Acute Heart Failure Cardiac Myosin Activators Professor John Cleland National Heart & Lung Institute Harefield Hospital Imperial College London Potential Conflicts of Interest:- I have received research support and/or speaker’s fees from Amgen, Medtronic, NI Medical, Novartis, Philips, Servier, Stealth BioTherapeutics, St Jude and Vifor. Omecamtiv Mecarbil
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Acute Heart Failure
Cardiac Myosin Activators
Professor John ClelandNational Heart & Lung Institute
Harefield HospitalImperial College
London
Potential Conflicts of Interest:- I have received research support and/or speaker’s fees from Amgen, Medtronic, NI Medical, Novartis, Philips, Servier, Stealth BioTherapeutics, St Jude and Vifor.
Omecamtiv Mecarbil
Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator
Malik FI, et al. Science 2011; 331:1439-43.
Mechanochemical Cycle of Myosin
Force production
Omecamtiv mecarbil
Omecamtiv mecarbil increases the entry rate of myosin into the tightly-bound, force-producing
state with actin“More hands pulling on the rope”
Increases duration of systole
Increases stroke volume
No increase in myocyte calcium
No change in dP/dtmax
No increase in MVO2
3
Omecamtiv Mecarbil Does Not Alter the Ca2+ Transient
Rat Adult Cardiac MyocytesContractility Transient
-20
-16
-12
-8
-4
0
0 0.2 0.4 0.6 0.8 1Time (sec)
Cel
l Len
gth
∆ (m
m)
BasalOmecamtiv mecarbil200 nM
Contractility Transient
-10
-8
-6
-4
-2
0
0 0.2 0.4 0.6 0.8 1Time (sec)
Cel
l Len
gth
∆ (m
m)
BasalIsoproterenol
2 nM
Calcium Transient
Time (sec)
Fura
-2 R
atio
0.7
0.9
1.1
1.3
1.5
0 0.2 0.4 0.6 0.8 1
BasalOmecamtiv mecarbil200 nM
Calcium Transient
Time (sec)
Fura
-2 R
atio
0.7
0.9
1.1
1.3
1.5
0 0.2 0.4 0.6 0.8 1
BasalIsoproterenol
2 nM
Malik et al, 2011
Intravenous• Healthy Volunteer Study• Pharmacokinetic Study (2-72hours)• ATOMIC
Oral• Angina Treadmill Study• COSMIC
Clinical Trials of Omecamtiv Mecarbil
Cleland JGF, et al. Lancet 2011; 378: 676–83.
Teerlink JR, et al. Lancet 2011; 378: 667–75. Dose limiting chest discomfort and troponin release
Haemodynamic Effects of Omecamtiv Mecarbil
Cleland JGF, et al. Lancet 2011; 378: 676–83.
Changes in Selected Echocardiographic Variables Over time in Patients with CHF
•Cleland JGF, et al. Lancet 2011.
Patients received 1.0 mg/kg per h for 1 h, then 0.5 mg/kg per h for 1 h, and then 0.1 mg/kg per h for 70 h.
Objective:• To evaluate the safety, pharmacokinetics/ pharmacodynamics, and
efficacy of IV omecamtiv mecarbil (OM) in patients with acute heart failure (AHF) – with HFrEF, raised NP and SysBP >90mmHg but excluding ACS
Hypothesis: • At least 1 dose level of IV OM will be well tolerated and will result in
improvement of dyspnoea (at 6, 24 & 48 hrs) in subjects with left ventricular systolic dysfunction hospitalised for AHF
ATOMIC-AHFAcute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure
PK Concentration Bin Analysis Control OM Conc. Bin 1
OM Conc. Bin 2
OM Conc. Bin 3
OM concentration (ng/ml) ≥88-200 >200-300 >300-787
Heart Rate (beats/min) LS means -4.3 -4.4 -6.3 -6.5 Difference from control -0.1 -2.0 -2.3 95% CI (-1.4, 1.1) (-3.6, -0.4) (-3.9, -0.6) p-value 0.835 0.016 0.008Linear regression slope p < 0.0001SBP (mmHg) LS means -4.6 -4.4 -4.0 -2.2 Difference from control 0.3 0.6 2.4 95% CI (-1.2, 1.7) (-1.2, 2.4) (0.6, 4.2) p-value 0.719 0.521 0.009Linear regression slope p = 0.0017
N: number of patients in the bin, n: number of observations in the bin. Heart rate measured by ECG. Control = observations in Placebo + PK below quantification limit. PK bin concentration analysis: repeated measures analysis of covariance. Linear regression slope analysis: repeated measures multiple linear regression.
H
R 4 -0.05
-0.04
-0.03
-0.02
-0.01
0
0.01
0.02
0.03
Troponin-I Change from Baseline (ng/mL) Compared with Pooled Placebo