. ATTs Are Associated With Risk Reduction for Progression to Next

Clinical Stage‘?

TRAILBLAZER-ALZ 2 (Donanemab) Clarity-AD (Lecanemab)
CDR-Global
30 2 Placebo
HR (95% Cl) = 0.614 (0.471-0.800) 03 y HR with lecanemab = 0.69

ds P=<.001 ö
s ES
Pe & Lecanemab
ie 2
83 E
Lo Donanemab El
CPs 31% risk reduction
E 5 9
29% É 01 for progression to
2 next CDR-G stage
a 36% lower risk of $ over 18 mo

progression over 76 weeks MIDA

do
EILILIIDEEEELEITITEN Da a 45 48
Time From First Infusion, d Visit, mo

1. Apostolova LG. AAIC 2023.2. van Dyck CH et a. Eng Med, 2022:368:921. PeerView

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49. hat if a Patient Is Not a Candidate or Does Not Wish to B

Treated With ATTs?

+ Refer to therapy, support groups, and social work if not already connected
+ Establish with community resources for at-home and community services

+ Counsel on the importance of lifestyle factors in building up “brain reserve” to prevent
cognitive decline

— Mediterranean diet, physical exercise, social engagement, cognitive engagement

— Maintaining stable overall health and properly managing chronic health conditions
(diabetes, OSA, HTN, HLD)

+ Medications for symptom management

- Cholinesterase inhibitors are appropriate for patients with mild, moderate, and severe
dementia due to AD

— Memantine is appropriate for patients with moderate to severe dementia due to AD
- SSRIs may be appropriate for symptoms of depression and anxiety
+ Clinical trials may be available
+ Other individualized management strategies PeerView

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50. When Should ATT Be Stopped Due to Disease Progression?

What is the optimal therapeutic window with ATTs?
+ These treatments are only approved for patients with early AD (MCI and mild dementia)

+ Lack of evidence supporting use of ATTs in patients who have progressed beyond mild
dementia

Discussion about whether to continue treatment can be framed as part of larger

ongoing narrative about how patients’ and care partners’ goals for treatment may
change over time

ATTs slow disease progression, which may lengthen time that patients suffer as dementia
progresses

Treatments also require significant commitment of time/effort/burden/expense

Shared decision-making approach can be employed to determine whether patients and
care partners feel that it’s still worthwhile to continue treatment

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51. Pharmacologic Chall

+ Prescribing any medication for patients with early AD must follow a risk-benefit
assessment

+ The majority of patients are over age 65 and have comorbid conditions

+ Physiologic changes of aging affect the pharmacokinetics and pharmacodynamics
of drugs

+ Patients may be taking other medications that can interfere with the effectiveness
of dementia medications

+ Patients with early AD are at elevated risk of AEs and drug-drug interactions that
can limit the use of dementia medications

+ Patients with early AD may find it challenging to remain compliant with their
treatment regimen

1. Codomio A et al. Neuro Sei. 2013:24:1881-1889, 2 Bishara D, Harwood D. Int Geriar Psychiatry. 201420.1230-1241. à:
3. Pasquale O ot al Can Intrv Aging. 2015.10 1457-1486. PeerView

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52. Possible Repercussions of Excluding Patients Fri

Decision-Making Process!

Excluding patients with AD from the decision-making process can
+ Reduce quality of life

+ Induce feelings of powerlessness, frustration, and decreased dignity
+ Increase potential for inappropriate care decisions

+ Reduce sense of autonomy as the patient may feel excluded from choices directly
impacting their lives

+ Worsen patients’ mental and emotional state

1. Smebye KL etal BMC Heath Sor Res. 2012:12241. PeerView

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53. + Listen carefully to what the person is saying; offer encouragement both verbally and
nonverbally (eg, make eye contact and nod)

+ Person's body language and facial expression can show a lot about their emotions

+ If you haven't fully understood what the person has said, ask them to repeat it; if you are still
unclear, rephrase their answer to check your understanding of what they meant

Supporting the person to express themselves

+ Allow the person plenty of time to respond—it may take them longer to process the
information and work out their response

+ Try not to interrupt the person—even to help them find a word—as it can break the pattern
of communication

+ If the person is upset, let them express their feelings; allow them the time that they need
and try not to dismiss their worries—sometimes the best thing to do is just listen and show
that you are there

aout dementatynploms and cagrosssymptometitocommuncate- :
oo on Aa A MN OO. PeerView

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54. Ways to Communicate With a Person With Dementia‘

+ Communicate clearly and calmly

+ Use short, simple sentences

+ Don't talk to the person as you would to a child—be patient and have respect for them

+ Include the person in conversations with others

How to pace conversations

+ Go at a slightly slower pace than usual if the person is struggling to follow you

+ Allow time between sentences for the person to process the information and respond

+ Try to let the person complete their own sentences

Tips for asking questions

+ Try to avoid asking too many questions or asking complicated questions

+ Try to stick to one idea at a time—too many options can be confusing and frustrating

+ Phrase questions in a way that allows for a simple answer (eg, a yes or no answer)

What to do if the person has difficulty understanding

+ If the person doesn't understand what you're saying even after you repeat it, try saying it in a slightly
different way instead

+ Consider breaking down what you're saying into smaller chunks

1. te stout cementalemploms and Gagne seynptameMou 1 communicate .
a nom O doy anda ACNE MÁ. PeerView

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