TTRemendous Advances in Transthyretin Amyloidosis Treatment: What Neurologists Need to Know

Chair, Michael Polydefkis, MD, discusses ATTRv-PN in this CME activity titled “TTRemendous Advances in Transthyretin Amyloidosis Treatment: What Neurologists Need to Know.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/3v99NfL. CME credit will be available until July 15, 2025.

1. TTRemendous Advances in

Transthyretin Amyloidosis Treatment
What Neurologists Need to Know

Michael Polydefkis, MD
Professor of Neurology
Johns Hopkins University
Baltimore, Maryland

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

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2. Our Goals for Today

Learn how to recognize the neuropathic signs
and symptoms of ATTR

Compare currently available treatments for
ATTR and learn how to integrate them into
individualized treatment regimens for
patients with ATTR polyneuropathy

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3. Getting to Know ATTR-PN

An Introduction to lts Complex Epidemiology,
Pathophysiology, and Burdens

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4. Pathogenesis of ATTR12

‘Amyloid deposits
Pathogenic process fold cena
Folded Misfolded Misfolded Amyloid Heart
TTR tetramer TTR monomer TTR monomer TTR oligomer re,
= Y ® Pecera
TIR production “% TIR tetramer & < si
dissociation Sem
Hereditary vs Wild-Type ATTR
Etiology Genotype Phenotype
Nonhereditary (ATTRwt) Only wild-type TTR ATTR-CA
Hereditary (ATTRv) >130 pathogenic TTR variants Various
1. Aimo A et al. Not Rev Cardio. 2022:19:655-667. 2. Adams D et al. Nat Rev Neuro. 2019,15:387-404. PeerView.com

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5. ATTR Terminology Is Changing’

Term ology Newer Terminology
Transthyretin amyloidosis (any signs/ _ ATTR
symptoms, either hereditary or wild-type)
Hereditary transthyretin amyloidosis hATTR ATTRv
Wild-type transthyretin amyloidosis - ATTRwt
Transthyretin cardiac amyloidosis - ATTR-CA
Transthyretin amyloid cardiomyopathy TTR-CM, ATTR-CM ATTR-CA
Transthyretin familial amyloid polyneuropathy TTR-FAP ATTRv-PN
Amyloid light chain cardiomyopathy AL-CM AL

1. Kitleson MM etal. JAm Col Cardiol, 2023:81:1076-1126, 2. Maurer MS etal. JACC. 2016:68:161-172. 3. SolvarajS et al. JAMA, 2024;331:1824-1833. PeerView.com

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6. ns in ATTR124

Genotype-Phenotype Correla

All genotypes have some degree of neurologic and cardiac involvement

Two systems of nomencatre are used to reer to ATTR variants, DNA level and protein evel. The numeri location used in the proteindevel nomenclature is 20 unis higher han in he
DNAvevelnomencaur, Hence, V1221 1 the DNA level nomenclature and te corresponding prteJvel nomenciauro sp VI4Z Din mutator rer 1 the same genet variant 24

1. Maurer MS et al, Cr Heart Fo, 2019.12.006075 2. Camol A ata. J Neuro Nowosurg Psyclty 2022.33 68 878. Fa

3! Lopes LR et al. Amyloid. 2019:26:243-247. 4. Gentle Lt al. PLoS One. 19:00292495, PeerView.com

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7. Natural History of ATTR13

Appearance of specific complications over time varies by
individual and genotype

© Polyneuropathy

‘Symptomatic

Fr = Cardiomyopathy
‘Arrhythmias

Amyloid fibril
accumulation

Structural and
functional alterations.

Amyloid Infiltration Burden

Time,
Presymptomatic Stage Symptomatic Stage y
1. Aime A ota. Nat Rev Cardo! 2022.19:655667.2. Scrpa R et al. Font Cardevase Med, 2025:10:1151803
3, Vera-Lionch M ot al. Orphanet J Rare Dis. 2021:16:25, PeerView.com

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8. Clinical Manifestations of ATTR Amyloidosis**

ATTR-CA

HFEF ATTR-PN CNS (leptomeningeal
- at + Small fiber neuropathy 2myloidosis)
Mi he Y + Headaches

+ Large fiber sensory or
sensorimotor neuropathy

+ Conduction block + Stroke-like episodes

+ Amyloid
Cerpal tunnel + Postural hypotension _ spels/seizures
syndrome + Bladder paresis + Ataxia
+ Tendon rupture 2 z >» , (hypotonia) + Spasticity
it 2 gÉ + Nocturia + Cerebral hemorrhage
+ Spinal canal stenosis $ 55 + Incontinence el
+ Shoulder, knee, and 3 BS Urinary retention
hip pain or surgery 3 Z& + Erectile dysfunction Gl
+ Trigger finger = + Abnormal sweating. Weight loss
+ Myopathy ay + Diarrhea or
BR alternating diarrhea
cata dus : Nepal syndrome and constipation
+ Glaucoma + Kidney failure + Early satiety, nausea
+ Abnormal conjunctival + and vomiting,
regurgitation

+ Pupillary abnormalities + Fecal incontinence

1. Navi JN a al. Hoor Fi Rev. 202227.785:93.2. Caro A otal. J Nour! Neurosurg Psychiat. 2022: 668-678. Mn
3 Karam C et al Muscle Nerve. 2024,69 273-287. PeerView.com

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9. Time Course of Development of the Signs/Symptoms of
ATTR in the 5 Years Preceding Initial Diagnosis’
os Other Systems a Cardiac System

Nervous System

Years Prior to Diagnosis

+ guta ond 28 nd y apres ATR, commercial and Med suplente ta, N= 4% part 42 macs cool N
Lone Mt at phat Rare Di 221.102 PeerView.com

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10. Diagnostic Delays Are Increasingly Common in ATTR:
Evidence From the THAOS Patient Registry!

Median Time From Symptom Onset to Diagnosis, y

3
ATTRv
2
>
$
E
=
1 ATTRwt
o+
2007-2010 2011-2014 2015-2017 2018-2021
Enrollment Period
No. enrolled
ATTRV are 1048 646 728
ATTRwt 70 230 28 132

1. Coelho T et al, Amo. 2023:30:445-448. PeerView.com
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11. Valt22He

\Val30Met (eat onset)
‘Val30Met (ato onset)
TrvBoAla

Lou et
essteu
Sorzrtye
GueoGn
GH7Gu
e84Sor
PhosaLou
Leusstis
Sorsoag
CA
Vaizote

Genetic and Clinical Characteristics
of TTR Variants Known to Cause ATTR!

3.5% in Black pationts
Most common variant
curently woddwde
{per mition in Japan

1% in County Donegal,
ireland

<1% of ll TTR variants
<1% of ll TTR variants
<1% of al TTR variants
<1% of ll TTR variants
<1% of al TTR variants
<1% of all TTR variants
<1% of ll TTR variants
<1% of ll TTR variants
<1% of al TTR variants
<1% of al TTR variants

<1% ofa TTR variants

Penetrance

37 4% with carpal tunnel
syndrome. polyneuropathy,
cardiomyopathy, or HF by age 75

20%.

00%
0%
300%
Unknown
Unknown
Unknown
Unknown

Unknown

ss
4s
“0
>50
>s0
>40

0

CountyfLocation

Hapanics West African Worduide

Portuguese, Japanese, „Portugal, Sweden. Japan,
‘Swedish Braal Cyprus, and Majorca

ordre Wot
wen ind Eng. US
Dan een,
alan, Geman tay Gomany
French, German, ys rane, Spin
alan tay
aan tay Gomany
Swiss, German us
talon tay, US
Seman Us, Gemany
Fn a ae
oman, akan Fe. German, a, France
Seman Germany

1. Kitieson MM e al. J Am Col Cardo. 2023:81:1076:1128.

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12. Some ATTR Variants Are Not Rare in the United States!+

¡e United States

is the most comm:

The p.V1421 (V1221) varia

Increased morbidity
and mortality

3.2% of Blacks carry

Large epidemiologic
ATTRY p.V1421

cohort studies

+ ARIC + 23,338 self- «HF
+ MESA identified Black hospitalization
+ REGARDS individual in the 4 «1 HFIEF risk
cohorts +7 all-cause death
o 754 p.V1421 in late life
carriers + Men and women
affected equally

+ WHI

Claims data for those with p.V142I found 89% had lower extremity numbness,
67% had spinal stenosis, and 44% had bilateral carpal tunnel syndrome

4. Selvara St a. JAMA. 2024:391:1824-1839.2. Kanipr tal. J Pors Mad. 2024:14271 7
3! Lopes LR et al Amyloid 2019:26:243-247. 4. Gentile Let al. PLOS One. 19:00282435, PeerView.com

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13. Racial/Ethnic Minorities Are Underrepresented
Across ATTR RCTs!

Polyneuropathy Trials Cardiomyopathy Trials
vizai NR 0% 0.9% 1.7% 4.3% 3% Top3 224% 56.8%
m

mWhite mBlack = Asian

¿e
&
A so
=
ö
co
s
$
Es
a
2
La
gor 2019 Wading Cruz AFOULO REUROTR EURO Tne aaa mon
nm) "2018 ¢atamce)——Gabaran) ‘intone torres too
RCT (agent)
1.Ekpo E ot al. Amoid,2024;31(Suppl 1)S141-$142, Abstract 343. PeerView.com

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14. Red-Flag Signs/Symptoms/Medical History Raising
Suspicion of ATTRv in Patients Presenting With Neuropathy’

WR Rapid rate of polyneuropathy progression TR motor weakness
- Predominant or early in the
JR Early autonomic dysfunction course of neuropathy
~ Erectile dysfunction
= Lightheadedness from postural hypotension WW Family history of ATTRv amyloidosis
Changes in bowel movements and GI symptoms
(often dismissed or misdiagnosed as IBS) Jen Prior famliy history of unexplained
- Rapidiy progressing
WR Bilateral CTS and/or prior surgery for CTS polyneuropathy of unknown cause
— Recurring after release surgery - Heart failure
— Present in other family members - Sudden cardiac death

- Cardiac arrhythmia
JE Accompanying or prior history of symptoms from

other systems TER Lack of response to specific
= Cardiac: shortness of breath, arrhyihmias, CHF with treatments for other neuropathies
preserved EF, features of hypertrophic cardiomyopathy (eg, IVIg for CIDP)

- Musculoskeletal: rotator cuff, biceps tendon
- Ophthalmologic: vitreous opacities, periorbital hemorrhages
- Renal: renal failure and proteinuria
- Gl: unexplained/unintentional weight loss,
constipation, diarrhea

1. Karam © et al. Muscle Nerve. 2024:69:273-287. PeerView.com

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15. Common Misdiagnoses for ATTRv!

Neuropathy Phenotype or Manifestation

Bilateral carpal || Unexpected

Length- Demyelinating Motor Small-fiber finial
dependent PN neuropathy neuropathy neuropathy syndrome weight loss
Diabetic

neuropathy Motor neuron , A
disease/ALS Fibromyalgia Malignancy

Occupational

Idiopathic O
neuropathy GE? és tunnel

Idiopathic
small-fiber
neuropathy

Autoimmune
disease

Misdiagnosi:

Alcohol
neuropathy

1. Karam © et al. Muscle Nerve. 2024;69:273-287. PeerView.com

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16. Knowing It When You See It
Improving Recognition, Diagnosis, and

Monitoring of Progression in ATTR-PN

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17. Key Considerations and Recommended Assessments for
Diagnosis of Patients With ATTRv-PN in the US!

Patient presents with sensory or sensorimotor
peripheral neuropathy

‘Assess for presence
Check for family ‚of comorbidities Has the patient

history of + Cordiomyopathy Does the patient Late eet
+ Poleuropathy + Peripheral edema have bilateral CTS omega id
- ATTRV amyloidosis en or a history of en,
+ Sudden cardiac death + Autonomie symptoms reciting CS, unclear origin and
(not oranany artery (eos ypoteneion, following surgery? hi

disease) arrhealconstipation)

y Involuntary weight loss

to therapy?

‘Suspicion of ATTRv amyloidosis raised by any of the above risk factors plus polyneuropathy

Not ATTRv amyloidosis

Potential ATTRwt amyloidosis
or other neuropathy

TTR variant

‘Paints may be assessed or gen conditions including Chacot-Matie-Tooth disease and hereditary newopathy wih Kaito pressure pases or
‘screened for vitamin 812 deficiency, dabetes (hemoglobin AIC assessment. thyoiddytuncton, monoclonal gammopathy (menunofcaton

‘loctophorei), or AL amyloidosis (mminoglobuin ro hgh chain assessment. 7:

1. Karam C et al. Muscle Nore. 2024.69 273-287. PeerView.com

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18. Key Considerations and Recommended Assessments for

Diagnosis of Patients With ATTRv-PN in the US, continued!

TAR variant

If US patients is <40 years old, ATTRV
amyloidosis unlikely as the cause of
neuropathy; however, clinicians should
be aware that some cases on
early-onset neuropathy are reported*

Confirm TTR amyloid® Confirm TTR amyloid

(tissue biopsy diagnos (cardiac scintigraphy);
skin, fat pad, nerve, PYP grade 3 positive scan

cardiac); analysis should | Negus | dep ere ee sea | and elevated NT-proBNP

include amyloid typing by ; in the absence of AL
immunohistochemistry or a indicates active ATTRV

mass spectrometry amyloidosis

‘Assess for other risk factors
If multiple risk factors present, likely
ATTRV amyloidosis

Positive
for amyloid

Diagnosis confirmed

+ Eary onset of paleuropathy has been reported in ATTRV amyoidosis.
‘Importance of issue agnosis realer when concurrent possible causes of porpheral neuropathy (eg. B12 deficiency, diabetes maltus, paraproteinemia) are present. In carin
cases where there o aerate cause for a progressive neuropathy, especialy when mulisystem features are present a biopsy may not be necessary. A negativo tssue biopsy in a
patent win a high suspicon of ATTRY amyloidosis does not exclude a diagnosis and thor investigation (e. scintigraphy) or dose fow-up s wanted 7

1 Karam O PeerView.com

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19. Diagnosis of AL Amyloidosis!

Clinical clues for AL amyloidosis

Unexplained proteinuria
Hepatomegaly
‘Acquired factor X deficiency with coagulopathy

Evidence of plasma cell dyscrasia

Evidence of amyloid tissue deposits
Biopsy of surrogate site vs ‘Serum free light chains,
affected organ serum IFE, urine IFE
If biopsy of surrogate
site is negativo, a
biopsy of the affected (Identity monoctonal protein © assess the plasma cell

organ is required to burden
accurately exclude AL = + Exclude multiple
amyloidosis Immunohistochemisty or | Sal” Hematology myeloma or B-cell
phoproliferative
7: emergency! ee
1. Kiteson MM e al. J Am Col Card. 2023:81:1076-1126, PeerView.com

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20. Recommended Assessments/Tools for Staging or
Monitoring Neurologic Symptoms in Patients With ATTRv!

Class | Class lla Class IIb

recommendation recommendation recommendation

+ Neurologic + Orthostatic + Autonomic reflex
examination or NIS BP/vitals screen

+ Electrodiagnostic + COMPASS-31 + Norfolk QOL-DN
testing questionnaire questionnaire

+ PND/FAP staging + QST

+ R-ODS
questionnaire

+ Skin biopsy

1. Karam C et al. Muscle Norvo. 2024;69:273-287. PeerView.com

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21. Recommendations for Staging or Monitoring Non-Neurologic Symptoms
in Patients With Symptomatic or Presymptomatic ATTRv-CA!

Strength of Sensitivity to Disea
Recommendation Progression (1-3)

[Assessment Tool

Frequency

Biomarkers
BNP lla 2 Initial evaluation/follow-up dependent of progressive symptoms
NT-proBNP 1 2 Annually
Troponin 1 1 1 Annually
Prealbumin Ita NA At BL and annually to monitor response to treatment

Frequency will be determined on a case-by-case basis
Echocardiography/TTE 1 1 depending on the clinical picture; can be performed at BL
screening assessment

3 Il evaluation; follow-up dependent on progressive
Scinigraphy (PYP) ! 1 Pete

Cardiac MRI lla 12 ‘Available option f other cardiac assessment are inconclusive
Kidney function (ie, eGFR), urine protein 1 2 Annual

Consider a collaborative multispecialty approach to assessment of non-neurologic symptoms?

1. Karam © et al. Muscle Nerve. 2024;69:273-287. 2. Kitieson MM etal. J Am Coll Cardiol 2023:81:1076-1126. PeerView.com

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22. Imaging and Pathology Findings in ATTR!

myelinated and
unmyelinated nerve fiber
‘density with evidence of
active degeneration (black
arrowheads); amyloid
‘deposition is observed in
endoneural blood vessels,
resulting in thickened
vessels walls (black arrow),
toluidine blue.

Scale bar = 0.05 mm.

B,C: Amyloid deposits in
the endoneurial blood

vessel wall (blue ‘pyrophosphate scintigraphy in

arrowheads), Congo red- hereditary transtnyretin
‘stained frozen sections, ‘demonstrating cardiac uptake
(6) Immunofuorescence ‘compared with surrounding tissues

with Texas red fier, and
©) transmitted light
Scale bars = 0.1 mm.

with a heart to contralateral lung
ratio of 2.1 (normal <1.5).

Anterior Posterior
1. Carol A ot al. J Nour! Neurosurg Psychiatry. 2022.83 668878. PeerView.com

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23. ns in ATTR124

Genotype-Phenotype Correla

All genotypes have some degree of neurologic and cardiac involvement

Two systems of nomencatre are used to reer to ATTR variants, DNA level and protein evel. The numeri location used in the proteindevel nomenclature is 20 unis higher han in he
DNAvevelnomencaur, Hence, V1221 1 the DNA level nomenclature and te corresponding prteJvel nomenciauro sp VI4Z Din mutator rer 1 the same genet variant 24

1. Maurer MS et al, Cr Heart Fo, 2019.12.006075 2. Camol A ata. J Neuro Nowosurg Psyclty 2022.33 68 878. Fa

3! Lopes LR et al. Amyloid. 2019:26:243-247. 4. Gentle Lt al. PLoS One. 19:00292495, PeerView.com

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24. Armando, a Man Aged 55 Years

Armando

Medical history

+ Persistent, bilateral numbness and
tingling in lower extremities

Occasional episodes of sharp, What are the possible

shooting pain in legs

Recent onset of weakness in feet
and difficulty walking with gradual
loss of sensation in his hands

diagnoses for Armando?

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25. Treating Them Right
Contemporary and Personalized

Management of ATTR-PN

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26. TR

slow
progression
+ Difunisal

1. Kitioson MM ot al. J Am Col Cardio. 2023:81:1076-1126,

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stabilizers may

+ Acoramidis

Tafamidis not FDA-approved for
neuropathy

TTR silencers are only FDA-approved
for ATTR disease

No evidence to date that carpal tunnel
‘syndrome, spinal stenosis are
impacted by disease-directed therapy
Vitamin A supplementation is required

Management of ATTR-PN!

Disease-directed therapy

+ TTR silencers to slow
progression and/or reverse
disease in ATTRV

‘Sensory neuropathy

‘Autonomic dysfunction

Compression stockings,
abdominal binders
Increased sau intake
Salt tablets
Flusrocorisone
Midodrino

Droxidopa
Pyridostigmino

Tricyclic antidepressants may be
effective but poorly tolerated due to
risk of orthostatic hypotension,
constipation, and urinary retention

All medications but pyridostigmine may be
poorly tolerated in patients with cardiac
involvementiestrictive physiology

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27. Mechanisms of Action for siRNA, ASO, and Gene Therapies

siRNA
TTR gene

LISIS.

| —_

TTR mRNA

siRNA

mm
ul

RSC (7
Tran „NUR

X
degradation Fe 9

1. Aimo A et al. Nat Rev Cardiol 2022:19:655-667.

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Targeting ATTRv!

ASO
TTR gene
LISIS.

| Fi

TTR mRNA

ASO
au
RNase H1 f

L

Yu +
aan LE Y

CRISPR-Cas9
SORNA

Frameshift
mutation
Suppression
Of TTR protein
synthesis

TTR protein

Ÿ

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28. Therapies Targeting the Amyloidogenic Cascade’

TTR production TTR tetramer dissociation and misfolding TTR deposits
Je
eS

Fir
Inhibition of TTR TIR stabilization TTR degradation
synthesis

+ Liver transplantation

+ RNA silencing Nonselective

Selective 5 =
agents (MÚDCA

Monoclonal Ab

PRXOO4

FDA Approval Status? jus

Y ATTRV-PN

Y ATTR-CM

1. Tomasoni Det al. Front Cardiovasc Med. 2023:10:1 154594. 2. ps www accessdata {da govscrpisicderial. PeerView.com

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29. Managing Polyneuropathy Is Just Part of Managing ATTR:
Cardiology Perspective!

Confirmed amyloidosis

Heart failure GOMT less wo Arrhythmias
tolerated than in

Cece) O ese mocivino
rase piysclogy Narrow window of therapies
MRA and SGLTZ may be considered suiema

Loop + ane dre agent

Hoar iranplatin sole advanced patents

Pola care

ATTRwt-CM AAN

Tafamidis

Cardiomyopathy Neuropathy Plasma cell-directed

‘Complex authorization process for treatment in collaboration
tafamiis wih potently high with hematologist

copayments
Avod prescribing to patents who are Tafamidis TTR silencer therapy
PeerView.com

100 wel (precinca) oF oo sick in collaboration with
(NYHA class I) to benott neurologist

Kittoson MM eta. J Am Coll Cardiol 2023;81:1076-1126.

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30. Symptom Management Options for Patients With ATTRv-PN'

Neuropathic pain Diarrhea Constipation ‘Appetite stimulant
Gabapentin, prgabalin Tincture of pois Soma ghccsise -Minazapine
“Duloxetine, venlafaxine “Loperamiée Docusate <Dranabnot
Acetaminopnen <Eusacoine ‘Metamuet
“Oxcamezapin, lamotrigine "Dioyeemine “Pyridostomine
*Nortiptyine,amipyine
Erectile dysfunction Orthostatic hypotension Gastroparesis ‘Nausea, vomiting
Senat -Midodine -Meocopramiée -Ondansenron
*Abpostag *Fhudrocorisone <Enromyoin
“Droiéepa
“Pyrdostigmine
“Atomoxetine
“Compression stockings,
comal binder
Dry eye Musculoskeletal Oculoleptomeningeal
-Presorave-tee artical tars | | -Hond weokress: occupational symptoms
Nightimo mask and eye Footer Seizures: anticonvulsants
pi tle -Foot op: anke-ootorheses | | “pyorocopnat VP shunt

+Carpal tunnel syndrome: wrist placement
splints, surgical eval

1. Karam € et a. Muscle Nervo. 2024:69:273-287 PeerView.com

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31. Shared Decision-Making Is Recommended in ATTR!

Optimal patient care decisions Ashared-decisions model
should properly reflect the regarding care decisions is
patient's preferences and appropriate, particularly when
priorities as well as those of the clinical equipoise exists in areas
managing clinician of treatment uncertainty

ATTR management is a team sport!

1. Kitleson MM et al. J Am Col Cardo. 2023:81:1076-1126, PeerView.com

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32. Interpreting Outcomes in ATTRv-PN Trials!

Abbreviation

Full name

What it assesses

Range of scale

Direction of change

1. Adams Det al. N Engl J Mod. 2018:379:11-21

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mNIS+7

Modified Neuropathy
Impairment Score +7

Neuropathic
impairment
0 to 304

Higher scores
indicate more
impairment

Norfolk QO! mBMI

Norfolk Quality of Modified Body

Life-Diabetic Mass Index

Neuropathy

Quality of life Nutritional status
-4 to 136 BMI x albumin in g/L

Lower values indicate
worse nutritional
status

Higher scores
indicate worse QOL

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33. APOLLO: Design!

+ Phase 3 RCT investigating change in neuropathy impairment on mNIS+7 (primary endpoint)
+ Change in Norfolk QOL-DN, 10-m walk test, mBMI (secondary endpoints)

Adults aged 18-85 y (62 y, median)

= 21% North American
Documented TTR variant P: in 0.3 mg/kg IV Q3W

= 14 y since diagnosis, median

- 43% V30M 21
- 0.9% V1221
Polyneuropathy Disability < IIIb
N= 225
1. Adams D et al. N Engl J Med. 2018:379:11-21. PeerView.com

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34. APOLLO: Primary and Secondary Endpoints’
mNIS+7 Norfolk QOL-DN Score
Ditrene at 18m = 21 Oierono at 18 mo =
(patisiran-placebo):

P<001

5
so] @atisran-placebo}:
40830
=
P<oot
2

180221
(N=67)

Least-Squares Mean Change
in mNIS+7
Loast-Squares Mean Chango
in Norfolk QOL-DN Score

Patisiran

5] Patisiran wee
ey (N= 141) .
BL 9mo 18 mo BL 9mo 18 mo
Baseline mNIS+7: 89.9 + 41.5 patisiran
74.6 + 37.0 placebo

‘an was statisticall icantly better than placebo on all end;

1. Adams D et al. N Engl J Mod. 2018:379:11-21 PeerVie

com

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35. APOLLO: Safety’

Event, n (%)

Any AE

[AEs occurring in 210% of patients in either group

Diarmea
Edema, peripheral
Fan

Patisiran
Event, n (4)
(n= 148)
29 (98) 55(37) Ba
wen 4460)
22029) zum en

143 07) ‘AE leading to discontinuation ofthe bal regimen
AE leading to withdrawal from the trial

fo
DIET]
um m
CT
u son
200 00

Nausea 1601 22115) Any severe AE
Infusion lated reaction 70) 28 (19)
ES 7 Z

un
Dizziness

Fatigue

Headache

Cough

Vomiting

Asthenia

Insomnia
Nasopharyngiis
Pain in exvemiy
Muscular weakness.
Anemia

Syncope

1418) ws)
109 19(13)
8(10) 18(12)
9(12) 16(11)
9012) 15(10)
8010) 15 (10)
sm 140)
70) 15610)
so 15610)
8010) vom
119 se
8(10) 3@)
so) 3@)

1. Adams Det a. N Engl J Med. 2018:379:11-21

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36. APOLLO OLE: Efficacy at 42 Months!

mNIS+7 Norfolk QOL-DN
Placebo group crossed over Placebo group crossed over
= , to treatment at 18 mo , to treatment at 18 mo
=
’
i ;
5 $
i !
ai ;
i E
$ à
3 <
vi 3
¿

a 9m LALA IMAZ 42maoez a om MALES IOMAOLENZ 42m OLE

a=” ms) oo) <=>

1. TuS et ak Amoi. 2024:31:1-11 PeerView.com

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37. HELIOS-A: Design!

+ 18-month RCT study investigating change in neuropathy impairment on mNIS+7
+ Primary endpoint assessed at 9 months; all patients eligible to receive vutrisiran after 18 mo

+ Adults aged 18-85 y (60 y, median)
= ~17.6% North American

* Documented TTR variant

— 2.2y since diagnosis, median

= 45.1% V30M

- 43% V1221
NIS 5 to 130
Polyneuropathy Disability <illb
Kamofsky Performance Status
score 260%

Vutrisiran 25 mg SC Q3M

Patisiran 0.3 mg/kg IV Q3W

Premedication 60 min prior to infusion
N=164

+ Historical controls from APOLLO
* Similar eligibility and endpoints Historical placebo
N=77

1. Adams D et al. Amyoid 2023:30:1:. PeerView.com

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38. HELIOS-A: Primary and Secondary Endpoints’

mNIS+7

28.09 (2.28)

224 (1.43)

E
13
ee

» 14:76 2.00)
3 ' Lo 2088 08 0
En eo)
58 0 Lswo=.rroogenc, | Press”
Ya ETE
ae Pasion
55 ©
EN Vutrisiran 0.46 (1.60)

ar om Tomo
Mo. at Risk
Vusran 122 m 12
Hstoreal
m e st
Baseline

+ 60.6 + 36 vutrisiran
+ 74.6 + 37 placebo

1. Adams D ot al. Amyloid 2023:30:19.

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Norfolk QOL-DN

19.8 (26)

a
F 129 (22)
E ite
i 3 ge CADET
5 RS
2° 0
zo
Er 15 Tomo
Mo. at Risk
Vatiscan 121 m an
seer se ss “
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39. HELIOS-A: Baseline Characteristics and Safety!

Selected Baseline Characteristics Adverse Events
APOLLO HELIOS-A APOLLO HELIOS-A
EEE Placebo | Vutrsiran | Patisiran Mg At Lesst One Event, n (1 Patisiran
ma | me se)
nage a a ‘Summary of AES
ml A SARA TR) ‘any AE 75074) 1190075) Aero)
Mates, (4) 58 (753) HE 27 643) Serious AEs 31403) 2062 184429)
Severe AES 2060) 19(156) 16081)
Previous tetramer stabilizer us 110592 75615) 23089
ators 270651) 531434) — 25(695) ABS Teading totreatment discontinuation 11(143) 325) 300
Dial we) 22180) 80190)
bre nt Li à 91.7) 3025) 2(48)
Neuropathy impairment score, n (%) oes aor AS Participation
Ss (45.5) (63.9) )
250-<100 33(429) 39820) 13 (31.0) Peete: ses 2016) 3071)
3100 SM SUN 242) Es occuringin 210% in vursiran-reated
patents
PND score, (%) à a 0
p gay MON HD ment ZN
la 7288) 16(181) à en wen mn 4
[3 m) 1208 3 ee VE a gan
Atala o won 405
NT-proBNP, n (0%) Be
Sooo nt" 2 66(85.7) 112) 37881) D vo, Ben, £
73.000 mp. sm 10682 So)
{cardiac subpopulation, n(%) 36488) 40028) 14093)
1. Adams D et al. Amyloid, 2023:30:1:. PeerView.com

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40. NEURO-TTR: Design and Primary Endpoints‘

+ 66-week, placebo-controlled,

double-blind RCT

+ Adults aged 18-82 y
(59.2 y, mean)

— 48% North American

1000 2013 958 <001
2127 3107 Ava <00t

M2 25 0 <om

+ ATTRY-PN with documented Error
‘sequence variant and amyloid
deposits (52% V30M, 1.7% mu mie 1095 m u

V1221), 3.4 y since dx, mean HA PE A

+ NIS 10-130 points “tee 1a 808 <0
- mNIS+7: 77.6 £376 1225 2158 20 0
+ Coutinho stage 1 or 2 CR RS A 0
+ Inotersen 300 mg SC weekly
+ 2:1 randomization
N=172
% ty

5
= Favors notersen Favors placebo

* Coutinho stage 1, ambulatory without assistance: Coutinho stage 2, ambulatory wih assistance; NIS, Neuropathy Imparment Scare, scor range 0-248, higher

‘alos Idate poorer function, N
1. Benson MD et al. N Engl J Mod. 2018:379:22:31. PeerView.com

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41. NEURO-TTR: Safety!

Eve Placebo
(n = 60)
Any AE 60 (100)
Event related to trial regimen 23 (38)
Any serious AE 13 (22)
Event related to trial regimen 1(2)
Glomerulonephritis 0
Thrombocytopenia 0
Deep-vein thrombosis 1 (2)
Intracranial hemorrhage o
Tubulointerstitial nephritis 0
Pulmonary embolism 0
Embolic stroke 0
Myelopathy 0
Death 0

1. Benson MO et a. N Engl Mod, 2018:379:22-31,

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Inotersen
(n= 112)

111 (99)
87 (78)

36 (32)

8 (7)
3 (3)
2 (2)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
5 (4)
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42. NEURO-TTRansform Trial Design’

Phase 3 study evaluating eplontersen in ATTRv-PN compared with historical placebo
Adults aged 18-82 years

- 53 y, mean Eplontersen
= _ 15% North American (N= 144)
+ ATTRv-PN with documented Open-label
sequence variant 1 es
— 2.5 y since diagnosis, mean
* NIS 10-130 points

Coutinho stage 1 or 2

or 20-wk
N= 168 NEURO-TTR historical placebo Lesh ra al
+ Historical controls CTA —,
+ Placebo group from week 66 ex mine, m - -
endpoint of phase 3 RCT

ds 85 105
(NEURO-TTR) um
N=60

* Coutinho stage 1, ambulatory without assistance; Coutnho stage 2, ambulatory wi assistance; NIS, Neuropathy Impaiment Score, score range 0-248, higher
values indicate poorer function,
1.Coelho Total. JAMA. 2023:390:1448-1458,

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43. NEURO-TTRansform: Primary Endpoints at 66 Weeks!

mNIS+7 Composite Score Nore QOL-DN Total Score

AMD: -24.8%
(95% Cl: -31.0% to -18.6%)

P<.001

7%
1 -25.6% to -13.8%)

q

‘Adjusted Mean Change From BL

Worse

PP. al;
:
0

° E
Time, wk Timo, wk

£
3

(95% Cl)
(95% cl)

Adjusted Mean Change From BL.

ii —

Baseline mNIS+7
+ 81.3 + 43.4 eplontersen
+ 74.8 + 39.0 historical placebo

‘Means, ite ces: medians, open diamonds, shi quarts lower and upper ends of whiskers; AMD, adjusted mean difference. e
1 Cocina Tet JAMA. 2023 200 1448 1458 PeerView.com

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44. NEURO-TTRansform: Secondary Endpoints at 65-66 Weeks!

Symptom severity (NSC total score)

t fis «| osas
Polyneuropathy disability (PND score) 8 5] (95% ct -107%10.58%) un
wove 222 0| BEE Historical placebo
m = Mn um w | ges
a a ae ns 3:2 o
waking unassisted walking walking monas Batter ZO .s
walking” Teaneor Zeanesor beandgen Y >
Tente 2 entehos 7 = >
Physical HR-QOL (SF-36 POS score) Time. wk
Eplontersen (n = 134) y ppp J Eplonterson
BL 7 Better $5 4
mae 2 Lo.
7 (95% CI 321074)
Historical placebo (n = 51) i 3é P<.001 at65 wk
AL di y E %
Week 65 ma À ‘Nutritional status (mBMI) =
"00
° = 5 E see ©
en pig
358 21 wwo:s2 rig? xot
Eplontersen vs historical controls, P< .05 at Worse 258 59] (95% Cl: 54610 110.8) Historical placebo
z P<.001 at 65 wk
week 65 y 200
o 3 y
Timo, wi
‘Means, filed cres; medians open damonds, Fest queres, lower and upper ends ol whisker: AMD, adusted mean dierenco à
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1. Goeino Tet al JAMA, 2023.390.1448-1488,

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45. NEURO-TTRansform: Safety!

Any TEAE
Leading to study drug discontinuation
Maximum severity of TEAES
Mild
Moderate
Severe
AEs of special interest
Vitamin A deficiency/decreased/abnormal
Ocular events potentially related to vitamin A deficiency
Thrombocytopenia
Glomerulonephritis
Leading to study drug discontinuation
Injection-site reactions
Flu-like symptoms
Abnormal liver function
Any serious TEAE
Related to study drug
Death
Death due to study drug

1. Goeino Total. JAMA, 2023:390:1448-1458,

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(n

Eplontersen

140 (97)
6(4)
74 (51)
53 (37)
130)
41 (29)
23 (16)
24 (17)
3(2)
o
o

12(8)
o
96)
21 (15)
o

21)
0

144)

Historical Placebo

{n = 60)
60 (100)
2(3)
7 (12)
40 (87)
13 (22)
12(20)
NR
9(15)
1(2)
293)
o

7(12)
2(3)
4(7)

12(20)
10)

o
o

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46. Revisiting Armando, a Man Aged 55 Years
Armando

Findings

Pergiéiént, ileteral nurnbness . Upon questioning, patient describes episodes
and tingling in lower consistent with orthostatic hypotension, as well
extremities as unintentional weight loss in the past year
Occasional episodes of sharp,
shooting pain in legs

Recent onset of weakness in PYP scan positive

feet and difficulty walking with . oo. o .
gradual loss of Genetic testing identified V30M variant

sensation in his hands

Medical history

Monoclonal gammopathy excluded

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47. Clinical Trials in ATTR Amyloidosis: Timeline’

ool Cl

oe | 2013 in 2015 > 2016 > 2017 a la 2020 > 2021 a 2023 > 2024 > 2025

NCT03336580
NCTO4360434
MED Aooramiis + ATTR is the target of intense research interest
Vutisian > :
ETS + The first phase 3 trials were completed just 6 years ago
Doxycicin+ ” EN odia de
[ Epiontersen ULA + Additional treatments and new indications are under investigation
= ~~
1. Tomasoni Dot al. Front Cordiovase Med. 2023:10:1154594. 2. Berk JL et a. Amoi, 2012:19(S1)37-38.3.Berk JLo al. JAMA. 2013:310-2858-2607. PeerView.com

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48. Key Takeaways

is occur commonly in th

involvemel it means that a very high index of suspicion is n

when initiated prom

tin amyloido
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