Implementing Targeted Therapies in Transthyretin Cardiac Amyloidosis: From Diagnosis to Stabilization

Co-Chairs and Presenters, Michelle Kittleson, MD, PhD, and Senthil Selvaraj, MD, MS, MA, discuss ATTR amyloidosis in this CME/NCPD/CPE activity titled “Implementing Targeted Therapies in Transthyretin Cardiac Amyloidosis: From Diagnosis to Stabilization.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/CPE information, and to apply for credit, please visit us at https://bit.ly/4ihyoSp. CME/NCPD/CPE credit will be available until October 26, 2026.

1. Implementing Targeted Therapies in
Transthyretin Cardiac Amyloidosis
From Diagnosis to Stabilization

Michelle Kittleson, MD, PhD Senthil Selvaraj, MD, MS, MA
Professor of Medicine Assistant Professor of Medicine
Smidt Heart Institute Division of Cardiology
Cedars-Sinai Medical Center Section of Advanced Heart Failure and Transplant
Los Angeles, California Duke University School of Medicine
Duke Molecular Physiology Institute
Durham, North Carolina

Go online to access full CME/NCPD/CPE information, including faculty disclosures.

© 2000-2025, PeerView

2. Our Goals for Today

Raise your index of suspicion for the signs and
symptoms of ATTR-CA in different populations

Equip you with strategies for prompt diagnosis
and treatment of ATTR-CA

Provide guidance on individualizing treatment
regimens for ATTR-CA incorporating the most
recent evidence

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3. MasterClass 1
Improving Recognition and Diagnosis
of ATTR-CA

4. ret

Transthyretin (TTR) is a protein
primarily synthesized in the liver

+ In the serum, TTR serves as the primary transport
protein for vitamin A via the retinol-binding protein, =, It was previously known as

and is a minor carrier for thyroxine? thyroxine-binding prealbumin?
+ TTR is also made in the choroid plexus, where itis, TTR is a sensitive indicator of

secreted into the CSF and serves as the primary malnutrition and illness, as it

transport protein for thyroxin and retinol? disappears at a rate of baut 50%

- TTR is made in small amounts elsewhere per day from the circulation?

in the body

4. Zhang KW ot al JACO Bose Tron! Sci. 2019449448, 2. Robbins J. Ci Chem Lab Mod. 2002.0:1189-1100. PeerView

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5. Cardiac Amyloi

Cardiac amyloidosis =
protein infiltrates myocardium >
restrictive cardiomyopathy

Light chains >
AL-CA

TTR protein >
ATTR-CA

Neuropathy
Nephropathy
Gl involvement

Orthopedic issues -

Mutation in
TTR gene:
ATTRV-CA

1. Rubin J, Maurer MS. Annu Rev Med. 2020.71-203-219.

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6. V30M
Early. C10R R34T G47A F64L L58H E89Q HO7V S23N Lim I68L

onset

F33L S50R S77Y A36P T49A Late W4iL H8BR
‘onset

Most common genotypes of
ATTR-CA in the United States

Predominant Predominant
Neurologic Features Cardiac Features

Mixed Phenotype

ATTRwt is not inherited, but rare cases of siblings with ATTRwt have been reported*

‘Two systems of nomenclature are used to ofr to ATTR variants, DNA level and protein evel. The numeri location sed in In protein devel nomenciatur 20 uns higher tan i tho
DNAevel nomenclature. Hence, VIZ2 is the DN&devel nomenclature and the corresponding protei-evel nomenclature is p.V 142, both reer to the same genetic varian =
1. Maurer MS etal. Ce Heart Fl 2019:12:2008075, 2. Carol A e al. J Nour Neurosurg Psychiatry. 2022:93:568-678.3. Maurer MS etal. JAm Col Corll. PeerView
2016.88:161-172.4. Westin OM otal. Eur Hurt J Case Rep. 2024:8:yta0199.5. Lopes LR et al. Amyloid, 2019:26:248-247. 6. Gentle Let al PLOS One. 19:w0202495. LLE

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7. Main Types of TTR Variants Known to Cause ATTR

With Cardiac Involvement'?
TIR ee Cardiac Other
Mutation A9%Y Male:Female RacelNationality nyolvement Involvement
US, Black or Caribbean
41 loeme); _HispanielWest African Always; Rare neuropathy,
ee, ancesly; 3.5% Black cardiomyopathy or — 37.4% with carpal
:1 (phenotype) patients, variable HF by age 75 tunnel syndrome
penetrance

US (Appalachia), ‘Autonomic >

Nearly always peripheral

neuropathy

1% in County Donegal,

Ireland
4 per million Japan; DRE Se E

v30m >50 24 variable
(late-onset) with origin worldwide
168L >55 Unknown US, Italy, Germany Nearly always Rare neuropathy
>30 Unknown Denmark Always Carpal tunnel
EHE a | Nw) a PeerView
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8. + Fatigue
+ Cardiac

— = — Atrial fibrillation/AV block/pacemaker
_ p — Aortic stenosis
| = “HFpEF”
\ | Increase LV wall thickness + discordant QRS voltage
+ Neurologic
- Sensory neuropathy
— Autonomic dysfunction; intolerance to vasodilators
+ Orthopedic
| ~ Carpal tunnel syndrome
— Spinal stenosis

1. Kitson BM ta. cular. 2020.14207.022. PeerView

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9. ATTR-CA May Be an Incidental Findi

Bone scintigraphy (non-CV)
AS surgical

Conduction disorders

AS

TAVI

HFEF

HCM

HFpEF/HFmrEF

Patients, %
1. Gonzalez Lopez E ot. Eur Haut 202548 990.1013 PeerView

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10. Practicum 1
Step-by-Step Guide to Evaluating a
Patient With Suspected ATTR-CA

2000-2025, PeerView

11. onard, a Black Man Aged 73 Years

Initial Presentation

+ Presented to ED with progressive shortness of breath al
+ Symptoms began about 1 mo ago: SoB at rest, orthopnea | . cap
+ Lower extremity swelling worsening over past week + Recent TTE noted LVEF ~45% to
50%, increased LVT
Pod + No ischemia on nuclear stress test

Physical Examination and Vital Signs

+ Elevated JVP, bibasilar rales, irregular rhythm, ola
2+ bilateral edema

+ BP 113/91 mmHg, HR 123 bpm, RR 27/min, temperature
36.5 C, SpO2 95% on 10 L oxygen via non-rebreather mask

Family Medical History
+ HF in two older brothers, father

|
|

| Current Medications
| + Aspirin

Laboratory Findings + Rosuvastatin
+ Elevated creatinine, liver enzymes, NT-proBNP, hsTn | + Amlodipine
|

y
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12. Red Flags for Cardiac Amyloidosis—What to Watch Out For!

Cardiac Manifestations Extracardiac Manifestations

=
a

a

Clinical
+ Fatigue

+ Heart failure symptoms

+ Family history of heart failure

Electrical

+ Conduction system disease/pacemaker

+ Atrial fibrillation

+ Pseudoinfarct pattern

+ Discordant QRS voltage for degree of increased
left ventricular wall thickness on imaging

Imaging

+ Increased left ventricular wall thickness.

+ Grade 2 or worse diastolic function

+ Abnormal longitudinal strain with apical sparing

+ Diffuse subendocardial or transmural late gadolinium
enhancement on cardiac magnetic resonance imaging
with increased extracellular volume fraction

Laboratories

+ Persistent low-level troponin elevation

a

m

Musculoskeletal
Bilateral carpal tunnel syndrome
Lumbaricervical spinal stenosis,
‘Spontaneous biceps tendon rupture
Hip or knee replacement

Neurologic
Peripheral neuropathy

Family history of neuropathy

‘Autonomic dysfunction

Intolerance to vasodilating antihypertensive medications
Orihostatic hypotension

Gastroparesis

Urinary incontinence

Erectile dysfunction

Renal
+ Nephrotic syndrome

+ Elevated B-type natriuretic peptide or Download the

N-terminal pro-B-type natriuretic peptide

Practice Aid
on Red Flags

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1. Kitloson tal. J Am Col Carol. 2023;81:1835-1878,

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13. Apply universal definition of HF

Is there a primary non-CV entity
causing symptoms?

HFpEF mimics
Does the patient's presentation
‘warrant specific diagnostic

assessment?

HFPEF
Identify relevant comorbidities
contributing to presentation that
‘warrant treatment

1. Kitloson el. Am Col Cardio 2023:81:1835-1878,

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ity
+ Coronary artery disease
+ Renal dysfunction

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14. Thick Heart? It’s Not Always “LVH”!!

Increased LV wall thickness

m +
Too much muscle Infiltration into muscle
nr |
| |
fs = Fabry's disease
Explained Unexplained | "See eect sorge Cane ey _
esse disease

Hypertension

| Aortic stenosis

At

Lysosomal enzyme alpha-gal A
Angiokeratomas, neuropathy,
proteinuria

Genetic testing

Enzyme replacement

+ Eye issues, skeletal myopathy,
developmental delay

+ Muscle biopsy, genetic testing

+ Gene therapy in development?

+

Amyloid cardiomyopathy
TTR or AL

+ ATTR-CA or AL therapy

+ Neuropathy, Gllorthopedic issues
+ Te-99m PYP scan + serum monoclonal light chain
screen > + genetic testing or biopsy

1. Rowin E, Maron MS. Amhythm Electrophysiol Rev. 2016 5:197-202. 2. Greenberg B el al. Oreulaion. 2024; 144[suopl 1 10727.

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15. Why AL Amyloidosis Must Be Evaluated Before Diagnosin

ATTR: Treatments Differ and Time Is of the Essence!

[ Amyloid deposits from AL and ATTR may look the same
| + On imaging (high rates of false-positive PYP scans)

_* Onbiopsy

[

The only certain way to tell them apart is through monoclonal protein screening tests’?
| * Serum kappa and lambda free light chains, serum immunofixation electrophoresis, and urine immunofixation
| electrophoresis used together have >99% sensitivity for detecting AL amyloidosis

1

FE

ALS

* Originates in bone marrow

+ Easily misdiagnosed as smoldering myeloma,
MGUS, or ATTR-CA

+ Treated with daratumumab, bortezomib,
cyclophosphamide, and dexamethasone

+ Needs to be seen by hematology
within 1 week

ATTR-CA2>

Originates in liver
Easily misdiagnosed as AL or HF

Treated with tafamidis, acoramidis,

or vutrisiran

Appropriate to initiate disease-modifying

therapy within 1 month

1. Kiteson MM ot al J Am Col Carn. 2023:81:1076-1126. 2. Karam € ota. Muscle Norve.2024:69:273-287. 3, Gertz M, Am J Homato.2024;98:300-324

4 Gam Atal. ACG Caso Rap. 2024:20:102285.

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16. idosis: 3 (+ 1) Tests > 3 Possible Diagnoses!

lues from history, ECG,
‘echocardiogram

1

Monoclonal proteins?
e light chain (abnormal if ratio is <0.26 or >1.65)

1 Adopted lor Kitieson MM ot al. J Am Col Caro. 2028;81: 1078-1126

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ATTR-CA

Cardiac amyloidosis unlikely

- 3
Genetic testing

_——

| ATTRY-CA | ATTRm-cA
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17. Cardiologists Play Key Roles at Every Stage of Genetic Testin
for Cardiomyopathies'

Genetic Testing and Diagnostic Pathway for Cardiomyopathies

1. Clinical diagnosis of cardiomyopathy

BR 4. interpretation of genetic results
Consider additional segregation study and functional
tests for variants of uncertain significance

5. Return results to patients and families

6. Tailored longitudinal follow-up and
target treatment when feasible
==

1. Ent P la Eur Hoot 202546344355. PeerView

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18. MasterClass 2

New Paradigms in ATTR-CA
Management

19. onard, a Black Man Aged 73 Years, co!

Leonard

Diagnostic Workup

Elevated BNP and hsTn in the context of increased
LVT and family history of cardiomyopathy raised
suspicion of ATTR-CA

ECG Findings

+ Low-voltage ECG with Q-waves
+ Atrial fibrillation

Monoclonal Protein Screen
+ Negative

Tc-99m PYP Scan
+ Grade 3 uptake

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Medical History

+ Hypertension

+ CAD

+ Recent TTE noted LVEF ~45% to
50%, increased LVT

+ No ischemia on nuclear stress test

Family Medical History

+ HF in two older brothers, father
Current Medications

+ Aspirin

+ Rosuvastatin

+ Amlodipine

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20. B blocker

2 xX vv yw
MM il IS

Non-vasodilating only

Regardless of
(eg, metoprolol), if HFrEF

CHA2DS,-VASc score
BET Diuretics
1. Moore PA oa reson, 2022:16:096-1082.2.Iannm Aol Er Hoa 2023442690291. 3 Koon MM aa. J Am Col Car PeerVi
2023:81:1076-1126. 4. Dobner $ et al. ESC Heart Foi. 2023;10:397-404. 5. Mohanty S et al. J Cardiovase Electrophysiol. 202435: 1422-1428. eerview

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21. Individualizing Current Targeted
Treatments for ATTR-CA!

Download the
Practice Aid on
Targeted Therapies

Most

Administration Vin Cardio Newropatny Common AES ya Acts;
myopa Y fala farnings in
andRoute Need? indication? Indication in Clinical El

Trials

Binds to thyroxi
» Oral tablet, Similarto May cause
binding sites of once daily» Ne des Ne placebo fetal harm
Diarrhea, Diarrhea,
L Mimics a protective Oral tablet, upper upper
2
Acoramidis? “variant (T119M)" twice daily No Nos id ebdominel abdominal
pains pain
Binds to hepatocyte SC injection, Pain in
receptors; every 3 months an
x targets anmRNA atinfusion Similar to .
Murisiran: sequence found in clinic; no Nes ‘ea Yes placebo" a
ATTRwt and premedication arin

ATTRW needed

* The 8079 dose olaaa prescribed as four 20-mg tablets willbe discontinued by December 2025.
1. Vynagal and Vynsamar (atoms) Prescribing Iromaton. pe am accossdata fen. gowidugeatsa_docafabel2023/2119062002,21216 e002.

2 Atruy (acoramids) Prserbng Information. hip ww. accossdata Ka. gowarugsatiso_docstabo!2024/2 16540300001 pl.

3 Amvutra warsran) rscrbing Information. hips wwe aecassdata da goulupsatfsa_cocalabo2028/215515s00604 pal

Mani tat Engl Med 2018378 10071016. Goo JO el Eng / Med 2084 SD ASE, Fontana Metal Eng Vas 202839232-4, Deor\/iew
7. Mis mm iercopharma comphormalpzer-iscontnucow-doseat-drugsryndageus-ahead-2028-plontoss. eervie

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22. Tafamidis C

Treatment Matters, But Doesn't Reverse the Disease Process!

Patients (N = 441)
stratified by wild vs
variant TTR status and
NYHA class (I-II)
Tafamidis 80 mg vs
20 mg vs placebo for
30 months

All-cause mortality
lower with tafamidis
(29.5% vs 42.9%)

— Benefit at 18 mo
RR of CV-related
hospitalizations also
lower: 0.48/y vs 0.7/y
(NNT 4.5)

NNT 7.5 to prevent
1 death over
30 months

All-Cause Mortality

ATTR-ACT!

Pooled
tafamidis.

E

Placebo

Survival Probability
8 8

HR (95% CI} 0.7 (051-0.96)

ATTR-ACT! ATTR-ACT LTE?

Placebo to PS

tafamidis Continuous tafamidis

os
0.

02 si
Extrapolated placebo

EEE TE TE TEE EEE

Time Since First Dose, mo

1. Mauror VS et al. N Engl Med. 2018:379:1007-1016.2. Elo Pot al. Cire Hoot Fal 2022.15:0008193.

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o
ELZITIELTETEITITIITZTTTT

Time to Event, mo

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23. o

Pooled
tafamidis

Least-Squares Mean
Change From Baseline, m
8 8 8

8

0 6 12 18 24 30
Time, mo

1. Mautor VS ot a. N Engl J Med, 2018:379:1007-1016.

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KCCa-0S

Pooled
tafamidis

Least-Squares Mean

14 points in favor
of tafamidis
(P<

Placebo

0 6 2 1 A à
Time, mo

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24. All-Cause Mortality and Hospitalization Benefit of Acoramidis Is

Maintained for at Least 42 Months: Evidence From ATTRibute-CM OLE!

D An Time to All-Cause Time to CV-Related Time to First CV-Related
(N= 421) patients Mortality Mortality Hospitalization
receiving 800 mg 10 10 i 10
acoramidis vs (N = 211) | Continuous
placebo os Cons 1 acoramidis 09 Continuous

+ Most patients had anes acoramidis

acoramidis 08
ATTRM: 08

+ Tafamidis treatment was

al

Placebo to

2
2
not allowed duringthe Zar acoramidis z Bor
first year of the study; À gee 3
tafamidis exposure was E E É
similar between groups °° é ge
+ 17.5% of all patients E Br E
received tafamidis at ges E gos
17.2 months (median a a
time to initiation) i m
+ Primary analysis 02 H
‘compared four Mo42 Mo42 Moz |
Serena 03 | HR (6% cn: HR 9% Co 03.1 HR (65% cn. H
hierarchical manner; 46404708 Le con H
‘comparisons favor o o
en ERZLIITEIZITTZT [BEE OTE IRAN
Time Since First Dose, mo Time Since Randomization, mo Time Since Randomization, mo
1. Judge OP otal J Am Col Cara 2025:85:1009-1014.2. Judge DP etal. Genion. 2026:11:601.611 7
4 Akne Kot a ESC 2028 Congress posaron; Aug 9,205, PeerView

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25. ATTRibute-CM: Efficacy of Acoramidis, a TTR Stabilizer, in

ATTR-CA (Phase 3 Trial), Cont'd.*

Change in Serum Transthyretin Level

3 mo
23 45 Acoramidis = §
ee 2
¿ ¿so 8
8% 25 3
38 3
BS g 00 E
28 3
Peas 5 5 EEES
gee 6 9 2 % e À EZ
z Time Since Randomization, mo Time Since Randomization, mo
fé Change in Kansas City Cardiomyopathy Questionnaire
er Change in NT-proBNP Level Overall Summary Score

23 Placebo A

2 25 ¿
fi A

88 20

3 £

EA 38
Sep ıs i 93
TY, Accramiso 98 pa

Bawinet 3801258 O ee
Time Sines Rapaoiizaos, m Time Since Randomization, mo

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1. Gilmore JD et al. N Engl Mod. 2024:390:132-142,

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26. Survival a

HELIOS-B*2

+ Patients (N = 655) with ATTR-CA Significant Reduction in All-Cause Mortality Up to 42 mo

Placebo

- 1:1 vutrisiran 25 mg SC vs placebo every 12 wk
for up to 36 mo

+ Primary endpoint: composite of death from any
cause and recurrent CV events

+ ~40% of patients used tafamidis at baseline

Adjusted Cumulative

0838888

OF CU REDANA HDB DAH

Compared with placebo in the overall population, Mime: SM OO Fat Dose, m0!

rn staninicanty Improved Significant Reduction in CV Mortality and CV Events
+ Urgent HF visits (| 46%) Up to 36 mo

+ CVevents (| 27%)

+ CV hospitalizations (| 25%)
+ HF hospitalizations (| 33%)
+ Allcause mortality (| 36%)

+ CV mortality (1 33%) 2: oF FOREN ADD ww
+ Composite of CV mortality and CV events (| 28%) Time Since First Dose, mo

PeerVi y
1. Fontana M ai al Eng! J Mod. 2025302:5%-4.2.Witlos RM etal. J Am Cl Card! 202585.1959-1970. PeerView

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27. HELIOS B: Vu

Capacity, Health Status, QoL.

HELIOS-B
Endpoint

KCCQ-OS

Impact of Vutrisiran
vs Placebo

Improvements in change from baseline
in 6MWT across all subgroups
26 m in favor of vutrisiran

Improvements in change from baseline
across all KCCQ-OS subgroups and
subdomains

6 points in favor of vutrisiran

isiran Maintains or Improves Functio!

d Biomarkers!?

NT-proBNP, Adjusted Geometric
‘Mean Fold-Change (95% CI)

0 5 8 8

Ratio atmo 30

Mean Fold-Change (95% CI)

‘Troponin 1, Adjusted Geometric

5 3 8 à @

1. Sholth FH ot al. J Am Col Carol. 2025.85:1943-1955. 2. Maurer MS et a. J Am Col Card. 2025;86:1927-1939,

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HR (69% Ch 0.68 062079)

NT-proBNP.

Ratio at mo 30
HR (O54 CI} 0.68 (061.078)
EEES
Timo, mo

= Troponin I

Facto

BRAD

Timo, mo .
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28. Time to All-Cause Mortality Among Trials in ATTR-CA!

ATTRACT

M(n on study drug) 441 (204) (632 (421),
‘Age.y.moansSD 748272 774265
0x, %

Noto 913 912
Female 7 ss
Race, %

vino: 799 ars
Black 140 48
Genotype, %

wid ype 74 903
Variant 29 97
NYHA class, %

1 91 121
a EN 6

m 25 183
NT-proBNP, pgmL 29059, 2,326
(range) (17524882) (1324019)
NAC stage, %

5 461 572
2 360 318
3 189 109
Tafamidis use, %

Baseline = 00
Drop = 45

1. Girard AA, Sperry BW. Hoot Fi Rov. 2025,30:68-73. 2. Maurer MS ot al. N Eng.) Mod. 2018;379:1007-1016. 3. Gilmore JO et al. N Engl Mod. 2024:300:132-142.

4 Fontana M otal. N Engl J Mod, 2025 392-3344.

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HELIOS-S

77.0 (range 4585)

850
74

ser
"3

150
767
83

2021

11383312)

638
307
55

400
135

Survival Probability, %

80

70 1
ATTRibute-CM, acoramidis
ATTRibute-CM, placebo

60 TATTR-ACT, tafamidis el
ATTR-ACT, placebo +

+ Censored

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Follow-Up Time, mo

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29. Unanswered Questions

PeerView.com/FRU827

How should
we monitor
patients?

+ Overall disease
process?

+ Response to
therapy?

reverse the
course of the

Is there a
role for
disease, or
prevent it
altogether?

combination
therapy?

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30. Criteria for Disease Progression

Clinical and Functional Laboratory Biomarker Imaging and ECG

1 in LV wall thickness (2 mm)

OR
+ in HF-related hospitalization 30% + in NT-proBNP + in diastolic dysfunction grade
eck (800 pg/mL cut off) OR
tin class OR Change in systolic
open measurement
Lin QoL: KCCQ 20%) ar (25% | in LVEF;
(5-10 points)/EQ-5D (10%) A 25 mL | in stroke volume;
OR Advance in NAC 21% t in GLS)
7 staging scale
30-40 m | in 6MWT every 6 mo OR
New onset conduction
disturbance

One marker from each domain provides the minimum requirement
for assessing ATTR-CA progression

1. Garcia Pavia Pet a. Eur J Hear Fo 20212305405. PeerView

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31. Early TTR Response to Acoramidis May Predict Survival!

Change from Baseline in sTTR Levels

@ 163 Acoramidis A
£ 1 -ATTR OS (2910 <12 mai)
5 Esc ATTR O4
In plato <20 mp)
&
aa =a Over scams
gt = iron) Eaty aTTR G2
$3 pen SU mp)
a 05
a

4
E 025
6
oF
5
& o

Boscino WO M6 MD MZ AS NIB MEN M26 MET MOD

Bascino 028 MS NS MO MI? MIS MIB Mar MA NOT ADO
Time, mo Time, mo

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1. Mautor VS ota. J Am Col Carol 2025,85:1911-1923,

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32. amidis/Acoramidis + Vutrisiran: More Evidence Is Needed!

‘Subgroup Analyses ofthe Primary Endpoint (Overall Population) Subgroup Analyses of Death From Any Cause (Overall Population)
Subgroup No. of Patents HR (99% C1) Subgroup No. of Patients HR (95% C1)

Yes 259 0.79 (0511.21) Yes 259 0.59 (0.32-1.08)

ATTR disease pe ATTR disease te
Variant 76 OS2(049172 Variant 76 10.39/0.59-205)
Widtype 578 0.67(051-090) Wid ype ES oe 061 (042-088)

NYHA cass NYHA class

tor so 07305509) tor 592 066 (047.084
m 2 0684033149 u @ 08 (0.24.69)
Baseline NT-proBNP level Baseline NT-proBNP level

52,000 pam 242 ai 053(035079) <2000pÿm 42 ÁS 0.35 0.18-0.68)

>2000pqiml 312 DS) >2,000pqim. 312 0.83 (055-124)

es os 2 os 0 1 à
—_ — pte MA
\urisran boter _ Piceho beter Vatikan batter Placebo beter

1. Fontane Metal N Eng! J Mo. 2025:30235-4. 2. Sversson So a JAMA Ino Med. 201373511612 PeerView

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33. Confirmed ATTR
amyloidosis
me Discuss lack of benefit
(A 2
Is there end. qe disease? ———>» of therapies
Does the patient's insurance | Pick that option |
dictate a preferred option? *___Pick that option |

Does the patient have
ATTR neuropathy?
y

Does the patient have a

preference (daily oral vs SC) Pick the favorite

every 3 months?

1. ios nytimes.com2025108/04Iwellcardiac amyloidosis. tm PeerView

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34. Strategies and Mechanisms of Acti

rgeted Therapy in ATTR-CA!

Producti
Stabilization Removal

RNA Interference Gene Editing

Prevent amyloid Prevent amyloid Prevent amyloid

>: 4 Reduce amyloid deposits

Mechanism formation by formation through formation through in tissue through antibody-

stabilizing the degradation of TTR silencing of TTR mediated phagocytosis

TTR tetramer mRNA expression phagocyt
FDA- on
approved ee an Vutrisiran (2025) = =
therapies EEE)
Investiga- PRX004 (coramitug;
tional Eplontersen A > NCT05442047)
ttheraples (CARDIO. Nexiguran ziclumeran May 20254

- (MAGNITUDE)

and study TTRansform) recruiting? ALXN2220
completion April 20262 (DepleTTR-CM)
dates June 20275
1. Kadaka KT ot al J Am Cof Cardo! 2025:65:1907-1910, 2. ps. inicias qovitudyINCTOS 136171. 3. tp Iicalvat gofsucyiNCTOB126620 PeerView

4. ntpeetnicatals govistudyINCTOS442047, 5, aps heal ost NCTOG183031

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35. Nexiguran Ziclumeran Gene Therapy:

Phase 1 Clinical Trial Results!

Serum TTR Level Kcca-os SMWD
+ Open-label, single-arm tial ape 8 ae
+ 18-mo median follow-up A H bs
+ 31% ATTR (19% with H A Bs
vi22ı) j H Ls
+ 50% with NYHA class Ill H is

+ Single, 2-h IV infusion of Le
nex-z (0.7-1.0 mg/kg) with Time, mo
dexamethasone
pretreatment

+ Primary endpoints: safety,
PD (incl. serum TTR level)

+ Secondary endpoints: Patients with change in NYHA class, (%)
NT-proBNP, hs-cTnT, Improved un 4 (22)

6MWD, NYHA class No change 16 (48) en
+ N=36 Morsened 36 st

ATTR-CM Population

Overall NYHA Class lor It
(N= 36) (n= 18)

4. Fontana Mt al. N Engl J Med. 2024.391:2231.2241.2. htpsJelnicalials govIstdy/NCTOS 128629. PeerView

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36. Upcoming Oral Presentations on ATTR-CA PASM 2025

Acoramidis Vutrisiran

Effect of acoramidis on cardiac conduction abnormalities
Sat 1:21 pm | Exh Hall B — Stage 2 | Brett Sperry

Continuous acoramidis treatment significantly reduced risk of
‘ACM and CV-related hospitalization at Month 42

Sat 1:33 pm | Exh Hall B - Stage 2 | Lily Stem

Effect of acoramidis on recurrent and cumulative CV
‘outcomes (ATTRibute-CM)
Sun 10:05 am | MCC — Main auditorium | Ahmad Masri

Patisiran + Tafa

Combination therapy with tafamidis plus patisiran versus
tafamidis alone
Sat 1:33 pm | Exh Hall B- Stage 1 | Godbless Ajenaghughrure

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HELIOS-B: 12-month results from the open-label extension
period

Sat 12:45 pm | Exh Hall B — Stage 1 | Ronald Witeles
Vutrisiran reduces days lost to death and/or hospitalization
versus placebo (HELIOS-B)

Sat 12:45 pm | Exh Hall B — Stage 2 | Mazen Hanna

Outcomes of the HELIOS-B monotherapy population
Sat 12:57 pm | Exh Hall B- Stage 1 | Ronald Witteles

Reduction in gastrointestinal events in ATTR-CM patients
treated with vutrisiran compared with placebo (HELIOS-B)

Sun 10:13 am | MCC - Main auditorium | Marcus Urey

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37. Practicum 2

Personalizing ATTR-CA Management

Copyright © 2000-2025,

38. Transfer from ED to ICU BIEETSECS
5 aa . . + Hypertension, CAD
+ Hemodynamic stability achieved after episode
of AF, treated with TEE/DCCV and amiodarone, Se

B i r 1 no ischemia
with resolution of respiratory distress + ATTR-CA p.V1421

Medication Optimization

+ Metoprolol succinate and vasodilators resulted in recurrent
hypotension and worsening kidney function

+ Discharged after 7 days with a plan to follow up on an + Furosemide
outpatient basis for targeted treatment for ATTR-CA + Apixaban

Genetic Sequencing (Outpatient) Spironolactone

Medications at Discharge
+ D/C aspirin, amlodipine
+ Continue rosuvastatin

Amiodarone

+ p.V142I variant identified Dapagliflozin

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39. + Genetic evaluations ideally involve
trained geneticists or genetic
counselors, with testing tailored to
the phenotype under investigation

Collect family history

2 +: Patients with a confirmed
KA Conduct pretest counseling diagnosis of ATTR-CA should
have genetic testing to

3 A i differentiate between ATTRv and
de Perform genetic testing ATTRwt variants; this allows for
=] early identification among relatives
we Interpret the variant + Variants of uncertain significance
= should not be overinterpreted, and

ndui t-test nselin: evidence for “causative” variants
A Conduct post-test counseling should be periodically reappraised

Screen the family
ane

1. Kentoroich AR. Am Col Carol HF. 20281: 199-142 PeerView

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40. Relative Risk and Age Dependence of V1221'

HF Hospitalization or Death All-Cause Death

30 5
i: i
E, ES
20
=
3 as as
5 SIDA a a nn
E Ago, y Age.y
x
= HFEF Hospitalization HF pEF Hospitalization
10 ty
è
Sa 5
Ba ® AA
E E
= £
os ae
rr 9 —
Age, y Agey

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1. Selvaraj $ ot a JAMA, 2024,331:1824-1833.

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41. Individual and Population Impact of V122I on Death!

Overall Survival Overall Difference in Survival: Noncarriers vs Carriers
38
>
20 i ; ‘
3
= Noncarriers SE
> 20 82
g 8
O 15 oe 4
10 88 o
5 SE à
o ge
50 6 6 6 70 75 80 85 % 9 53 2

Age, y 50 55 60 65 70 75 do 85 90 9

Age,
Remaining Years Lost Among Carriers 2)

so
x 2 Estimated US Estimated US Total Number of
2% Black Individuals Black Carriers. Carrier Years Lost
zo 250 y 250 y (95% Cl)
50
5 e 957,505
5 13,284,819 435,851 (834,475 to
sm 6 6 6 7 75 0 6 0 95 1.380595)
Ago, y A
1. Setar Sot JAMA, 2024.991:18241853. PeerView

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42. Can We Prevent Cardiomyopathy and/or Polyneuropat!
Disease Manifestation in Asymptomatic Carriers?’

ACT-EARLY
+ Prospective, multinational,

double-blind, RCT evaluating Screening Period Treatment Period
acoramidis in asymptomatic
carriers of a pathogenic Acoramidis
ATTRv ‘Asymptomatic 800 mg BID Pen 800 mg BID
- N=~500 TTRY carriers.
- 5-year trial n= 500

+ Inclusion criteria
— Aged 18-75 years

— Within 10 years of
predicted age of Risk of developing symptom ATTR (CA and/or PN)
disease onset

Now recruiting! Estimated completion October 2031

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1. Garcia Pavia Petal. Amyloid. 2024;34[suppl 1,877; Abstract 190.2. htpslnicaltials govistudyINCTOES63095,

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43. Download the Practice Aids on

Support Resources and
Multidisciplinary Management

MES

+ Avoid over-diuresis

+ Caution with
vasodilators and
B blockers

+ MRA and SGLT2
inhibitors relieve
‘congestion

Disease-modifying agents

1. Adaptod fom Kiteson MM ot al J Am Col Cardo, 2028;81:1076-1126 and emerging evidence.

+ Tafamidis, acoramidis, or vutrisiran
based on
= Cost
= Access
— Patient preference
+ Insufficient evidence to recommend
‘combination therapy with TTR
stabilizer and TTR silencer

+ Vutrsiran
+ Neurology consultation

Anticoagulation in
atrial fibrillation
regardless of
CHADS-VASc

2 Vyndagel and Vyndamax (afamids) Prescrbng information. ps vw accessdat fa govirugsatiéa_docstabel2028/211996s002,212161s0021 pa.
3. Atruby(acoramidis)Preserbing Information. hips ww accessdata fé. govidugsatida, docsfabel”2024/216510:000K pat.
4. Ama (wir) Proscrbing Information. hits accessdata da govrugsatféa_docs/abel2025-2155 15800811 pal.

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44. Key Takeaways

fa) ATTR-CA is not as rare as once thought; most types have age-dependent
i expression and variable penetrance

“We are gain an era where you will die with ATTR-CA as opposed
to from it.” ichelle Kittleson, MD, PhD!

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45. Ask Your =?)
Questions