novel medical therapy
TRANSCRIPT
CHALLENGES FOR CLINICAL TRIALS:
Epidemiology
Heterogeneous patient spectrum (stages)
Low-event rates
Surrogate end-points: uncertain value
Limited economic interest
Referral Center for Cardiomyopathies Careggi University Hospital - Florence
Stages of Intervention: The Importance of Moving Upstream
Referral Center for Cardiomyopathies Careggi University Hospital - Florence
DIRECT EFFECTS ON
SARCOMERE FUNCTION
SARCOMERE GENE
MUTATION
DOWNSTREAM MYOCYTE
ABNORMALITIES
CLINICAL MANIFESTATIONS
Antagonize gain-of-function Prevent energy profligation Prevent phenotype?
Improve metabolic efficiency Antagonize cardiomyocyte
remodeling and calcium overload
Repair
Circulation, 2010
Referral Center for Cardiomyopathies Careggi University Hospital - Florence
Circulation, 2012
Referral Center for Cardiomyopathies Careggi University Hospital - Florence
Circulation, 2012
-100
-80
-60
-40
-20
0
20
40
1 s
HCM Basal HCM + Rano
M
em
bra
ne
po
ten
tial (m
V)
-100
-50
0
50
2 s
M
em
bra
ne
po
ten
tial (m
V)
Referral Center for Cardiomyopathies Careggi University Hospital - Florence
Ranolazine reduces diastolic Ca2+ and diastolic tension
10 s
0.2
F/Fo
10 s
0.2
F/Fo
0.2Hz 0.5Hz 1Hz0.15
0.18
0.21
0.24
0.27
Dia
stol
ic [C
a2+]
(F/F
max
)
Pacing rate
* * *
R Coppini et al., Circulation 2012
BASAL RANOLAZINE
Late Sodium Current as a Therapeutic Target
Sarcomere mutation
Late INa
Na+ Overload
Increased diastolic tension
Myocardial Ischemia
Arrhythmias
Ca++ Overload
Ranolazine:
Inhibits the late inward
Na+ current
Referral Center for Cardiomyopathies Careggi University Hospital - Florence
Protocol Code: MEIN/11/RAN-HCM/001
RANOLAZINE IN PATIENTS WITH SYMPTOMATIC HYPERTROPHIC CARDIOMYOPATHY: A PILOT STUDY ASSESSING THE EFFECTS ON EXERCISE CAPACITY,
DIASTOLIC FUNCTION AND SYMPTOMATIC STATUS (RESTYLE - HCM STUDY)
Study Design 80 patients
13 centers
3 countries
Exercise
Capacity
Diastolic
Function
QoL Arrhythmias
Zio Patch
Echo
MLHFQ
CPET (VO2) Obstruction
(GS-6615)
40 Sites in 7 Countries: USA, Italy, UK, France, Germany, Netherlands, Israel
Pioneering Molecularly-targeted Medicines for Cardiovascular Diseases
Lung Adenocarcinoma
Source: Pao and Hutchinson, Nature Medicine 2012. 18:349-351
Targeted Therapies
10 years ago
Heritable Cardiomyopathies
Currently
Sub-type by genetics and disease mechanism
MYBPC3 MYH7
TNNI3,
TNNT2, TPM1
G-, FHx+
MYH7,
TNNT2, TPM1.
TTN
HCM DCM
Targeted Therapies
Science, 2011
Proprietary Assays Measuring Changes in Velocity and Force of Contraction
flourescently-labeled actin being moved by myosin “motor” fixed to well
Control MyoKardia Compound Reduces Contraction
Source: Unpublished Company data
MYK-461: Oral small molecule allosteric modulator of myosin in R403Q mouse
0.7
0.8
0.9
1.0
1.1
1.2
1.3
0 4 8 12 16 20
Le
ft V
en
tric
ula
r P
os
teri
or
Wall
Th
ickn
ess (
mm
)
Treatment duration (weeks)
HCM mouse
with water only HCM mouse
with MYK-461 Wild-type mouse
with MYK-461
Source: Unpublished data from the Seidman Lab, Harvard University. NOT FOR DISTRIBUTION.
Le
ft V
en
tric
ula
r P
os
teri
or
Wall
Th
ickn
ess (
mm
)
Treatment duration (weeks)
HCM Mouse Prevention Study
HCM Mouse Regression Study
0.9
1.0
1.1
1.2
0 2 4 6 8 10
HCM mouse withwater only
HCM mouse withMYK-461
Treatment with MYK-461 prevents and
regresses disease • Reduces fractional shortening
• Returns wall thickness to control levels;
prevents fibrosis
PHASE 1
Referral Center for Cardiomyopathies Careggi University Hospital - Florence
The field is moving quickly / increasing interest (and investments).
From «extrapolation»/empiric to disease-specific therapy.
From one-fits-all to personalized approach.
Fasten your seatbelts.
CONCLUSIONS
Referral Center for Cardiomyopathies Careggi University Hospital - Florence