Cardiac Amyloidosis

Rodney H Falk MD

Brigham and Womenrsquos Hospital Amyloidosis Program

Harvard Medical School

Boston MA USA

rfalkbwhharvardedu

Thank you to the organizers

The heart in amyloidosis is different from all other hearts

When faced with possible cardiac

amyloidosis things are not always

what they seem at first glance

Diagnosis of cardiac

amyloidosis

You can do it on a desert

island

CHECK THE NECK

A clue to the presence

and

type of amyloidosis

AMYLOID HEART DISEASE

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Thank you to the organizers

The heart in amyloidosis is different from all other hearts

When faced with possible cardiac

amyloidosis things are not always

what they seem at first glance

Diagnosis of cardiac

amyloidosis

You can do it on a desert

island

CHECK THE NECK

A clue to the presence

and

type of amyloidosis

AMYLOID HEART DISEASE

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

When faced with possible cardiac

amyloidosis things are not always

what they seem at first glance

Diagnosis of cardiac

amyloidosis

You can do it on a desert

island

CHECK THE NECK

A clue to the presence

and

type of amyloidosis

AMYLOID HEART DISEASE

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Diagnosis of cardiac

amyloidosis

You can do it on a desert

island

CHECK THE NECK

A clue to the presence

and

type of amyloidosis

AMYLOID HEART DISEASE

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

CHECK THE NECK

A clue to the presence

and

type of amyloidosis

AMYLOID HEART DISEASE

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

A clue to the presence

and

type of amyloidosis

AMYLOID HEART DISEASE

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

AMYLOID HEART DISEASE

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Modified from Patel and Hawkins J Internal Med 2015 278 126-144

Infiltration

Infiltration

Light chain toxicity

Infiltration Infiltration

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Normal or Abnormal Systolic

Function

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Speckle Strain Imaging

Normal Longitudinal Strain

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Speckle strain Imaging

Cardiac Amyloidosis

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Cardiac MRI in amyloidosis

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Cardiac Therapy in Amyloidosis

bull Calcium channel blockers are often harmful

bull Beta-blockers may not be tolerated and may worsen clinical conditionrsquo

bull Digoxin of little or no help

bull ACE-inhibitorsARB may or may not be tolerated

bull Anticoagulation is safe

bull Pacemakers when needed should be chosen carefully

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Donrsquot forget the atria

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

RESERVOIR CONDUIT CONTRACTILE

72 15

MILD HYPERTENSION SR AMYLOIDOSIS

THE ROLE OF ANTICOAGULATION

10

72

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Case 2

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

From Feng D et al Circulation 20071162420-2426

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

To anticoagulate or not

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

AMYLOID HEART DISEASE

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

NATIVE CONDUCTION GLS ndash 174 RV PACE GLS ndash 166

BI-V PACING GLS -171

The effect of pacing on

global longitudinal strain

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

NATIVE CONDUCTION RV PACE

BI-V PACING

LV TWIST

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Is light chain toxicity of clinical

significance

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Serial strain Imaging

Effect of light chain resolution

Pre-Chemotherapy 18 month Hematologic remission

Apical 4 strain -78 Apical Strain -114

Global Strain -92 Global Strain -135

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Early Cardiac AL Amyloidosis can be Detected by18F-florbetapir PETCT

Dorbala et al Work in progress

ECV 027

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

הרב ל־המ וכ רלספ י חמש ז ההר ב

(And anyone who extends his telling

he should be praised)

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

155151

108

97

138

158

97

112

0

2

4

6

8

10

12

14

16

18

PLACEBO PATISERAN BASAL PLACEBO BASAL PATISERAN

THE EFFECT OF 18 MONTH PATISERAN ON LV STRAIN

Minamisawa et al

JAMA Cardiology

Published on line

March 19 2019

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Case 1

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

DisclosuresConsulting fees from Akcea Ionis Pfizer Eidos GSK

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

BEFORE TREATING BE SURE OF

PRECISE DIAGNOSIS

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull September 2016 4 months of dyspnea No chest pain

bull Admitted because of slight troponin elevation

bull Work up for CAD including MIBI was negative but he only

exercised lt 3minutes stopping due to chest pain and dyspnea

and had an abnormal ECG

bull

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

ECHOCARDIOGRAM

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

CARDIAC MRI

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

CASE 3 A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull GENOTYPED Heterozygous for Val22 Ile mutation

DIAGNOSIS (Early onset) Familial amyloid cardiomyopathy

Pre-biopsy confirmatory pyrophosphate scan------

EXPECTED

OBTAINED

PROCEEDED TO BIOPSY

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

A NIGERIAN MAN WITH CHEST PAIN HYPERTENSION AND A THICK VENTRICLE

bull Gene positive for Ile122 TTR mutation

bull Serum free light chains near normal with normal ratio Negative immunofixation

bull Biopsy showed large amounts of fibrosis with small specks of amyloid

bull MASS SPECTROMETRY SHOWED AL (LIGHT CHAIN-DERIVED) AMYLOID

DEPOSITS

bull FINAL DIAGNOSIS AL AMYLOIDOSIS WITH COINCIDENTAL

AMYLOIDOIGENIC TTR MUTATION

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

64 YEAR OLD MAN WITH CHF AND NEUROPATHY

Investigations showed amyloid deposits with a lambda monoclonal gammopathy in the serum

Free light chains said to be elevated

Diagnosis of AL was made and CyBorD initiated

Should anything else have been done

DIAGNOSIS

ATTRm (Ala60) with unrelated MGUS

Chemotherapy-induced worsening of

neuropathy

Iatrogenic near ndashdeath

AMYLOID TYPING IS CRITICAL

Planar

SPECT

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

MONOCLONAL GAMMOPATHY IN WILD-TYPE TTR AMYLOIDOSIS

COINCIDENCE OR UNEXPLAINED COMPANION

Abnormal Ration=941

Normal Ration=1359

FLC Ratio in MGUS

MGUS is common in ATTRwt and may be related

No MGUSn= 101

82

MGUSn=2218

123 consecutive patients with ATTRwt

Geller Singh et al Mayo Clinical Proceedings 2017

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

THE IMPORTANCE OF AMYLOID TYPING

bull Congo red sulfated Alcian blue staining will determine presence of amyloid but not typing

bull Immunohistochemistry ideally on fresh sample is helpful but not as accurate as previously believed even in skilled hands

bull This is particularly true in the setting of TTR with unrelated MGUS

bull Therefore if ANY doubt as to precise diagnosis mass spectrometry (now considered the gold standard) is critical

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

AL AMYLOIDOSIS

Is it ever too late to treat

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Kumar S et al2012

Adverse

risk

factors

NT-proBNP

gt1800

pgml

Troponin T

gt0025

ngml

Free light

chain

difference

gt180 mgL

Each risk factor

gets 1 point

Stage 1 =0 points

Stage 4= 3 points

Revised prognostic system for light-chain amyloidosis

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

BE CAREFUL OF HISTORICAL

CONTROLSAnd suspicious of published prognostic indices

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Mayo score Previously

published

median

survival

(months)

Observed median

survival with

bortezomib-based

therapy (n=52)

1 941 492

2 403 Not reached

3 14 Not reached

4 58 403

Cardiac amyloidosis in the

proteosome-inhibitor era

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

AL amyloidosis

Markedly improved prognosis over past decade due to

use of proteasome inhibitors

Still remain about 25 non-responders and 25

incomplete responders

Daratumumab - IgG1κ human monoclonal antibody that

binds to CD38 and inhibits the growth of CD38 expressing

tumor cells by inducing apoptosis

For suboptimalresistant patients daratumumab has

become an important option with a high response rate

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

WHATrsquoS ON THE HORIZON

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Tackling TTRmdash

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Tackling TTRmdashpreventing unfolding

AG10

Tafamadis

Diflunisal

Tolcapone

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Primary Analysis and Components

Maurer MS et al N Engl J Med 20183791007-1016

THE ATTR-ACT

TRIAL

Tafamidis in TTR

cardiomyopathy

30-month study of tafamidis 20 mg 80 mg or placebo in TTR amyloid cardiomyopathy (wild-type or mutant)

Primary endpoint combination of mortality or cardiac hopitalizations

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Maurer MS et al N Engl J Med 20183791007-1016

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

AG10 mimics disease-protective T119M mutation

56

Disease-protective T119M mutation AG10-bound TTR

Strong inter-monomer H-bonds

See Penchala SC 2013 PNAS 1109992 doi101073pnas1300761110Miller M 2018 J Med Chem DOI 101021acsjmedchem8b00817

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Silencing TTR-siRNA and antisense

oligonucleotides

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Inotersen in FAP

Antisense oligonucleotide

Administered weekly subcutaneously

gt70 suppression of TTR production

Highly effective in familial amyloid polyneuropathy

Thrombocytopenia is main side-effect Can be managed by regular monitoring

N Engl J Med 2018 37922-31

Primary endpoints at 64 weeks

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Patisiran in FAP

Si RNA

Administered q 3 weeks by infusion

Highly effective in familial amyloid

polyneuropathy

Main side-effect is infusion

reactions

N Engl J Med 201837911-21

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Might results in neuropathy

translate into cardiomyopathy

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Effect of patisiran on cardiac parameters in

Apollo study

126 patients with echo features of cardiac amyloidosis

Reduction of LV wall thickness by 09 mm (p=0017) 18 month cw placebo

Strain imaging improved by -14

Increase in EDV and cardiac output

NTproBNP lower in treated group

Solomon et al Circulation 2018 In press

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Too late for therapy

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

ANTIBODY THERAPY FOR AMYLOIDOSISPipe dream or pipe line

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Prothena antibody

NEOD001 Humanized form of murine monoclonal antibody

Binds to an epitope unique to the misfolded light chain protein

The cryptic light chain epitope is thought to be exposed during misfolding

and aggregation but is not available in light chainrsquos native conformation or

in fully formed immunoglobulin

American Journal of Hematology Vol 91 No 12 December 2016 doi101002ajh24531

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

NEOD001

PRONTO

Phase 2b Randomized Double-blind Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction (PRONTO STUDY)

Primary end-point was best cardiac response (NTproBNP)

Inclusion ge1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response

Cardiac involvement

NT-proBNP ge 650 and lt 5001

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Antibody therapy to remove amyloid deposits

Richards DB et al

NEJM 2015 373 1106-14

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Is cardiac amyloidosis a ldquozebrardquo

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Is TTR amyloidosis a ldquozebrardquo as

a cause of heart failure

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Val122Ile Cardiomyopathy

How big a problem

3-4 of African-Americans are heterozygous for the Val122Ile gene

associated with a late-onset (7th decade) amyloid cardiomyopathy

If penetrance is high then gt1000000 African ndashAmericans carry the gene and

approximately 130 000 gt 65 years old are at risk of amyloid

cardiomyopathy

Where are they

Underdiagnosed poor penetrance or both

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

What is the

effect of V122I

TTR variant on

mortality

3732 wild-type TTR

African-Americans in the

ARIC Study compared to

124 (3) carriers of

Ile122 variant

Median follow up 215

years

Quarta CC et al NEJM 201537221-29

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Effect of Val122Ile Mutation on

Survival and Heart Failure

SURVIVALFREEDOM FROM HEART

FAILURE

From Quarta CC et al NEJM 2015372 21-29

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

HEART FAILURE IN AN ELDERLY AFRICAN-AMERICAN MAN WITH ILE122 GENE

CARDIAC AMYLOIDOSIS OR NOT

ILE 122 Positive PYP

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

From Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fractionEur Heart J 201536(38)2585-2594

How common is TTR

amyloidosis as a cause of

heart failure

bull 13 of 120 patients admitted to Spanish hospital with HF PEF and LV gt12 mm had positive DPD scans cw amyloidosis

bull Approximately 12 million heart failure hospital discharges annually for CHF in USA

bull If 50 are HFPEF and 50 of these gt 65 years old with LV gt12 mm there are potentially 40000 TTR amyloidosis patients annually admitted with CHF

bull Most probably remain undiagnosed

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

Association Between Ruptured Distal Biceps Tendon and Wild-Type

Transthyretin Cardiac AmyloidosisGeller HI Singh A Alexander KM Mirto TM Falk RH

JAMA 2017318962-963

Prevalence is 33 cw 8 per 100000

in the general population

Positive predictive value in a man

gt 70 years with HfPEF is 66

CARDIAC AMYLOIDOSIS

You canrsquot treat it if you

donrsquot diagnose itAND YOU CANrsquoT DIAGNOSE IT IF YOU

DONrsquoT THINK OF IT

Unexplained CHF with a non-dilated

ventricle ndashhistory and physical still help