Targeted Therapy for Hereditary Transthyretin Amyloidosis Polyneuropathy (ATTRv-PN): You Don’t Want to Miss It!

Co-Chair & Presenter, Michelle C. Kaku, MD, and Chafic Karam, MD, discuss hereditary transthyretin amyloid polyneuropathy (ATTRv-PN) in this CME activity titled “Targeted Therapy for Hereditary Transthyretin Amyloidosis Polyneuropathy (ATTRv-PN): You Don’t Want to Miss It!” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/4b22DdQ. CME credit will be available until October 14, 2026.

1. Targeted Therapy for Hereditary Transthyretin

Amyloidosis Polyneuropathy (ATTRv-PN)
You Don’t Want to Miss It!

Michelle C. Kaku, MD Chafic Karam, MD

Associate Professor of Neurology
Vice Chair of Education

Icahn School of Medicine

at Mount Sinai

New York, New York

bé

Professor of Neurology

Chief, Neuromuscular Division
Director, Neuromuscular Fellowship
Department of Neurology
University of Pennsylvania
Philadelphia, Pennsylvania

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

Copyright © 2000-2025, PeerView

2. Our Goals for Today

Increase your index of suspicion for ATTRv-PN
using patterns of signs and symptoms across
organ systems

Equip you with strategies for diagnosing and
treating patients

Provide guidance on developing systems of care
for ATTRv-PN

Copyright © 2000-2025,

3. Transt

TTR) Is Prealbum

Trans — THY (roid) — RETIN ol)

Front View Side View
D

Transthyretin is a protein made

primarily in the liver, with a small

amount made in the choroid plexus

and retinal pigmented epithelium

« It transports vitamin A (retinol)
and the thyroid hormone
thyroxine to parts of the body

1.2hang KW ea JACC Base Tons! Si 2019443844, 2 Robbins J. Cin Chem Lab Hed, 200240:1169-1190..Songuinti al Bomeciina. zu anne. Peer View

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4. Amyloid Deposition Patterns in ATTRv and AL Amyloidosis??

Causes of Amyloid- Differential Pathology

Only ATTRv aI
Hereditary 9 Impaired ... … results in
Biceps tendon rupture Ea Orthostatic
*—— Autonomic nerves hypotension,
an Amoi dopostedin meninges E W een
ATTRv more than AL Sudomotor nerves Loss of sweat
Amyloid deposited in ocular ® Amyloid deposited in ... results in
‘comea and vitreous humor GPS
¡pee neuropathy
Amyloid deposited in ri
transverse ligament — > Kidney pericapsular vessels, Nephrotic
carpal tunnel syndrome medullafeorex interstitium, ten
tubular membrane basement yn
Amyloid deposited in lamina of Enteric autonomic.
cervical and lumbar spine — Gl tract plexus impairment
spinal stenosis
Muscle Weakness
AL r
Myeinalechmyoinaied Eoyneuropatny
Hepatomegaly and elevated tx
A kaline phosphatase
Acquired see, 7
1. Obici, Adams DJ Popo Nor St 2020.2585-101.2. Chompoopeng Pel. Ann Now. 2024:96423-40. PeerView

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5. logy of Transthyretin Amyloid‘

oligomers: A
& e. as © ue,
DUR =
Misfolded S

amyloidogenic
aaa monomers AMOPROUS Amyloid
aggregates fibrils

TIRMRNA TTRtetramer Folded dimers

+ ATTRv is the most common hereditary type of amyloidosis
+ Autosomal dominant, variable penetrance, and variable time of onset

+ Tetramer made of four identical monomers; monomers dissociate and form

5 Peripheral and/or
soluble non-fibrillar aggregates

automatic neuropathy
+ Aggregates change conformation to a B-pleated sheet, which then assumes
a non-soluble fibrillar structure that is deposited in tissues
Y Maron Beta Am Hoot Asse 2021:10.02105. 2 Mangan Fetal Nowe! Si 2022 Auf 2 85059808 PeerView

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6. ATTRv-PN Is a Highly Burdensome Disease
for Patients and Their Families’

Consider the broad impact of the disease when managing patients y
| May include disability, pain, and mental health challenges IM

= Long diagnostic odyssey with delays in appropriate treatment and
worsening symptoms

x Physical and emotional stress from progressively worsening pain,
a fatigue, and motor weakness

Severe QoL impact from uncontrolled pain, Gl dysfunction; and motor
difficulties affecting work, social activities, ADL, and life satisfaction

y
PO Family emotional toll: significant anxiety and distress associated with
caregiving, especially spouses

a Multigenerational burden due to heritability, creating a cycle of
concern, suffering, and loss

Riel Det Ophonet J Roe Ds 20211670. 2 Karam C ta. Muscle Nerve. 2024:59273297. PeerView

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7. When the Goal Is Early Identification
The Neurophysiology of ATTRv-PN
and Best Practices for Early Diagnosis

8. The Modern Geographic Distribution of ATTRv Ge:

n Patterns

a | Leu111Met
ty

Val1221
E A e
160Ala „ValSoMet à Yle58Leu \ À voisonet
ers” pare Suwa ra A
Vaz Sc
Us coratesn

Yalzomet

de "e

OSA eL tit deBokey Corona .2022.18:1.28.2.Ni.lampoktismuaton com, 3. Kaku MO 0 al Apio 202229:14-89 PeerView

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9. ATTRv Has a Variable Phenotype a
of Nomenclature’

wo System

+ Two systems of nomenclature are
used to refer to ATTR variants:
DNA-level and protein-level

* The numeric location used in the
protein-level nomenclature is 20
units higher than in the DNA-level
nomenclature

| For example: V1221 is the
DNA-level nomenclature and

ont Neurologic dde the corresponding protein-level |
Phenotype nomenclature is p.V1421; |
both refer to the same
genetic variant2.3

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1. Semigron M. J Am Col Cardiol 2016.68:173.75.2. Lopes LR ot al. Amy. 2019;28:243-247. 3. Gent Lt al. PLOS Ono. 19:00202435.

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10. Neuropa in Amyloidosi

Distribution of Sensory

7 Mr Loss in ATTRv-PN25
+ Stocking-and-glove polyneuropathy: progressive,
symmetric, length dependent sensorimotor neuropathy
+ Early (V30M): small fibers affected
- Distal sensory loss with selective involvement of pain and
thermal abnormalities
+ Later (V30M) or simultaneously (other ATTRv):
larger myelinated sensory and motor fibers affected
= Impaired light touch, vibration, joint position sensation, and
eventually distal motor weakness that progresses proximally
Decreased Absolute loss of
pain and touch pain and touch

4. Champoopong P et al. Ann Nowra. 2024:96:423-440. 2. Benson MD. Genetics: cinical implications of tansthyresn amyfoiosis. PeerVi
In: Richardson SJ, Cody V (eds). Recent Advances in Transthyretin Evolution. 2009. Springer: Berlin, Heidelberg. 3. Adams D et al. Not Rev Nourol. 2019:15:387-404. eerview

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11. Red-Flag Signs/Symptoms/Medical History Raising Suspici

of ATTRv in Patients Presenting With Neuropathy

TER Rapid rate of polyneuropathy progression

TE Early autonomic dysfunction
- Erectile dysfunction
— Lightheadedness from postural hypotension
= Changes in bowel movements and GI symptoms
(often dismissed or misdiagnosed as IBS)

I Bilateral CTS and/or prior surgery for CTS
- Recurring after release surgery
- Present in other family members

TEM Accompanying or prior history of symptoms from
other systems
- Cardiac: shortness of breath, arrhythmias, CHF with
preserved EF, features of hypertrophic cardiomyopathy
- Musculoskeletal: rotator cuff, biceps tendon

= Ophthalmologic: vitreous opacities, periorbital hemorrhages

- Renal: renal failure and proteinuria
— Gl: unexplained/unintentional weight loss,
constipation, diarrhea

1. Karam © ot al. Muscle None. 2024.69273-287.

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B® Motor weakness
- Predominant or early in the course
of neuropathy

B® Family history of ATTRv amyloidosis

A Prior family history of unexplained
= Rapidly progressing polyneuropathy of
unknown cause
— Heart failure
- Sudden cardiac death
- Cardiac arrhythmia

JR Lack of response to specific
treatments for other neuropathies
(eg, IVIg for CIDP)

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12. How Do Patients Present?

First Manifestation of Disease Associated Symptoms at Time of CTS Release

GI
Cardiac 10%
14%

None
40%
Cardiac
20%
Autonomic
24% Autonomic
10%
1. Karam © et Newel Ci Proc, 2019:9:308:19. PeerView

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13. ATTRv Is Often Misdiagnosed: OHSU Experienc

+ The initial diagnosis was
incorrect in 68% of patients
with pathogenic variants

+ The rate of misdiagnosis
was 45% when considering a
modified definition of
misdiagnosis (2 or more
organs involved)

+ Atotal of 47 different
diagnoses (15 unique) were
documented prior to ATTRv,
translating to an average of
2.2 incorrect diagnoses per
patient (ranging from 1-8)

1. Karam C et al. Amyloid 2020:27:69-70.

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Misdiagnosis

PN From" Cardiac CTS" Fibre. ‘ALS Other

OerChuse Disease Associated myala autonoma
E Win

one Stor
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14. ATTRv Diagnosis Is Often Delayed:
losis Center Experience’

BU Amyloi

Retrospective review of neurologic profiles of all patients with TTR
mutations in the center from 2016 to 2018

« 92 patients with 19 different TTR mutations
— V1221 > T60A > V30M

Patients Reporting Symptoms, %

CTS symptoms

Large fiber neuropathy
Bilateral CTS symptoms
Neuropathy in V1221 mut

Dysautonomia
1. Kaku MC el. Amt. 20222:184-180.

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73

Average Delay Between Onset of
‘Symptoms to ATTRv Diagnosis, y

6.7
29
Carpal tunnel Large fiber
syndrome neuropathy
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15. Blood Tests‘?

Hypothetical Course of NL in a TTRv Carrier Who
+ BNP Develops ATTRv Amyloidosis With Polyneuropathy

+ Troponin

+ Creatinine

+ Urine protein

+ SPEP, IFE, FLC
+ TTR (pre alb)

+ B12, A1C

+ SNFL

1. Boronds Metal. Int J Mol Se 2024,25:3770.2. Ticu S el al. Nouology.2021.96:0412:2.

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Levels of NfL in Healthy Controls and P:
Treated With Placebo or Patisiran Over

NL Level, logs

7 Healthy Placebo Patisiran Placebo Patisiran Placebo Patisiran:
PeerView

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16. ATTR-PN Diagnostic Flowchart! Download the

diagnostic

flow Practice

Suspected Amyloid Polyneuropathy 72)

83 NA

+ + y
TTR VUS, TTR pathogenic TTR pathogenic variant, TIR €),
no gammopathy variant, + gammopathy no gammopathy no gammopathy

I |

=
— Tissue biopsy
AO |

+

Congo red positive L_ GradeOor1 Grade2or3
Start TTR targeted (ifATTRwt
treatment spected)

1. Karam Got. Aogured and Genetic Amis Neuopates. Noel Cial press PeerView

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17. Early Diagnosis

How | Think, How | Treat

18. Case Study: Man, Aged 64 Yea
Peripheral Neuropathy

, With P

Presentation

+ Neuropathy
- Numbness in feet began 3 y ago sl fl
(112022); slowly spread to involve Family History
the entirety of his feet + Father developed neuropathy

that eventually involved his hands and
lead to functional impairments in his 70s
(eventually needed a wheelchair)

- Passed away with congestive heart

— Significant pain in the feet at night that
affects his sleep

- Mild numbness in his fingertips

— Outside neurologist diagnosed him with failure in the setting of a lung infection;
prediabetes-related neuropathy unclear if he had longstanding
+ Gl: constipation, several days without bowel heart failure
movement + Two brothers; neither has any symptoms
+ CV factors thus far

— Orthostatic hypotension (stopped BP meds
but still has issues)

— Several years of ED (treatment resistant) PeerView

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19. Case Study: Examination Findings

=e ‘Summary Table
Examination a fey Te [ae [Oo TA "par Then a
+ Normal strength (apart y | un ES proue fran fr Ree |
from EHL 4/5 bilateral) En "PEPE e
teams)
4 Tensor LOL NL | aa bill kid
* Normal gait ha bad bad bad Nl cal LL
+ DTRs absent at ankles = = =
Motor Nerve Conduction Studies
+ Pinprick sensation absent at the Were? hE I Ic
toes up to midfoot on both sides TA] TEA
Fans — UE m mm:
+ Light touch sensation normal ane a HE En A
+ Proprioception sensation normal
+ Vibration sensation slightly
reduced at the fingers and at the
toes on both sides
+ NIS= 16 PeerView

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20. Case Study: Man, Aged 64 Yea
Peripheral Neuropathy

, With P

Presentation

+ Neuropathy
- Numbness in feet began 3 y ago sl fl
(112022); slowly spread to involve Family History
the entirety of his feet + Father developed neuropathy

that eventually involved his hands and
lead to functional impairments in his 70s
(eventually needed a wheelchair)

- Passed away with congestive heart

— Significant pain in the feet at night that
affects his sleep

- Mild numbness in his fingertips

— Outside neurologist diagnosed him with failure in the setting of a lung infection;
prediabetes-related neuropathy unclear if he had longstanding
+ Gl: constipation, several days without bowel heart failure
movement + Two brothers; neither has any symptoms
+ CV factors thus far

— Orthostatic hypotension (stopped BP meds
but still has issues)

— Several years of ED (treatment resistant) PeerView

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21. Case Study: Genetic Test Results, 3 Weeks Later

(©) RESULT: POSITIVE

‘One Pathogenic variant identified in TTR. TTR is associated with autosomal dominant transthyretin
amyloidosis.

Additional Variant(s) of Uncertain Significance identified.

GENE VARIANT ZrGosımy VARIANT CLASSIFICATION
TR EG (pValsoMer) heterongeus PATHOGENIC
pura BOT (PTMI) heteronygous Uncertain Significance
‘About this test

This diagnostic test evaluates 102 gene(s) for variants (genetic changes) that are associated with genetic disorders. Diagnostic
genetic testing, when combined with family history and other medical results, may provide information to clarify individual risk,
support a clinical diagnosis, and assist with the development of a personalized treatment and management strategy.

+ Reason for testing: personal history of disease
+ Test performed: sequence analysis and deletion/duplication testing of 102 genes
(comprehensive neuropathies panel) PeerView

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22. Case Study: Imaging S Ss

+ Echo IVS 1.4 cm (nl < 1.1 cm), EF 65%, strain imaging suggestive of infiltrative process

+ NT-proBNP 433 (nl < 125 pg/mL), tropT normal, NFL levels 53 pg/mL.

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23. 3/2022
+ Started patisiran and vitamin A
+ TTR levels (prealb) = 5 (nl 10-36)

112024

+ Most recent follow up

+ Stable neuropathy (NIS 14), no AEs
with vutrisiran, mild OH

+ TTR levels 5.6, BNP 294 (nl < 376)

o

9/2022
+ Stopped patisiran
+ Started vutrisiran

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4

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24. Take-Home Messages From Our Case

( Y Maintain a high level of suspicion

O y Utilize genetic testing and biopsies |

be 1
e Diagnose patients as early as possible (treatable neuropathy) |

ae prevents disabilities and decreases mortality |

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25. A Focus on Clinical Trial Evidence
Informing Treatment Decisions in ATTRv-PN

Copyright © 2000

26. Management of ATTR-PN Requires a Two-Pronged Approach

Amyloid neuropathy

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

+ Eplontersen, inotersen,*

patisiran, vutrisiran

+ Pregabalin + Compression stockings, abdominal
+ Gabapentin binders

+ Duloxetine + Increased sallfluid intake
+ Tricyclic antidepressants + Salt tablets
+ Fludrocortisone
+ Midodrine
+ Droxidopa
+ Pyridostigmine

No longer avalabl to patients in ho US as ol Segtomber 27, 2024.

1. Kitloson MM e al. J Am Cal Card. 2023:81:1076:1128.

2. Vyndamax (atamicis)Proscribin Information. hip www accosscata Ia govicrugsatida_docs/abel2028/211996s002.21216 50021 pot

3. Attruby (acoramicis) Prescribing Information. htips:/iwew accessdata.fda govidrugsatfda_docs/label2024/216540s0001bL pdf. PeerView
4.Pan Y tal. Cardiovasc Diabetol.2022,21-170.

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27. Therapies Targeting the Amyloidogenic Cascade’

Pathogenic process

Folded Misfolded
TTR monomer TTR monomer
4 ‘TTR tetramer 4
TTR production A dissociation y ÑO
—— > == +
Prevent TTR TTR mRNA Silencers, TTR Stabilizers
Mutation #Eplontersen (ASO) Y Tafamidis Amyloid Fibril Degraders
Liver transplant * Patisiran (siRNA) Ÿ Acoramidis Monoclonal antibodies
Gene therapy W*Vutrisiran (siRNA) Diflunisale (investigational)
(investigational)
Therapeutic Strategies and Mechanisms of Action
Y inacato to eat ATTRVECA of ATTRECA. » Indkated to eat ATTRMPN. abuse.
1. Adams Dot. at Rev Neurol 2018:18:387 404 2. Navi Ncolau et al. Cur Opn Cardo! 2018:3:57 579. PeerView
3 Kadakia KT el J Am CoN Carol 2025.85:1907-1910.4- Bok JLo JAMA. 2013 310:28582687

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28. TTR Silencers Are Highly Effective at Re ng Serum TTR Levels

APOLLO HELIOS-A NEURO-TTRansform
(patisiran)! (eplontersen)?

A
&

&

&
8

Patisiran (n = 42)

Patisiran Eplontersen

(25th, 75th Percentile), %
&

B
&

Vutrisiran (n = 122)

Mean Change in Serum TTR, %
Beeaeeb sees og

Mean Change in Serum TTR Concentration

Mean + SE Change From BL in Serum TTR (mg/L), %

Time, wk Time, wk Time, wk
1. Adams Dei. Eng J Med. 2018:379:1-21.2. Adams Det Anyi. 2029.05... Coo ea JAMA.2029:30-1449-1458 PeerView

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29. + 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 n 0.3 mg/kg IV Q3W
- 1.4y since diagnosis, median

- 43% V30M 2A
- 0.9% V1221
Polyneuropathy Disability <I!lb
N = 225
1.Adams D tal. Engl Med. 2018:379:1121 PeerView

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30. mNIS+7 Norfolk QOL-DN Score

144827
35] Diference at 18 mo Nes 2°] Diferenee at 18 mo nee
+ | (eisen pacodo); (patsren-lacabo}
8 Boss PO 4
> Be
E ee 140221 és | ro (N=65)
En (N=67) FE
po E.
g En ÉS
gs 53
Io FE
s
3 Patisiran
“0 0
aL mo 18 mo eL 9 mo 18mo
Baseline mNIS+7: 89.9 + 41.5 patisiran

74.6 + 37.0 placebo

1. Adams Det NEng Y Med. 2018:370:121 PeerView

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31. APOLLO OLE: Patis

Total NIS2 Norfolk QOL-DN
5 Peco penis
o i pers
, El Te
pl Praceb patents APOLLO placebo jo i APOLLO placebo
2 an 2
230 H à
ja 5 15
ve Eo wore À 9
¿
Co ES
$1 en
85 APOLLO pasan
o Better hd # APOLLO patisiran
3 —
AAA E E
ea ea 2 GLO Gib Yeart Your? Years Years Yeo

EI) SOL => a),

Rae Ota Au New 20258222828, PeerView

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32. APOLLO OLE: Patisiran Reduced Worsening in PND Score

Change in PND Score From Parent Study Baseline and Global OLE Enrollment to Global OLE 24 mo

Assessment, n (%)

PND score
Improved
No change
Worsened

Missing

A. Teau S ot al Amyloid. 2024311

PeerView.com/AJT827

From Parent Study Baseline

APOLLO-

Placebo
(n=77)

o
11 (14.3)
23 (29.9)

43 (55.8)

APOLLO-
Patisiran
(n = 148)

12 (8.1)
67 (45.3)
38 (25.7)

31 (20.9)

Phase Il OLE-
Patisiran

(n=27)

2(7.4)
16 (59.3)
7 (25.9)

27.4)

From Global OLE Baseline

APOLLO-

Placebo
(n= 49)

4 (82)
24 (49)
6(12.2)

15 (30.6)

APOLLO-

Phase Il OLE-
Patisiran
(n= 25)

Patisiran
(n = 137)

12 (8.8) 2 (8)

67 (48.9) 16 (64)

38 (27.7) 7 (28)

20 (14.6) 0
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33. a TTR Varian

« 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
— 2.2 since diagnosis, median
= 45.1% V30M
- 4.3% V1221
+ NIS5 to 130
Polyneuropathy Disability <lllb
Karnofsky Performance Status
score 260%

N= 164

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

Vutrisiran 25 mg SC Q3M

Patisiran 0.3 mg/kg IV Q3W

Premedication 60 min prior to infusion

Historical placebo

1. Adams D et al, Amyloid 2023:30:1.

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34. HELIOS-A: Vi

mNIS+7 Norfolk QOL-DN
19828)
28.09 (228) 2
go» A een
Es E
SE m 1476200) SE
3 wesen. BR
ir eo A
Be Pesos 55
cad 33
go à 13
ia E | vatican
Sg Pe a 0.48 (150) 38 |
‘av one om as
No. at Risk No. at Risk
Vunsen 22 va m2 Vatrstan 121 114 m
meo y e si nl 7 6 “
Baseline

+ 60.6 + 36 vutrisiran
+ 74.6 +37 placebo

1. Adams Dal Amat 20:30:10 PeerView

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35. NEURO-TTRansform: Phase 3 Trial of Eplontersen in Adults

With ATTRv-PN12

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 0 dl Open-label
sequence variant : De
— 25 y since diagnosis, mean lnotersen™
— 59% V30M, 3% V1221 (n= 24) Eplontersen
+ NIS 10-130 points
+ Coutinho stage 1 or 2° or 20-wk
Weiss NEURO-TTR historical placebo ee
- Historical controls aa ——
Study Timeline, wk
+ Placebo group from week 66 1 = oa = z T Is

endpoint of phase 3 RCT
MECC any

+ Covinto sage 1, ambuaony witout assistance Coin sigo 2, ambulatory wäh assistance; NS, cor range 0244, higher vales nat poorer funcion.
À Holen o ange arado o patents the US as el Sptonber 27, 200% i
1 Goethe Tet JAMA, 2023 200.18 498. PeerView

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36. NEURO-TTRansform: Eplontersen Met Prim

at 66 Weeks!

Norfolk QOL-DN Total Score

mNIS+7 Composite Score

E : -24.8% AMD: -19.7%
Bd {| (95% Cl: 31.0% to-18.6%) (95% Cl: -25.6% to -13.8%)
E a] P<.001 P<.001
E Worse
Worse $_ 2 Historical placebo
85%
2s
#80
o
0
poner 2 5
do.
° E o 5 5 de
Timo, wk Time, wk
Baseline mNIS+7
+ 81.34 43.4 eplontersen
+ 74.8 + 39.0 historical placebo
festivas quarts, lower and upper ends of whiskers PeerView

‘Means, fled cris; medians,

1 diamond
1. Coco Tot ol JAMA. 2023 280-1418 1458,

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37. NEURO-TTRansform: Eplontersen Met Secondary Endpoints

at 65-66 Weeks!

AMD: -82%

Polyneuropathy disability (PND score) Worse 358 9] (5%CI:-10.7% 10-58%) Historical placebo
ee Pe 001 at 6d wk
CR CT Bus me a | ES
Unassised Impaired Assisted Assisted Comimodio Za 0 =
waking unassisted walking walking wheakcha or Better Yi 6 Eplonterson
waking dome Zoo Den Ÿ 3
Yeuten Zenienen hy = à
Physical HR-QOL (SF-36 PCS score) ‘Teme, wit
Eplontersen (n= 134) 4 ska y N Epoersen
de +

AMD:53

(95% CI 32 to 7.4)
P< 001 at 65 wk Historical placebo.

Eplontersen

Porcentage of Patients

AMD: 82:7 kom? x gl.
Eplontersen vs historical controls, j (95% CI 516 01108) Historical placebo
<.001 at 65 wi

P<.05 at week 65

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E
Time, wk
1. Coulno Total. JAMA, 2023;390:1448-1858,

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38. NEURO-TTRansform: Eplontersen Prevents Clinically Meaningful

Deterioration in Measures of Autonomic Neuropathy’

‘Change From BL. Mean (+ SE)

‘Autonomic Component Score Change From BL Eplontersen Placebo
mNIS+7: HR with deep breathing h
Week 35. ' 1 22401 011604)
Week 66 1 40 18 | 0101) 0.1 (20.1)
Week 85 ! | 02609 =
Norfolk QoL-DN: autonomie neuropathy H
domain ñ 102602) 04409
Weck 35 \ Tg 59 | 08602) 0804)
Week 66 1 40 m = 1 03602) =
Week 85 4 +e 1
1
NSC: autonomie Gl and UI domain 106
Week 36 1 HUA : 410604) 031402)
Week 66 1 43 am {a 23801) 05(202)
Week 85 1 == 1 0304) =
1 1
NSC: autonomie domain other than GUL 1
Week 35 Q os 0.5 (40.2) 0.8 (£ 0.2)
Week 38 i $4 [phone])
Week 85 i 04 (20.2) -
HO 075 05 02% O0 02% 05 07 10 1% e a
=—— ' — 2
Improvement Worsening Eplontersen Placebo
nett n=9

| Minimum threshold for clinically meaningful improvement _ ! Minimum threshold for clinically meaningful deterioration. A
1. Winery tl Ampli. 20253229-9. 2 FolajonF el Muscle Nero. 202471:1:96-107, PeerView

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39. Individual

Administration

Agent Dosing Ro DtE

SC injection once monthly

1
Eplontersen' Fixed via autoinjector

Lipid complex injection via
IV infusion every 3 weeks;
premedication needed

Weight-

cise
Patisiran based

SC injection, every
3 months at infusion clinic;
no premedication needed

Vutrisiran Fixed

Vitamin A
Supplement
Needed?

Y

Y

ng Current Targeted Treatments for ATTRv-PN!

Cardio- Newropath Most Common
myopathy Ina 5 Y AEs in Clinical
indication? !Nieation Trials
FDA Fast Y | vitamin A,

Track vomiting

Upper respiratory
x Y tract infection,
infusion-related
reactions

Pain in extremity,
arthralgia, dyspnea,
| vitamin A

Y Y

Download the Practice Aid for more

info on targeted therapies

1. aus (eplontersan) Preserbing Information. ps: accessdat fda govidrugsatida_ doca/abeV20287217 328010150041 pc.

2 Onpatto(paisan) Prescribing information. tps wvr-accessdat id. govidrugsatida_docsabel’2023/210922s0120 po,
3. Ama (wirsiran) Preserbing Information. Hips ww accessdala fda govidrugsat

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, docs/aboV2028/21551550081a pal

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40. TTR Stabilizers: Current Evidence, Future Promise

Are There Polyneuropathy Benefits to Available ATTR-CA Agents?

Medication Topline Results Randomized Controlled Clinical Trial Experience

+ Reduces PN. Diflunisal significantly reduced the rate of neurologic deterioration on NIS+7, and

eae Progression slowed decline in quality of life (Norfolk QoL-DN) vs placebo over 2 years in a
ET | Met mixed population of ATTRv types and disease duration (early vs late)!
ea + Did not evaluate mortality outcomes

+ Some effect * FX-005 trial missed both co-primary endpoints at 18 months in early-stage ATTRv-

on PN V30M (NIS-LL “responder” rate and change in Norfolk QoL-DN), but most
progression Secondary endpoints favored tafamidis vs placebo?
+ Preserved neurologic function and QoL in the efficacy-evaluable subgroup;
+ Improves delayed neuropathic progression was seen in the open-label extension, FX-0062°
survival in. Approved for treatment of ATTRv-PN in Europe, but not US*
ATTR-CA + Improves survival in ATTR-CA®
+ Work in + ATTRibute-PN was withdrawn before completion®
progress + Improves survival in ATTR-CA?
for PN + ACT-EARLY study will evaluate asymptomatic carriers of pathogenic TTR
EZB |, temas variants to assess whether acoramidis can prevent or delay the onset of either
AiO ATTR-PN or ATTR-CM vs placebo"
ATTR-CA + Estimated primary completion date: October 2031

1. Ba ta JAMA. 201:31026582067. 2. Coso T at a. Nour, 201279785792. 3. Coëho Teta. Neuro! 2013260 202-2814
{os ven ma ep ut curator fomatontyraleparsroaciomaion on pa Mata Seta, N Eng Mod 208481007018 Do oi
So Joao gos NOTOMEEETS. 7. Glow JD eo Mg J Med 20243001821, Moral pus 70696308 eerView

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41. ical Trial Outcome FDA Status

APOLLO (post-hoc) | LV strain/thickness,
Patisiran'2 4 NT-proBNP Declined
APOLLO-B | decline in 6MWT approval
Patirisan?S# Stable vs worse KCCQ-OS
| death from any cause and recurrent CV events
ee | decline in 6MWT Approved
| decline in KCCQ-OS
NEURO-TTRansform (post-hoc)’
Eplontersen 1 LVEF and stroke volume Fast Track
CARDIO-TTRansform A A F F
Eblontersen® Estimated primary completion April 2026 TBD
FDA denis prall atan for crckomyopaty base on phase 3 APOLLO 8 Wal Historia placebo Used as tha comparto
1 Salomon SO a Cova 20160940). À Mourssawa Met al Alta Cargo! 2019048042, 2 Mauer NS eral N Eng! J Med. 2023:300:1559-165.
4 Mona orpatsran teense. 8 Long Set al Er Hear J Sup 2024 26(upp\2)u00098 002 6. Fontana Metal N Engl Med 20252820944 PeerView
7. Masri etal. J Card Fal. 2024;30:975-960. 8. hitp:iclncalals. govistudyNCTO4136171, eer

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42. Current Status of Potential Future Therapies for ATTRv-PN

Nexiguran ziclumeran Nucresiran Coramitug
(NTLA-2001)** (ALN-TTRsc04)*5 (NNC6019-0001)3+

+ Gene therapy; silences TTR Long-acting TTR silencer + Amyloid fibril depleter
expression

+ Phase 1 study to evaluate safety,
tolerability, and PK/PD is in progress

Phase 1 results showed rapid, + Phase 2 results in ATTR-CA
sustained knockdown of TTR levels expected 2025
over 180 days or more

(N= 72)
+ MAGNITUDE-2 Phase 3 study in ATTRv-PN
— Placebo-controlled phase 3 RCT pen zeig 20
(N=50)
— Single-dose study

— 12-18 months duration
— Endpoints include NIS, changes in
TTR levels Favorable effects on serum TTR level, KCCQ-OS, and 6-minute walk

+ Study started November 2024 distance were observed over 12 months in a phase 1 study of

os PU ELD a single dose of nexiguran ziclumeran in patients with ATTR-CA®

1. os eines govstcyANCTOAG0105I. 2 ps Ilicarats gout NCTOSET2237. 9. Kacain KT ta Am Col Card 202565:1907-1910,
4 itor onpnp contorted 202507 2628 ATTR Cinca Tractor Fur Sides pl 3 ip inver yon compas rise c= 2654 Rey
$. Fontana Mot al N Eng! Med 2024 2912231-2241 PeerView

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43. Choosing Treatments

How I Think, How | Treat

44. Symptoms
+ Pain and sensory issues
- Progressive numbness starting in
hands (2021), spreading to elbows, knees
= Cramps in calves
— Electric-shock sensations at night
+ Motor impairment
= Difficulty gripping, buttoning, tying shoes
— Must look at things to hold them

+ Sensory impairment: impaired temperature
sensation in hands, visual floaters

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Case Study: Man, Aged 68 Years, With Rapidly Progressive PN

Additional Medical History
+ Mobility
— Requires walker (-6 months
post-symptom onset)
— Nnable to climb stairs
+ Weight loss
— 30-40 pounds over 2 years
- Decreased appetite and nausea
immediately after eating
+ Gl issues: sudden-onset diarrhea, nausea,
early satiety
+ Autonomic dysfunction
- Urinary hesitation
- Postural hypotension (BP as low as 60s)
— Syncope

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45. Case Study: Examination Findings

MI II

Examination
+ DTRSO Deltoid Hip flexion
+ Pinprick sensation reduced at the Triceps Hip abduction
fingers and absent at the toes on :
both sides Biceps Hip adduction
+ Light touch sensation reduced at Wrist extension Knee extension

the fingers and reduced at the
toes on both sides
Proprioception sensation normal
at the fingers and reduced at the
toes on both sides

Vibration sensation normal at the

fingers and absent (0) at the toes, Abductor pollicis brevis
ankles, and knees on both sides

Wrist flexion Knee flexion

Finger extension Ankle dorsiflexion

Finger flexion Ankle plantarflexion

Interosseoi Toe extension

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46. Case Study: Examination Findings, cont'd

Sensory Nerve
Conduction Studies

Motor Nerve
Conduction Studies

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Weve Sites
Index (Anüdromie)

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47. Case S

ly boratory Workup

Proximal weakness root involvement and/or

Genetic Testing evidence of superimposed myopathy
+ Pathogenic variant: c.349G>T; zT n

p.Ala117Ser (TTR gene) 5 rs
Skin Biopsy Srl under

fluorescence
microscopy with
Texas red filter
. Adipose biopsy,
Congo red statin
Positive for
amyloid, light
microscopy
Adipose biopsy,
Congo red stain
positive for
amyloid, showing
apple-green
birefringence
under polarization
microscopy
Surat nerve
biopsy, toluidine
blue stain

+ Congo red positive (amyloid deposition)

Laboratory Results

+ TTR level: 15.2 mg/dL (normal >18 mg/dL)

+ NT-proBNP: 211 pg/mL (normal
<124 pg/mL)

Echocardiogram

+ Left ventricle: normal size, with mildly
increased left ventricular wall thickness,
consistent with concentric hypertrophy

+ LVEF: 65% (normal)

+ Global longitudinal strain: reduced * PeerView

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48. ATTRv-PN Progresses Much More Rapidly Than DPN or CMT

Weighted Mean Annual Rate of Change in NIS Total Score

Author voor

cur

Soren 2005 272104310248) ot
‘Shy 2008 1.37 (0.62-2.12) 22.34
En 202 MISE TS
Sipe (sms) fat 002 4) ‘00
on

Hemandez-Ojeda 2012 > 3.04 (6.74 to 12.83) 570

for 1 = anne Am
Ziegler 1999 q -7.49 (-10.28 lo 4.70) 20.05
Ziegler 2011 H 0.15 -007 100.38) 2574
Koon 220 a Tetozewzet) 2102
‘Subgroup (I-squared = 94.6%) -1.96 (-4.60 to 0.69) 100
arr en

a 2018 1878 (201740) 902
bax 28 en war
Lenta 2008 ES
Koon 2020 feu) 1620
‘Subgroup (I-squared = 80.8%) 11.77 (7.24-16.30) 100

EEE ,
ne MC Nowet 2021210, PeerView

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49. ke-Home Message From Our Case

Management Takes a
Two-Pronged Approach? Treatment Plan | Gp )
+ Start vutrisiran (first

injection 5/2024; delay
due to insurance) and

A Re vitamin A
ie |
+ Take loperamide
Disease-Directed Symptoms for diarrhea
Therapy + Orthostatism + Midodrine 2.5 mg
+ Reducing TTR + Diarrhea/constipation three times a day
production + Urinary hesitation + Pregabalin 75 mg
+ Pain at night
1. Karam ota Mal Non, 20 60279-2872 Kern Ve An Cal Crd 202081: 176-1128 PeerView

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50. Developing Multidisciplinary Amyloid
Clinics for Individualized Management

Michelle C. Kaku, MD
Associate Professor of Neurology
Vice Chair of Education
Y Icahn School of Medicine at Mount Sinai
New York, New York

Copyright © 2000-2025, PeerView

51. tQ) * ATTRv-PNisa multisystem, progressive disease that may affect the
© nerves, heart, Gl tract, musculoskeletal system, kidneys, and eyes—
ES neurologists can't go it alone

Centralizing care improves diagnostic accuracy, accelerates therapy,
reduces hospitalization, and mitigates inequities!-3

As of August 2025, there were only 56 amyloid clinics in the US
A + Of these, 52 have a neurologist on staff

1. Karam ea. Masco Nono 2024602792672. Puyol ta. Rov Chor Mod 20242581. 3, Vera nc Mot a. Orphanot J Rae Dis. 20211025. ï
À an myamlodospainnderorfeenters PeerView

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52. Multispecialty Team and Clinic Infrastructure’

RT N

lien) m] Consider establishing

Core multidisciplinary

room MS Meetings to iscuss Cf] Q
shared patients

Infusion
Extended Et
Team

+ Include EMR order sets (red-flag alerts,
standardized diagnostics), multidisciplinary
care pathways

+ Use disease-specific screening tools, standardized
care protocols, and integrated referrals

Neurologist

Cardiologist

Download the Practice Aid for more
info on multispecialty approaches

1. Karam el. Muscle Nono. 2028 89-27-27. 2. Phya ot al. Rov Carovese Med 20242551 PeerView

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2000-2025, PeerView

53. lag Screening a

Red flags

+ Rapid neuropathy progression

+ Autonomic dysfunction

+ Bilateral carpal tunnel syndrome

Rule out AL

Clinical amyloidosis

evaluation (monoclonal

protein screen)

1. Karam © et al. Muscle Norve, 2024,69:273-287.

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stic Workflow

HFpEF
Weight loss
Gl symptoms

Cardiac
scintigraphy
(PYP/SPECT) +

genetic testing

Biopsy as

needed

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54. Monitoring a

Neurologic Monito Cardiac Monitoring

«NIS

+ PND

+ R-ODS

+ COMPASS-31

+ Autonomic screens every
6-12 months

E

Treatment Pai

ay

+ NT-proBNP
+ Troponin

+ Echo

+ Scintigraphy
+ Cardiac MRI

+ Renal labs annually

é

+ Initiate TTR gene-silencing
therapy (ie, patisiran,
vutrisiran, eplontersen) as
first-line

+ Utilize stabilizers (eg,
diflunisal) as bridging

+ Symptom management

1.Karam © ot al. Muscle None. 2024.60 273-287.

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55. Estimated Expenses, Staffing, and Revenue

for an Amyloid Clinic!
Estimated E: id Re fe

+ Costs: initial investment of $1.5 million to $5 million aN Chic e D

in the first year 8
+ Staffing: 5-7 FTE staff for a small clinic managing EN

100-200 patients/y = Toll revenue

- Neurologist

- Cardiologist

= NPIPA

- Genetic counselor (part-time)

= Radiologic technologist (if imaging in-house)
- Clinic manager

— Receptionist/medical assistant

- Pharmacist (part-time)

+ Revenue: potential revenue could range from $500,000 to
$50 million/y, depending on the clinic size, patient volume,
and types of services offered, with targeted therapies and

diagnostics contributing heavily to income 1 2 Tim 4 5
ime, y

y GhatGPTS const m Hear Busnes Nous, AMA estates, BLS sass, Per

roy cogen eu te Aneto Sc dl ethene Enge ha, comet! rel seso Gare, Govt Aa Pecan Fee Scheu eae

Swan desa, Do

Amount, Millions of $

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56. Amyloid Clinics Provide Num

for Neurology Residents and Fellows’

Supports education and development of
future amyloidosis specialists

+ Patient Evaluations: conduct neurological exams
(eg, NIS, R-ODS)

History Taking: review symptoms (eg, sensory/
autonomic dysfunction) and contribute to diagnoses

Supervised Procedures: assist with nerve
conduction studies and sensory testing

Follow-Up Visits: participate in patient follow-ups,
adjust treatment plans under supervision

Case Discussions: present complex cases and
collaborate with multidisciplinary team

> Increases patient access to care

1. ChotGPTS consults the flowing resources: ACGME standards for residency and folowship programs,

maneging complex neurological diseases, Mayo Cane waning model or residents and felows n specialized care, NI Wainng and fotos programs in rare diseases,

OM report on team-based care, WHO guidelines on patient-centered care, ARC guidelines on cinc setup and paint cae, JAMA, and Annas of intemal Medico,
0Request%sZ0lork20Appcations pe.

2 Ms mad statusplus.comiealtabe formallSA%202028-2027%420Felowship%20-%2

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us Training Opportunities

How to involve residents and

fellows in amyloid clinics

+ Include as part of clinical rotation
in neurology, cardiology, genetics

+ Provide hands-on experience with multidisciplinary,
multisystem, and collaborative care

Supervise management of complex patients and
participation in multidisciplinary team meetings,
case conferences, and grand rounds

Contribute to clinical research

+ Triage patients

> Fellowship funding available from the
International Society of Amyloidosis?

AGP guidelines on teamwork in patient caro, AAN guidelines on

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57. Multidisciplinary Care in Action

How I Think, How | Treat

58. y History of ATTRv

Presentation ti Hi
on y Family History
+ Asp18Gly ATTR genopositivity + Mother developed

found in 2011 due to family history

hydrocephalus at age 43
+ Asymptomatic until 2016, when - Had a VP shunt placed
he developed - Repeated blockage required three
o . replacements
anne one fect — Analysis of the shunt revealed
— Multiple episodes of vertigo congophilic material +Congo red

+ She required orthotopic liver
transplantation at age 55

- Progressed to develop cardiomyopathy
— One episode of dysarthria and congestive heart failure

- Died 4 years after liver transplant

— Cognitive difficulties/word
finding difficulties

— Developed intermittent
unilateral tinnitus

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59. Case Study: Examination a

Laboratory/Imaging Work-up

Examination

+ Neurologic exam
was normal

+ Discs were normal
+ NIS=0

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Prealbumin

CSF protein

Fat pad aspirate

EMG

Negative

EEG

Negative

Retinal
ophthalmology exam

Negative

ECG and TTE

Normal

Brain MRI with and
without contrast

Hydrocephalus, leptomeningeal enhancement surrounding
brainstem and basal cisterns extending into upper cervical spine

MRI orbits

Negative

OCT

Normal macular volume and fovea thickness bilaterally

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60. N
o All Why tolcapone for
— Started on diflunisal and EGCG12 leptomeningeal ATTR?35
— Third ventriculostomy, surgical + TTR silencers notably do not significantly
pathology with R frontal brain tissue cross the blood brain barrier (BBB)

seo mininalireactive|alices + Tolcapone is a TTR stabilizer and has been

+ 2018 demonstrated to cross the BBB
— Ventriculoperitoneal shunt placed + Used off label; boxed warning for liver
2019 toxicity, monitored needed

— Started on tolcapone

+ Phase 1 clinical trial completed

1. Zou H, Zhou S. Int J Mol Se 2023:28-14146. 2. aus dem Siepon F et al. Drug Dos Dovel Thor. 2015;9:6319-6325. 3. Gamez J eta. Amyloid 2019:26:74.84. 4. Takahashi Y etal. Amyioë.
2022.29.190-196. 5. Tasmar (lolcapone). Prescribing Information. hitps:/iwww.accessdata Ida.govidrugsatida_docsabel2013/02069750041bl pd. PeerView
8: Marc orgwp-contenuploads/2025/07uly-2025-ATTR-Cincal-il-Updates-Full Sides pal.

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61. e-Home Messages Fro! ur Case

+ Leptomeningeal amyloidosis may present with central
nervous system symptoms!2

— Eg, headache, transient focal neurological
episodes, cognitive difficulties, ataxia,
hearing loss/tinnitus

— May notably have absent neuropathy

+ Of the >150 TTR mutations, ~14 have been reported
to have CNS involvement

+ Notable features of work-up

— CSF protein often elevated

- Brain MRI may demonstrate diffuse
leptomeningeal contrast enhancement, Symmetric calcification in the cortex
hydrocephalus or superficial siderosis along the Sylvian fissure in two patients

— Head CT may demonstrate hyperdensities with leptomeningeal ATTRV?

along the Sylvian fissure?

1. Jo Ket a. J Neue No Poyehioby.2004,75:1483-146, 2. Gaz Fel. Moral. 1963718821887 PeerView

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62. Key Takeaways From Today's Symposium

AÑ ATTRv is a hereditary, rapidly progressive peripheral neuropathy, but
Ls el fl le. even within ss

specific signs and symptoms are highly variabl

(2 ATTRv is not as rare as previously assumed; increased access to
multidisciplinary amyloid clinics is needed

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