GENOMIC-GUIDED THERAPIES:

CAN WE CURE CARDIOMYOPATHY?

Carolyn Ho, MD
Medical Director, Cardiovascular Genetics Center
Brigham and Women’s Hospital
Associate Professor of Medicine, Harvard Medical School

HEART FAILURE UPDATE 2018– TORONTO

MAY 12, 2018
DISCLOSURES

• Research support from MyoKardia, Inc to fund a

patient registry
CURING GENETIC CARDIOMYOPATHY:
WHAT DO WE NEED TO LEARN?

• How do gene mutations lead to disease?

o Phenotypic spectrum and disease mechanisms
• Why do some patients do poorly and others do
well?
• How can disease progression and emergence be
prevented?
 GENES PATHOGENESIS TREATMENT

Early/Preclinical HCM
G+/LVH-
Fertilization Birth Adolescence+
Identify Early Phenotypes: Isolate changes caused by the
mutation from changes related to disease itself
X
How Do Sarcomere Mutations Lead to HCM?

How can disease progression be interrupted?

Gene mutation
introduced
Detectable LVH
Clinical Diagnosis of HCM
HOW DO SARCOMERE MUTATIONS CAUSE HCM?
HOW CAN DISEASE PROGRESSION BE INTERRUPTED?
Sarcomere Mutation
MYK461
MYK-461

Increased
Force

Angiotensin
Activate
TGF-beta
Receptor
Diltiazem Blocker

Fibrosis
Activate Fibroblasts

Teekakirikul P et al. JCB 2012;199:417-421

MYK-461 (Mavacamten): Reduces ATPase and Force
0.6
Myofibrils

ATPase Rate (sec-1)

0.4

MYK-461
0.2

MYK-461 0.0
Rate of 0.0001 0.001 0.01 0.1 1 10 100

ATPase [MYK-461] (mM)

ATP
120

Fractional Shortening (% Basal)

hydrolysis
100
Cardiomyocytes

ATP Actin 80
binding binding
ADP 60
release
40

Power 20
Stroke
Pi 0
release 0.03 0.1 0.3 1 3

[MYK-461] mM
Green et al, Science 2016
Early MYK461-Treament Attenuates Hypertrophy and Fib
R403Q p=0.002 p=0.001
1.4
R453C
p=0.0006
p=0.0001 Untreated
1.2 R403Q

LVWT (mm)
R719W
1.0 Treated
R403Q
0.8 --WT Naïve
R403Q
__Treated
0.6
0 2 4 6 10 14 18 22 26
Weeks of treatment

p=1x10-17
12
untreated treated
10
Fibrosis area (%)

p=5x10-16
8

0
untreated treated untreated treated
R403Q R453C wt
Green et al, Science 2016
PIONEER-HCM (PHASE 2 STUDY): MAVACAMTEN (MYK-461)
REDUCES LVOT GRADIENTS & IMPROVES FUNCTIONAL CAPACITY

Resting Gradient
(mmHg)
Post Exercise Gradient
(mmHg)

Clinical Trials
- EXPLORER: pivotal study for obstructive HCM
- MAVERCIK: non-obstructive HCM
EARLY TREATMENT WITH DILTIAZEM:
ATTENUATES LVH AND FIBROSIS (IN MICE)
↓ Hypertrophy ↓ Fibrosis

Placebo
LV Wall Thickness

+ Diltiazem

Wild Type Mutation +

• Treatment was most beneficial when started before LVH develops

• Unable to reverse/rescue established disease
• Clinical Implications: Early pharmacologic intervention to improve Ca2+
balance may improve the natural history of HCM
Semsarian, et al. JCI 2002;109:1013-20
PILOT TRIAL OF DISEASE MODIFICATION:
DILTIAZEM VS PLACEBO IN PRECLINICAL (G+/LVH-) HCM

Treatment: 1-3 years

Annual Final Post-

Screening/ Evaluation Evaluation Treatment
Baseline Diltiazem Follow Up
R
Visit
a N=18 Symptoms Year 5
G(+)/ Stratify 14 ± 2yrs Exam Symptoms
Hx By n Exam
LVH(-) PE
ECG Hx
AGE d Echo ECG PE
Preclinical EKG
>/< 15 o Biomarkers Echo EKG
Echo Placebo CMR
HCM MRI
yrs
m N=20 Biomarkers
Echo
MRI
Biomarkers i 17 ± 2yrs Biomarkers
z
e

Pilot study: Safety and Feasibility

• Can medications be safely and reliably given to young,
otherwise healthy and asymptomatic individuals?
• Can treatment response be detected?
DILTIAZEM TREATMENT:
IMPROVEMENT OF LV CAVITY SIZE TOWARDS
NORMAL
Population 0
Mean
Wall Stress ~ P
-0.5
Thickness
Diameter
LVEDD z-SCORE

-1
Lower diastolic
Diltiazem
pressures
Placebo
needed to
-1.5 fill LV
 Geometric effects
-2 influence diastolic
filling
-2.5
Baseline End of Approximately 1 Year
Treatment After Treatment

Decrease in Thickness:Diameter Ratio

Ho, et al. JACC:Heart Failure 2015
GENOTYPE MAY MATTER:
MORE PROMINENT TREATMENT BENEFIT FOR MYBPC3
MUTATIONS3.5
Maximum LV Wall Thickness z-SCORE
3

2.5

2 MYBPC3- Diltiazem N=6

MYBPC3- Placebo N=6
MYH7- Diltiazem N=10
1.5 MYH7- Placebo
N=11
P<0.01
1

0.5

Similar0 beneficial
Baseline
patterns
End of
seenFollow
with:
Up
CMR LV mass,
serum troponin,
Treatment E/E’ (p<0.01)
Off Treatment

Response to disease-modifying treatment may vary based

on genetic background Ho, et al. JACC:Heart Failure; 2015
DISEASE MODIFICATION VIA INHIBITION OF TGF-b:
ATTENUATE LVH AND FIBROSIS

TGF-b Neutralizing Ab or
Untreated MYH7/+
Losartan-treated MYH7/+

Teekakirikul P, et al. JCI; 2010

 INHERIT: INHibition of the renin angiotensin system in HCM
and the Effect on hypertrophy

Primary Endpoint: Change in LV mass

Mean difference
1 g/m2 (95% CL, -3 to 6 g/m2)

p=0.60

• N=133 patients
• Randomized 1:1 to losartan 100
mg daily (n=64), or placebo (69)
for 12 months
Baseline 12 months

INHERIT Axelsson, et al. Lancet Diabetes-Endocrinology. 2014

 Conclusions and Future Perspectives
• No significant effect of losartan on LV mass or secondary
endpoints in patients with overt HCM
– Average age 52 years; 33% NYHA II/III
• The observed safety suggests that losartan may be used for
other indications in patients with obstructive physiology
• Future studies needed to determine if ARBs can attenuate
disease progression in preclinical or earlier stages of HCM
– Right Patient?:
• Younger- shorter disease duration, milder/reversible
manifestations
• Sarcomere mutation carriers
– Right Outcomes?:
• More dynamic/ responsive phenotypes
INHERIT
Axelsson, et al. Lancet Diabetes-Endocrinology. 2014
 HCM♥Net
Multicenter Clinical Network
Phase II Randomized, Placebo-controlled, Double-Blind Clinical Trial of Valsartan for
Attenuating Disease Evolution in Early Sarcomeric HCM
1° Composite Outcome
Z-score of change from
baseline across domains:
• Myocardial injury
Active Run In Evaluation at •Hemodynamic stress
Baseline STRATIFY
12 and 24 •Collagen metabolism
1◦ Analysis Valsartan •Functional capacity
Titration over Pre-pubertal R months
Cohort n ~75 •Myocardial fibrosis
2 week or Post- a
History Group 1 •Cardiac morphology
intervals to pubertal*
8-30 years old, Family History
AND
n •Cardiac function
Goal Dose: History
NYHA I-II, no Genotype NYHA Class I d
Adults: 320 PE 2° Endpoints
obstruction PE or Class II o
mg/d ECG •Safety
ECG AND
Children ≥35
m Echo •Clinical outcomes
Exploratory Echo LVWT < or ≥
kg: 160 mg/d
i Biomarkers •Individual components of
Cohort Biomarkers 14 mm Placebo
z primary composite outcome
CMR Children <35 AND n ~75 •Quality of Life and Physical
G+/LVH- CPET kg: 80 mg/d Group 1 or e Group 1
CPET and Activity
Age 10-25 years Group 2 •Alternative assessments of
CMR at 24M
cardiac function
*Post-pubertal: •Interactions with age,
Males ≥17 years; Females ≥16 years genotype, baseline
characteristics

Randomization Completed May 2017

(n=178 Primary Analysis Cohort)
ClinicalTrials.gov Identifier NCT01912534
Follow-up To Be Completed May 2019
 LMNA CARDIOMYOPATHY
• LMNA encodes Lamin A/C which
provides structural integrity for the
nucleus and plays a role in
mechano-transduction and gene
expression
• Highly penetrant
• Heart block and atrial fibrillation
are nearly universal and often
present before overt CMP
• Increased risk for cardiac arrest,
heart failure and stroke
• Gene-specific diagnosis can help
guide management
• Targeted therapies are being
studied
From Neal Lakdawala, MD, BWH
 NOVEL THERAPY FOR LMNA HEART DISEASE

• Activation of the p38 16 week old LMNAH222P/H222P mice

MAPK pathway has randomized to 4 weeks of placebo or
p38 MAPK inhibitor (ARRY-371797)
been established in
murine models of
LMNA heart disease FS 15% FS 25%
(e.g. LMNAH222P)
• Small molecule
inhibitors of p38 MAPK
have favorably
influenced natural
history in LMNAH222P
mice (ARRY-371797)
Muchir A. Hum Mol Genet. 2012
Choi Sci Trans Med 2012
Wu Bioorg Med Chem 2017
 NOVEL THERAPY FOR LMNA HEART
DISEASE

• Phase 2 trial of ARRY- Improved functional status in

patients with LMNA HF treated
797 in patients with with ARRY-797
heart failure caused by
LMNA mutations
showed:
– Improved 6MWT
– Decreased NT-BNP
– Stable LVEF
• A phase 3 clinical trial of
is pending

MacRae CA. Judge DP. Eur Heart J 2016:37;AS 1011

SILENCING AND EDITING HCM GENE MUTATIONS
• Injecting a short • Genome editing with
fragment of RNA(RNAi) CRISPR-Cas9
interferes with • Germline “correction” of
expression of mutation heterozygous MYBPC3
– Expression ↓~30% mutation in zygotes
• Prevented
development of HCM
in mice

Jiang, et al. Science, 2011. 342:111-114 Ma, et al. Nature, 2017

SUMMARY
• Collaborative basic discovery and clinical
translational studies can improve understanding of
the molecular basis of genetic cardiomyopathies

• Mechanistic insights can begin to transform

management:
• Develop rational, mechanism-based therapy
• Identify and target the highest risk cohorts before
irreversible changes occur
Human Translational Studies
Allison Cirino
Carolyn Ho
Neal Lakdawala
Calum MacRae
Barbara McDonough
Christine Seidman
Boston Children’s Hospital
Dominic Abrams
Steve Colan
Renee Margossian
Anne Marie Valente
Biostatistics
John Orav
Basic HCM Investigation
Seidman Laboratory
Brigham and Women’s Hospital
Harvard Medical School
J.G. Seidman
Christine Seidman
Euan Ashley- Stanford
Steve Colan- Boston
Sharlene Day– Michigan
Alex Pereira- Incor, Brazil
Iacopo Olivotto- Florence
Michelle Michels- Rotterdam
Gunnar Gunnarson- Iceland
Dan Jacoby- Connecticut
Collagen Biomarkers
Division of Cardiovascular Sciences,
Centre of Applied Medical Research,
University of Navarra, Pamplona, Spain
Javier Díez
Begoña López
Arantxa González
HCM♥Net
Euan Ashley- Stanford
Lee Benson- Hospital for Sick Children, Toronto
Charlie Canter/ Richard Bach- Wash. U. St. Louis
Steve Colan- Children’s Hospital, Boston
Sharlene Day/ Mark Russell – Michigan
Jason Becker- Vanderbilt
Kevin Hall- Yale
Harry Lever/ Ken Zahka- Cleveland Clinic
Beth McNally/ Elfi Pahl/ Lubna Choudhury- Northwestern
Amit Patel – University of Chicago
Luisa Mestroni/ Matt Taylor- University of Colorado
Anne Murphy- Johns Hopkins
Anjali Owens/ Joe Rossano- HUP/CHOP
Harry Rakowski- Toronto General Hospital
Alex Pereira- Incor, Brazil
John Lynn Jefferies- Cincinnati Children’s Hospital
Anna Axelson, Henning Bungaard- Rigshospitalet, Denmark