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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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 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
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