Cohort 1
1 hr + 1hr
n=8
ECHOCARDIOGRAPHIC DETECTION
1
OF INCREASES IN
0.125
0.0625
0.25
0.125
0.5
0.25
EJECTION FRACTION
0.75
ABSTRACT
WITH
0.25
0.5
HEART FAILURE RECEIVING
EF < 40%, investigator verified
Echos at Baseline, 1.5, 24, 48 hours
Four treatment sessions/patient*
0.05
0.5
Cohort 4
1hr + 1hr + 22hr
n=8
0.025
0.5/0.25
0.05
1.0/0.5
0.1
Cohort 5
1hr + 1hr + 70hr
n = 10
1.0/0.5
n=8
0.075
Methods: Using echos obtained before, during and after infusion of the
selective cardiac myosin activator, CK-452, EF was assessed by MoD and by
Doppler derived LVOT SV as a percentage of ventricular volumes assessed
by MoD.
<0.0001
316
From across
the five
cohorts,
of 564
echocardiograms
coincident
NS a total
p < 0.0001
p < 0.0001
p < 0.0001 p < 0.0001 and
p < 0.0001
(msec)
plasma samples for measurement of CK-452 concentrations were obtained
LVOT SV
0±2
1±2
5±2
11 ± 3
9±3
10 ± 2
<0.0001
69
before, during
CK-452.
EF was
assessed
0.0001 and by
NS
NS
p = 0.01
p < 0.0001
p = 0.001by
p <MoD
(mL) and after infusion
each of two “hybrid” methods that employed both Doppler-derived LVOT
LVOT CO
-32 ± 116 52 ± 123 180 ± 141 408 ± 173 400 ± 189 330 ± 142
0.0005
4423
SV and ventricular
volumes
NSassessed
NS by MoD:
NS
p = 0.02
p = 0.03
p = 0.02
(mL/min)
PLACEBO CORRECTED CHANGES
FROM
BASELINE
1±4
SET
18 ± 4
47 ± 5
58 ± 6
59 ± 6
80 ± 5
EFHYB-EDV
0 ± 1 = (LVOT
0 ± 1 SV/LVEDV)
-2 ± 1 - 4 ± x
2 100
-2 ± 2
66
NS
NS
p = 0.06
p = 0.005
-4 ± 1
NS
p = 0.001
EFHYB-ESV = (LVOT SV/[LVESV + LVOT SV]) x 100
EFHYB-ESV
(%)
LVEDV
(mL)
32
0 ± 1 DOSING
1±1
0.5
243
0.5
1±1
1±1
NS
NS
0±1
NS
p = 0.02
SCHEME
3±2
8±2
7±2
10 ± 1
5±1
5±1
6±1
NS
NS
0.125
Cohort 3
1hr + 23hr
n = 10
0±1
NS
168
0.25
Cohort 2
1 hr + 1hr
n=9
Cohort 4
1hr + 1hr + 22hr
n=8
33
0±1
Loading Dose
mg/kg/hr
31
Cohort 1LVESV
1 hr + 1hr (mL)
n=8
NS
P = 0.07
Maintenance Dose
2±
1 ±mg/kg/hr
1
0±1
NS
1±4
3 ± 0.0625
4
-5 ± 5
1±5
5±5
NS
NS 0.125
NS
NS
0.5
0.25
0.025
0.5
0.05
1.0
0.1
NS
p < 0.05
OBJECTIVES
In patients receiving CK-452
• To compare EF changes calculated by “hybrid” methods (employing
both Doppler and 2D data) to EF changes calculated by MoD
• To explore whether the hybrid EF employing left ventricular endsystolic volume (LVESV) by MoD performs better than the hybrid EF
employing left ventricular end-diastolic volume (LVEDV) by MoD
LVOT CO
(mL/min)
LVOTHR
(bpm)
EFMOD (%)
EFHYB-EDV
(%)
EFHYB-ESV
(%)
0.05
0.05
1.0
0.1
0.1
0.25/0.125
0.025
0.025
0.5/0.25
0.05
0.05
1.0/0.5
0.1
0.1
0.1
0.1
EF < 40%, investigator
EF < 40%, verified
investigator verified
Echos at Baseline,
24, 48 hours
Echos1.5,
at Baseline,
1.5, 24, 48 hours
Four treatment
sessions/patient*
Four
treatment sessions/patient*
verified
EF 30%, core
EFlab30%,
core lab verified
Echos at Baseline,
24, 48 hours
Echos1.5,
at Baseline,
1.5, 24, 48 hours
Three womenThree
required
women required
Four treatment
sessions/patient*
Four
treatment sessions/patient*
[CK-1827452]
[CK-1827452]
1-100
(ng/mL) (ng/mL)
Mean
Mean
Variable Variable
Baseline Baseline
SET
(msec)
DEMOGRAPHICS
1-100
Mean
Baseline
AND
LVOT SV LVOT SV
69
(mL)
(mL)
78
11 ± 3
p < 0.0001
>500
124
LVOT COLVOT CO -32 ± 116 -32
52±±116
123 52
180± ±123
141180
408±±141
173408
400±±173
189400
330±±189
142330 ± 142
0.0005
4423
NS
NS
NS
p
=
0.02
p
=
0.03
p
=
0.02
4423
(mL/min) (mL/min)
NS
NS
NS
p = 0.02
p = 0.03
p = 0.02
0.0003
0±1
32
NS
01±±11
13±±12
38±±22
87±±22
10± ±2 1
7
10
±1
<0.0001
<0.0001
p < 0.0001
0.009
EFHYB-ESVEF
HYB-ESV
31
(%)
(%)
0±1
31
NS
01±±11
12±±11
pNS
= 0.03
p
0.0001 pp<<0.0001
0.0001 p < 0.0001
= 0.0001
0.03 pp<<0.0001
p<
25±±11
55±±11
56±±11
6<0.0001
±1
<0.0001
LVESV LVESV
168
(mL)
(mL)
LVEDV LVEDV
243
(mL)
(mL)
1±4
168
NS
13±±44
3-5±±45
-11± ±5 6 -11
-13±±67 -13
-15±±75 -15
-5
± 5 <0.0001
<0.0001
p NS
= 0.08
0.06
0.003 p = 0.003
pp==0.08
pp == 0.06
1±5
243
NS
15±±55
5-2±±56
-14± ±6 8 -14
-15±±88 -15
-16±±86 -160.0005
-2
±6
0.0005
p NS
= 0.07
p
=
0.07
0.01
p = 0.07
pp==0.07
p = 0.01
<0.0001
0.0005
LVOTHR LVOTHR
66
(bpm)
(bpm)
EFMOD (%)
EF
MOD
p < 0.0001
31
29 IHD
1±1
NS
NS
P = 0.07
2±1
p = 0.03
<0.0001
<0.0001
0.0003
0±1
NS
Correlation
versus
48 – 96
-2 ± 2
-4 ± 1
NS20 – 55
p = 0.001
32
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
2±1
0.009
NS
p = 0.02
7±2
10 ± 1
<0.0001
5±1
6±1
<0.0001
p < 0.0001 p = 0.0009 p < 0.0001
16 DCM
5±1
NS
NS
NS
NS
PNS
= 0.07
NS
NS
NS
NS
NS
NS
-40.0003
±1
0.0003
p=
0.001
NS
p = 0.001
2±
1
0.009
p NS
= 0.02
p
0.0009 pp=<0.0009
0.0001
P<
= 0.0001
0.07 pp<=0.0001
p = 0.02
EJECTION FRACTION
VERSUS
EFMOD (%)
EF
MOD
(%)
SYSTOLIC EJECTION TIME
0.80
0.80
0.0006 0.0006
EFHYB-EDV
EF(%)
(%)
0.83
0.83
< 0.0001
< 0.0001
EFHYB-ESV
EF(%)
(%)
0.89
0.89
< 0.0001
< 0.0001
HYB-EDV
* Generalized
r2 is calculated
ejection
fraction
by the
indicated
* Generalized
r2 is using
calculated
using
ejection
fraction
by themethod
indicated method
versus systolic
ejection
time
treating
patients
as
random
effect
versus systolic ejection time treating patients as random effect
** P-value is
ANOVA
analysis
based
on the
following
** computed
P-value is using
computed
using
ANOVA
analysis
based
on themodel:
following model:
ejection fraction
by
the
indicated
method
=
systolic
ejection
time
+ Error,
treating
ejection fraction by the indicated method = systolic ejection
time
+ Error, treating
patients aspatients
random as
effect
random effect
p < 0.0001 p < 0.0001 p < 0.0001
ax
Mean Mean(m i n - m
(m
i n) - m a x )
Cyril Clarke
Roxy Senior 58
30 – Jamil
77 30Mayet
Age (yrs
) (yrs
Age
)
– 77
58
Manchester, England
London, England
London, England
78
W eig htW(kg
78 52 – 11552 – 115
eig) ht (kg )
Barry Greenberg
Tamaz Shaburishvili
Mark Monaghan
S ysStates
tolic
BP
(m mHg
) mHg
San Diego, United
Georgia
London,
96 – England
183
124 96 – 183
S ys
tolic
BPTbilisi,
(m
) 124
(m mHg
) mHg
Chim Lang Dia s tolic
Tsyrlin
Evgeny
Nifontov
57 – 117
75 57 – 117
DiaBP
s tolic
BPVitaly
(m
) 75
Dundee, Scotland
St. Petersburg, Russia
Russia
69
48 – St.
96Petersburg,
He a rt RHe
a te
48 – 96
a rt(bRpm)
a te (b pm)
69
John McMurray
John Cleland 33
Saltzberg
20 – Mitchell
55 20 – 55
Eje ction
Fra
ction
(%)
33
Eje
ction
Fra
ction
(%)
Glasgow, Scotland
Kingston Upon Hull, England
Newark DE, United States
Ludwig Neyses
Manchester, England
Jonathan Goldman
Cohorts
1- 5
Cohorts
1- 5
San Francisco,
United States
n om e n
39 Me n39 Me n 6 W om6e W
29 IHD 29 IHD 16 DCM16 DCM
CONCLUSIONS
0.009
p < 0.05 p < 0.05
HYB-ESV
69
-4 ± 2
p
33= 0.005
0±1
NS
NS
NS
(r2)*
Variable
Correlation
(r2)*P-value**
Variable Correlation
P-value**
0.0005
33
0.0005
EFHYB-EDVEF
HYB-EDV
32
(%)
(%)
96 – 183
0±1
10± ±3 2
9
0.0001 p < 0.0001
pp =< 0.001
02±±11
p = 57
0.03– 117
p = 0.02
0±1
1±1
1±1
NS
NS
Cohorts 1- 5 NS
± 1n 3 ± 26 W om
8 ± e2 n
391Me
9 ±± 3
3
511± ±2 3 11
p
0.001
p<
= 0.0001
0.01 p p< =0.0001
10±±11
75
p = 0.02
0±1
pNS
= 0.01
11±±11
[CK-1827452]
(p value)
9 ±523 – 115
10 ± 2
p = 0.001
15±±22
Cohorts
1-5 (n=45)
CY 1121 INVESTIGATORS
Cohorts
1-5 (n=45)
-32 ± 116 52 ± 123 180 ± 141 408 ± 173 400 ± 189 330 ± 142
He a rt R a te (b pm)
0±1
0±1
-2 ± 1
66
NS
NS
p = 0.06
Eje ction Fra ction (%)
10
±2
<0.0001
<0.0001
NS
NS
p < 0.05 p < 0.05
(m i n - m a x )
Mean
1±4
18 ± 4 47 ± 5 58 ± 6 59 ± 6 80 ± 5
NS (yrsp )< 0.0001 p < 0.0001 p58
< 0.0001 p < 0.0001
p < 0.0001
30 – 77
Age
NS
01±±22
01±±11
< 0.0001
Placebo Corrected Changes from Baseline
Cohorts
1-5 (n=45)
Difference of Least Squares
Means
± SEM
4423
NS
Dia s tolicNSBP (m mHg
)
80
±5
<0.0001
<0.0001
00±±11
EF < 40%, core lab verified
Echos at Baseline, 1.5, 24, 72, 96 hours
Two period crossover
Dose reduction in last 2 patients
p < 0.05
p = 0.01
47±±45 47
58±±56 58
59±±66 59
80±±65
118± ±4 4 18
p <NS
0.0001 pp<<0.0001
0.0001 pp<<0.0001
0.0001 pp<<0.0001
0.0001 pp<<0.0001
0.0001 p < 0.0001
0±1
33
NS
BASELINE CHARACTERISTICS
5±2
0±2
69
NS
[CK-1827452]
Changes from
Baseline
Placebo Corrected
Placebo Corrected
Changes
from Baseline (p value) [CK-1827452]
(p value)
DifferenceDifference
of Least Squares
± SEM
of LeastMeans
Squares
Means ± SEM
33(%)
p = 0.07
p = 0.07
p = 0.01
EF < 40%, investigator verified
Echos at Baseline, 1.5, 24 hours
Four treatment sessions/patient*
>100-200 >200-300 >300-400 >400-500
0 ± ht
2 (kg1) ± 2
69 W eig
NS
NS
S ys tolic BP (m mHg )
1±4
316
NS
SET
316
(msec)
Correlation
Correlation
>500
versus versus
>100-200
>200-300 >200-300
>300-400 >300-400
>400-500 >400-500
>500
1-100
>100-200
-4±±21
-2
0.0006
0.075
0.075
- 4-2±±22
Three women required
Four treatment sessions/patient*
0.830.1
0.075
0.75/0.375
p = 0.08
= Baseline,
0.06
p 1.5,
= 0.003
24 hours
Echospat
Four treatment sessions/patient*
-14 ± 8 -15 ± 8 -16 ± 6
EF < 40%, core
verified
EFlab
< 40%,
core lab verified
Echos at Baseline,
24, 72, 961.5,
hours
Echos1.5,
at Baseline,
24, 72, 96 hours
Two period crossover
Two period crossover
Dose reduction
in
last
2
patients
Dose reduction in last 2 patients
or
-11 ± 6EF <-13
7 -15 ±verified
5 <0.0001
40%,±investigator
0.800.1
or
or
0.005 p = 0.005
NS
pp == 0.06
EF 30%, core lab verified
P-value**
Echos at Baseline, 1.5, 24, 48 hours
0.05
1.0/0.5
ECHO PK/PD RELATIONSHIP: POOLED ANALYSIS
RESULTS
LVOT SV
(mL)
0.025
0.5
- 4±± 12
-2
EF < 40%, investigator verified
Echos at Baseline, 1.5, 24, 48 hours
Four treatment sessions/patient*
0.025 (r2)*
Correlation
(%)
EFMOD 1.0/0.5
316
SELECTIVE CARDIAC MYOSIN ACTIVATOR, CK-1827452
0.025
pNS
= 0.06
* Generalized is calculated using ejection fraction by the indicated method
versus systolic ejection time treating patients as random effect
** P-value is computed using ANOVA analysis based on the following model:
ejection fraction by the indicated method = systolic ejection time + Error, treating
patients as random effect
SET
(msec)
THE
0.25
RESULTS (CONTD.)
r2
Variable
0.5
0-2±±11
<0.0001
p < 0.0001 p < 0.0001 p < 0.0001
Entry EF and Cohort Features
-2 ± 6
0.25
0.375
0.5/0.25
[CK-1827452]
(ng/mL)
0.5
00±±11
0.89
< 0.0001
(%)
EFHYB-ESV
* Each patient receives double-blind placebo randomly interspersed in dosing order
Ejection fraction (EF) remains a standard measure of left ventricular
function in heart failure. Stroke volume assessed by Doppler interrogation
of the left ventricular outflow tract (LVOT SV) is likely a more accurate
measurement than is EF assessed by the standard 2D image-derived
Method of Discs (MoD), but it is not as familiar as EF. The selective cardiac
myosin activator, CK-452, has been demonstrated to increase various
echocardiographically-assessed indices of systolic function in heart failure
patients by prolonging systolic ejection time (SET)1.
1.0
0±1
66
NS
2±1
p < 0.0001 p = 0.0009 p < 0.0001
NS
0.25
1.0
0.25/0.125
Variable
1
p = 0.03
NS
0.75
Cohort 5
1.0/0.5
EFHYB-EDV (%)
1hr + 1hr + 70hr
0.75/0.375
n = 10
INTRODUCTION
1.0
EF < 40%, investigator
EF < 40%, verified
investigator verified
Echos at Baseline,
24 hours 1.5, 24 hours
Echos1.5,
at Baseline,
Four treatment
sessions/patient*
Four
treatment sessions/patient*
* Each patient*receives
double-blind
randomly
interspersed
dosing order
Each patient
receivesplacebo
double-blind
placebo
randomlyininterspersed
in dosing order
This first Phase II trial of CK-452 was a multi-center, double-blind,
* Each patient receives double-blind placebo randomly interspersed in dosing order
randomized, placebo-controlled
study in heart failure patients treated with
an ACE inhibitor (or ARB) and a beta-blocker, ± diuretics. In Cohorts 1-4,
patients each received four treatments; three escalating doses of CK-452
and one placebo treatment which was randomized into the dosing
sequence to
maintain blinding. Each of the four treatments was at least
[CK-1827452]
Correlation
1-100
>100-200 >200-300 >300-400 >400-500
>500
one week apart.
(ng/mL) In Cohort 5, patients received two 72-hour treatments,
versus
[CK-1827452]
CK-452 and placebo,
in
a
double-blind
crossover
fashion.
The
dosing
Mean
Placebo Corrected Changes from Baseline
(p value)
Variable
Difference of Least Squares Means ± SEM
Baseline
scheme is shown in the table below.
Conclusions: Hybrid EF calculations relating Doppler-derived LVOT SV to a
2D image-derived ventricular volume may be more sensitive to increases in
systolic function than assessments of EF based entirely on 2D imaging.
0.25
0.375
1hr + 1hr + 22hr
1.0/0.5
n=8
EF < 40%, core lab verified
Echos at Baseline, 1.5, 24, 72, 96 hours
Two period crossover
Dose reduction in last 2 patients
0.1
or
EFHYB-EDV
(%)
0.25
0.375
Cohort 5 Cohort 5 1.0/0.5
1hr + 1hr + 70hr
1hr + 1hr + 70hr
n = 10
n = 10 0.75/0.375
EF 30%, core lab verified
Echos at Baseline, 1.5, 24, 48 hours
Three women required
Four treatment sessions/patient*
METHODS
0.75/0.375
EFMOD (%)
0.5
0.75
University
of California,
San Francisco, San Francisco, United States of America; 3 Cytokinetics, Inc., South San Francisco, United States of America
0.1
1.0
2
0.25/0.125
LVOTHR
(bpm)
0.5
0.75
3
Cohort
4 Cohort 40.25/0.125
JH.
Goldman1, JR.
Teerlink2, KG. Saikali3, F. Malik3, AA. Wolff
0.25
0.025
0.5/0.25
1hr + 1hr + 22hr
Purpose: Ejection fraction (EF) remains a standard measure of left
ventricular function in heart failure. Stroke volume by Doppler
interrogation of the left ventricular outflow tract (LVOT SV) is more
accurately measured than EF by the standard 2D image-derived Method of
Discs (MoD), but it is not as familiar as EF. CK-1827452 (CK-452) increases
LVOT SV in heart failure patients by prolonging systolic ejection time (SET).
We compared EF changes calculated by “hybrid” methods (employing both
Doppler and 2D data) to EF changes calculated by MoD for patients
receiving CK-452.
Results: EF by MoD did not increase significantly; hybrid EFs increased
significantly at [CK-452] >300 ng/mL. Correlation (r-square) of change from
baseline in EF vs. change from baseline in SET was 0.73 (p=0.02) for EF by
MoD, 0.77 (p<0.0001) for the hybrid EF based on left ventricular enddiastolic volume (LVEDV) and 0.83 (p<0.0001) for the hybrid EF based on
left ventricular end-systolic volume (LVESV).
Cohort 2
1 hr + 1hr
n=9
Cohort 3 Cohort 3 0.25
1hr + 23hr 1hr + 23hr 0.5
n = 10
1.0
n = 10
EF < 40%, investigator verified
Echos at Baseline, 1.5, 24 hours
Four treatment sessions/patient*
0.375
1.0
Cohort 3
1hr + 23hr
n = 10
of America;
ICON Medical Imaging, Warrington, United States
PATIENTS
IN
0.5
Cohort 2
1 hr + 1hr
n=9
Cohort 2
1 hr + 1hr
n=9
EF < 40%, investigator verified
Echos at Baseline, 1.5, 24 hours
Four treatment sessions/patient*
John Teerlink
San Francisco, United States
REFERENCES
1 Malik FI, Saikali KG, Clarke CP, Teerlink JR, Wolff AA. Systolic Ejection Time is a Sensitive Indicator
of Left Ventricular Systolic Function During Treatment with the Selective Cardiac Myosin
Activator, CK-1827452. 2007 Annual Heart Failure Society of America Meeting, Washington, DC.
September, 2007.
• CK-452 increases systolic
ejection time, stroke volume,
cardiac output, and ejection
fraction in a concentrationdependent manner
• While ejection fraction by all
three methods increased with
the plasma concentration of
CK-452, increases of greater
magnitude were observed
with the hybrid methods
• As expected, ejection fraction
assessed by hybrid methods
that employ a measurement
of stroke volume based
on Doppler interrogation of
the left ventricular outflow
tract correlates much better
with systolic ejection time
(a measurement also based
on Doppler interrogation of
the left ventricular outflow
tract) than does ejection
fraction assessed by the
Method of Discs
• Ejection fraction by the
hybrid method based on
left ventricular end-systolic
volume was slightly better
correlated with systolic
ejection time than the hybrid
EF based on left ventricular
end-diastolic volume