Hereditary ATTR (hATTR) Amyloidosis: Cardiomyopathy—An OverviewIdentifying the link can lead to a crucial diagnosis

Hereditary ATTR (hATTR) Amyloidosis: CardiomyopathyInformation about mechanism of disease, signs and symptoms, diagnosis, and treatment

What is amyloidosis?

• The amyloidoses are a heterogeneous group of disorders characterized by deposition of insoluble misfolded protein aggregates, known as amyloid fibrils, in tissues1,2

—36 unique amyloid fibril proteins have been identified in humans2

—Amyloidosis can be acquired or hereditary, and systemic or localized3

References:1. Shin S, et al. Mt Sinai J Med. 2012:79(6):733-748. 2. Sipe JD, et al. J Protein Fold Disord. 2016:23(4):209-213. 3. Rowczenio OM, et al. Human Mutat. 2014;35(9):E2403-E2412. As of

8/22/17

The most common types of systemic amyloidosis1

Four types are seen most frequently1,2:

Type Precursor Protein Organs/Systems Targeted

AL lmmunoglobulin light chain All organs except central nervous system

AA (Apo) serum amyloid A All organs except central nervous system

Aβ2Mβ2-microglobulin, wild typeβ2-microglobulin, variant

Musculoskeletal systemAutonomic nervous system

ATTRTransthyretin, wild typeTransthyretin, variants

Heart mainly in men, tenosynoviumNerves, heart, and GI tract

References:1. Hazenberg BPC. Rheum Dis Clin N Am. 2013;39:323-345. 2. Damy T, et al. J Cardiovasc Transl Res. 2015;8(2):117-127. 3. Sipe JD, et al. J Protein Fold Disord. 2016:23(4):209-213.

Nomenclature: The amyloidoses are named based on the disease-causing protein, with an “A” designating amyloid fibril. For example, when the type is “ATTR” the “A”

designates amyloid fibril, and the “TTR” designates the transthyretin protein.3

As of 8/22/17

Types of ATTR amyloidosis

wtATTR hATTR

DescriptionWild-type ATTR (wtATTR) amyloidosis, formerly known as senile systemic amyloidosis (SSA), is a nonhereditary, progressive disease of undefined etiology.1-3

Hereditary ATTR (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease.8-10

EtiologyMisfolded transthyretin (TTR) proteins accumulate as amyloid fibrils in multiple organs, including the heart.4,5

Caused by a mutation in the TTR gene that results in misfolded TTR proteins accumulating as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.1,8,11

Symptoms Can cause cardiomyopathy and neuropathy, resulting in heart failure and mortality.4,6,7

A multisystemic disease with a heterogeneous clinical presentation that includes sensory and motor, autonomic (e.g., diarrhea, erectile dysfunction, hypotension), and cardiac symptoms.8,12,13 Can lead to significant morbidity, disability, and mortality.4,8-10

Time to Mortality

Within 2 to 6 years (median overall survival of 3.6 years).4,6 Within 2 to 15 years.4,8

References:1. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. 2. Dubrey S, et al. Postgrad Med J. 2015;91(1078):439-448. 3. Kourelis TV, et al. Expert Rev Cardiovasc Ther. 2015;13(8):945-961. 4. Castaño A, et al. Heart Fail Rev. 2015;20(2):163-178. 5. Westermark P, et al. Amyloid. 2003;10(suppl 1):48-54. 6. Pinney JH, et al. J Am Heart Assoc. 2013;2:e000098 doi:10.1161/JAHA.113.000098. 7. Coelho T, et al. Curr Med Res Opin. 2013;29(1):63-76. 8. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 9. Mohty D, et al. Arch Cardiovasc Dis. 2013;106(10):528-540. 10. Adams D, et al. Neurology. 2015:85(8):675-682. 11. Damy T, et al. J Cardiovasc Transl Res. 2015;8(2):117-127. 12. Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 13. Shin SC, et al. Mt Sinai J Med. 2012;79(6):733-748. As of

8/22/17

Formation of amyloid fibrils in hATTR amyloidosis1,2

Liver TTR TTR Misfolded Amyloid Fibrils

Amyloid Deposits

TTR is primarily synthesized in the liver

Normally, TTR is a tetramer composed

of four identical monomers

In hATTR amyloidosis, the tetramer becomes destabilized, resulting in protein misfolding and aggregation into

amyloid fibrils

Amyloid fibrils are deposited at multiple

sites in the body, including the nerves,

heart, and the GI tract, causing damage that

leads to clinical symptoms

References:1. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 2. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. As of

8/22/17

hATTR amyloidosis—a hereditary condition

• hATTR amyloidosis is an autosomal dominant disease; thus, a person only needs to inherit one copy of the mutated TTR gene from one parent to develop the condition1,2

• Penetrance is variable, and some individuals may remain asymptomatic despite having a TTR mutation1-3

References: 1. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 2. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 3. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. As of

8/22/17

TTR gene mutations

• More than 120 different TTR gene mutations have been discovered1-3

—The most common mutation is Val30Met. Individuals with this mutation often initially present with polyneuropathy

• Prevalence is higher in Portugal, Sweden, Japan, Brazil, and Spain

—The Val122Ile mutation is common in individuals who initially present with cardiomyopathy; found in 3 to 4% of the African American population

• Symptoms can present differently, even among people in the same family and in the same mutation3

References: 1. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 2. Rowczenio DM, et al. Hum Mutat. 2014;35(9):E2403-E2412. 3. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. As of

8/22/17

hATTR amyloidosis affects an estimated 50,000 patients worldwide1

• In the disease continuum of hATTR amyloidosis:

Disease symptoms fall along a spectrum

References:1. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. 2. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 3. Rapezzi C, et al. Eur Heart J. 2013;34(7):520-528. 4. Adams D, et al. In: The XVth International Symposium on Amyloidosis. Uppsala, Sweden: ISA International Society of Amyloidosis; July 3-7, 2016. PA 82.

Polyneuropathy Cardiomyopathy

—A substantial proportion of patients with hATTR amyloidosis presents with a mixed phenotype3,4

—Some patients present primarily with polyneuropathy symptoms, historically known as familial amyloidotic polyneuropathy (FAP)1,2

—Other patients present primarily with cardiomyopathy symptoms, historically known as familial amyloidotic cardiomyopathy (FAC)1,2

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hATTR amyloidosis: a life-threatening,multisystem disease1-4

• Because amyloid fibrils are deposited in tissues throughout the body, including the nerves, heart, and GI tract, patients with hATTRamyloidosis can present across a spectrum that includes sensory and motor, autonomic, and cardiac symptoms1-6

• In addition to the varied symptom presentation, age of onset varies among patients—with a median age of 39 years, with some presenting as early as their 20s7,8

References:1. Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 2. Mohty D, et al. Arch Cardiovasc Dis. 2013;106(10):528-540. 3. Shin SC, et al. Mt Sinai J Med. 2012;79(6):733-748. 4. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 5. Damy T, et al. J Cardiovasc Transl Res. 2015;8(2):117-127. 6. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. 7. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 8. Coelho T, et al. Curr Med Res Opin. 2013;29(1):63-76. As of

8/22/17

Constellation of possible signs and symptoms of hATTR amyloidosis1

• Progressive dementia• Headache• Ataxia• Seizures• Spastic paresis• Stroke-like episodes

• Proteinuria• Renal failure

• Orthostatic hypotension• Recurrent urinary tract

infections (due to urinary retention)

• Sexual dysfunction• Sweating abnormalities

• Vitreous opacification• Glaucoma• Abnormal conjunctival vessels• Papillary abnormalities

• Conduction block• Cardiomyopathy• Arrhythmia

• Nausea & vomiting• Early satiety• Diarrhea• Severe constipation• Alternating episodes of diarrhea & constipation• Unintentional weight loss

• Neuropathic pain• Altered sensation (i.e., change in

sensitivity to pain and temperature)• Numbness and tingling• Muscle weakness• Impaired balance• Difficulty walking

Reference:1. Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. As of

8/22/17

Symptom presentation can vary among patients1

In a multicenter study that included 186 individuals with hATTR amyloidosis, 58% (109/186) of hATTRamyloidosis patients presented with a mixed phenotype characterized by cardiac and neurologic involvement2

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Sensory and motor Autonomic Cardiac

References: 1. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 2. Rapezzi C, et al. Eur Heart J. 2013;34(7):520-528. https://doi.org/10.1093/eurheartj/ehs123.

• Baseline clinical characteristics of 186 individuals with hereditary ATTR amyloidosis in a multicenter study2

• Echocardiographic abnormalities included increased LV wall thickness, granular sparkling of ventricular myocardium, increased thickness of atrioventricular valves or interatrial septum, or pericardial effusion2

• Electrocardiographic abnormalities included advanced A-V block or intraventricular conduction disturbances2

As of 8/22/17

Symptoms of hATTR amyloidosis can progress quickly, leading to life-threatening dysfunction1-3

• As the disease progresses, symptoms increase in severity, leading to significant disability, decreased quality of life, and untimely death3,4

• hATTR amyloidosis can lead to mortality within 2 to 15 years1,5

• Due to the variability of the disease, progression of symptoms can also be considerably different from patient to patient6

References: 1. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 2. Mohty D, et al. Arch Cardiovasc Dis. 2013;106(10):528-540. 3. Adams D, et al. Neurology. 2015:85(8):675-682. 4. Adams D, et al. Curr Opin Neurol. 2016;29(suppl 1):S14-S26. 5. Castaño A, et al. Heart Fail Rev. 2015;20(2):163-178. 6. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31.7. Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 8. Obici L, et al. Curr Opin Neurol. 2016;29(suppl 1):S27-S35.

Due to the rapid natural progression of the disease, patients with hATTRamyloidosis require an early and accurate diagnosis.4,7,8

As of 8/22/17

Consider hATTR amyloidosis in your differential diagnosisBecause the symptoms of hATTR amyloidosis may overlap with those of other diseases, detailed diagnostic history may help to identify patients with hATTRamyloidosis.1-4

Diseases with symptoms that overlap with those of hATTR amyloidosis1-4

References:1. Adams D, et al. Curr Opin Neurol. 2016;29(suppl 1):S14-S26. 2. Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 3. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 4. Ruberg FL, et al. Circulation. 2012;126(10);1286-1300. 5. Lalande S, et al. Drugs Today (Barc). 2008;44(7):503-513. 6. Rapezzi C, et al. Amyloid. 2012;19(suppl 1):16-21. 7. Linart A. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006. Chapter 20. 8. Dharmarajan K, et al. J Am Geriatr Soc. 2012;60(4):765-774.

Diagnostic assessment5-7 Potential diagnoses5-7

Left ventricular hypertrophy Hypertensive heart disease

Diastolic dysfunction Hypertrophic cardiomyopathy

Heart failure with preserved ejection fraction Fabry disease

AL amyloidosis

For patients with cardiomyopathy, accurate diagnosis may be even more critical, as some medications for common cardiac conditions may be harmful. These medications may

interact with amyloid fibrils and exert negative effects.8

As of 8/22/17

Red flag: Ask about family history

• Obtaining a family history is an important step in the diagnostic process1-3

• Though patients may be unaware of hATTR amyloidosis in their family, inquiring about relatives who have experienced any of the symptoms, including symptoms different from their own, or who have died prematurely, can help identify a family history

References:1. Adams D, et al. Curr Opin Neurol. 2016;29(suppl 1):S14-S26. 2. Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 3. Tan BY, et al. Circ Cardiovasc Genet.2012;5(6):697-705. As of

8/22/17

Historical and clinical findings that mayindicate hATTR amyloidosis

Historical and physical findings1

Heart failure with normal or preserved ejection fraction in the absence of hypertension, particularly in men

Hypotension in a person with previous hypertension

Evidence of right-sided heart failure: loss of appetite, hepatomegaly, ascites, and lower extremity edema

Intolerance of commonly used cardiovascular medications: digoxin, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers

Bilateral carpal tunnel syndrome

Reference:1. Dharmarajan K, et al. J Am Geriatr Soc. 2012;60(4):765-774. As of

8/22/17

Imaging findings that may indicatehATTR amyloidosis

Imaging findings1

• Low QRS voltage ± thick interventricular septum (low voltage to mass ratio)• Pseudo-infarction pattern• Progressive reduction in QRS voltage over time

• Thick interventricular septum• Refractile myocardium (granular sparkling)• Low tissue Doppler velocities, strain, or strain rate

• Thick interventricular septum• Subendocardial late gadolinium enhancement

• Cardiac update of 99mTc-DPD or 99mTc-PYP

ECG

Echo

CMRI

Scintigraphy Scan

In addition, consider hATTR amyloidosis in a patient who has a family history of ANY of these symptoms.

Reference:1. Dharmarajan K, et al. J Am Geriatr Soc. 2012;60(4):765-774.

ECG=electrocardiogram; CMRI=cardiac magnetic resonance imaging; 99mTc-DPD=technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc-PYP=technetium-99m-pyrophosphate.

As of 8/22/17

Confirming an hATTR amyloidosis diagnosis

References:1. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 2. Dharmarajan K, et al. J Am Geriatr Soc. 2012;60(4):765-774.

Diagnostic tools for patients presenting with cardiomyopathy1,2

Cardiac examination

Electrocardiography

Echocardiography

Cardiac serum biomarkers

Cardiac magnetic resonance imaging

Nuclear scintigraphic imaging with 99mTc-DPD or 99mTc-PYP

Genetic analysis to determine pathologic mutation

Tissue biopsy + Congo red staining

Identification of amyloid protein

Immunohistochemistry

Mass spectrometry

As of 8/22/17

Genetic screening

If patient symptoms and a family history lead to a suspicion of hATTRamyloidosis, genetic counseling can help patients understand the potential diagnosis, the genetic screening process, and the implications of the disease.

As of 8/22/17

hATTR amyloidosis: linking pathophysiology to potential therapeutic approaches1,2

Liver TTR TTR Misfolded TTR

Amyloid Fibrils

Pathophysiology

Suppression of amyloidogenic TTR

Liver transplantationAntisense oligonucleotides (ASO)

RNAi therapeutics

Tetramer Stabilizers Inhibition of amyloid deposits

Monoclonal antibodyFibril disruptors

THERAPEUTIC APPROACHES**This visual represents approved and investigational approaches.

References: 1. Ueda M, et al. Transl Neurodegener. 2014;doi:10.1186/2047-9158-3-19. 2. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 3. Richards DB, et al. N Engl J Med. 2015;373(12):1106-1114.

Current investigational approaches: TTR tetramer stabilizers, RNAi therapeutics, ASOs, monoclonal antibodies, and fibril disrupters1-3

As of 8/22/17

Current treatment options: liver transplant

• Orthotopic liver transplant removes approximately 95% of the production of TTR. It has improved survival rates but does not permanently halt disease progression and requires lifelong use of immunosuppressants1,2

—Transplant may be less effective for patients who present primarily with cardiomyopathy

—The limited availability of organs, as well as the exclusion of older patients and patients with advanced disease or with comorbidities, warrants the development of other treatment options

References:1. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 2. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. As of

8/22/17

Investigational therapies in development

There are multiple investigational therapies in development that target different points in the disease pathway1-4

Therapies that may help to reduce fibril accumulation:• Monoclonal antibodies may suppress ATTR amyloid deposition by binding

to amyloid fibrils and targeting them for immune system destruction1,2,4

• Fibril disrupters bind to amyloid fibrils and disrupt their association1,2

Therapies that may address the underlying cause of amyloidosis:• Antisense oligonucleotides (ASOs) are short chemically modified

oligonucleotides that bind to TTR mRNA and prevent production of TTR protein via ASO-RNAse H mediated cleavage1-3

• RNAi therapeutics are double stranded small interfering RNAs that bind to transthyretin (TTR) messenger RNA (mRNA) and prevent production of TTR protein via the RNA interference (RNAi) pathway1-3

References:1. Ueda M, et al. Transl Neurodegener. 2014;doi:10.1186/2047-9158-3-19. 2. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 3. Ando Y, et al. OrphanetJ Rare Dis. 2013;8:31. 4. Richards DB, et al. N Engl J Med. 2015;373(12):1106-1114. As of

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Treatments that stabilize TTR protein

TTR tetramer stabilizers bind to the thyroxine binding site on the TTR protein, stabilizing circulating TTR tetramers and preventing the dissociation into monomers, but do not inhibit the synthesis of disease-causing protein1,2

References:1. Sekijima Y. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043. 2. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31.

As of 8/22/17

Recognize the signs.Suspect hATTR amyloidosis.• Hereditary ATTR (hATTR) amyloidosis is an autosomal dominant disease1-3

• hATTR amyloidosis is caused by a mutation in the transthyretin (TTR) gene that results in misfolded TTR proteins accumulating as amyloid fibrils in multiple sites including the nerves, heart, and GI tract1,2,4

• Affects multiple organs, resulting in varying symptoms5-7

• hATTR amyloidosis can lead to mortality within 2 to 15 years1,8

• Obtaining a family history is an important step in the diagnostic process5,9,10

• There are multiple investigational therapies in development that target different points in the disease pathway3,11-13

References: 1. Hanna M. Curr Heart Fail Rep. 2014;11(1):50-57. 2. Hawkins PN, et al. Ann Med. 2015;47(8):625-638. 3. Ando Y, et al. Orphanet J Rare Dis. 2013;8:31. 4. Damy T, et al. J Cardiovasc Transl Res. 2015;8(2):117-127. 5. Conceição I, et al. J Peripher Nerv Syst. 2016;21(1):5-9. 6. Mohty D, et al. Arch Cardiovasc Dis. 2013;106(10):528-540. 7. Shin SC, et al. Mt Sinai J Med. 2012;79(6):733-748. 8. Castaño A, et al. Heart Fail Rev. 2015;20(2):163-178. 9. Adams D, et al. Curr Opin Neurol. 2016;29(suppl 1):S14-S26. 10. Tan BY, et al. Circ Cardiovasc Genet. 2012;5(6):697-705. 11. Ueda M, et al. Transl Neurodegener. 2014; doi:10.1186/2047-9158-3-19. 12. Sekijima Y. J NeurolNeurosurg Psychiatry. 2015;86(9):1036-1043. 13. Richards DB, et al. N Engl J Med. 2015;373(12):1106-1114.

Access this information and these updates, and learn about genetic screening made available at no charge in the US, by visiting:

https://hATTRamyloidosis.com

As of 8/22/17