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Improving Cardiac Function:
Reconsidering Concept of
Inotropic Therapy
Kirkwood F. Adams, Jr. MD
Associate Professor of Medicine and Radiology
University of North Carolina at Chapel HIll
HF Management 2019
Amelia Island Meeting
Disclosures
• Research Funding
• Amgen
• Consulting
• Amgen
• Cytokinetics
Reconsideration of Concepts Related
to Inotropic Therapy for CHF
• Classical Inotropes• Digoxin
• Catecholamines – Dobutamine
• PDE Inibitors - Milrinone
• Ca++ Sensitizers – Levosimendan
• Novel Investigational Inotropes• Myosin Activators – Omecamtive Mecarbil
• Mediators of Mitochrondrial Function
• Cardimyocyte Microtubular Modifiers
Strategy for HFrEF Drug Development
• First Approach: Directly address reduced LV
function with drugs whose primary action
improves cardiac contractility
• Second Approach: Target consequences of
reduced LV function which may be critical to
adverse effects that promote long-term
progression of LV damage and dsyfunction
Early Approach to Inotropic Agents
• Assumption - Central problem of CHF with LV
Dysfunction is Low Cardiac Output
• Goal of Drug Development was to identify
agents that increased cardiac contractility
• No Concern for “Too much of a good thing”
• Idea: Maximize Hemodynamic Benefit
Evidence for Inotropic Effect of Milrinone
Baim D Grossman W et al. NEJM 1983;309:748
Progressive LVD In Chronic Oral PDE III Rx
Sinoway LS LeJemtel TH et al JACC 1983;2:327
Milrinone Amrinone
Maskin CS LeJemtel TH et al Am J Med
1982;72:113
Dig Milrinone Trial – Proarrhythmia Mil Rx
DiBianco et al NEJM 1989;320:677
Packer M et al NEJM 1991;325:1468
Dose Given was 10 mg q6H
VEST Trial
Main Results
Vesnarinone
N=3833
Cohn JN et al NEJM 1998;339:1810
Paradox of Classical Inotropic Rx
That Augments Myocyte Ca++
• Short-Term Benefit• May be life saving in “Low Output” Advanced HF
• Bridge to LVAD or TP
• Deadly AE’s – Especially Long-Term• Pro-arrhythmic – VTach-VF – Also AF w RVR
• Worsen Myocardial Energetics – Inc O2 need
• Pro-Apoptotic with Adverse Remodeling
Basic Science Supports Adverse Effects of Early Inotropic Agents
Toxicity of Calcium Critical to Story
• Adverse Effects of Excess Intracellular Ca++
• Pro-arrhythmia
• Apoptosis
• Chronic Reduction in Contractility
• Worsening Energetics – Inc O2 Consumption
• Increased Heart Rate
Unfortunately There is a Downside
To Calcium Loading Myocytes
Pogwizd SM
Wang Y Goldhaber JI PNAS 2004;101:5697
Regulation of Cardiac Inotropic State
Maack C EHJ 2018 ePub
Reconsideration of Concept of Inotropic Rx
Psotka MA JACC 2019;73:2345
Reconsider
Concept of
Inotropes:
Modulators
Myotropes
(Sarcomere)
Calcitropes
(Inc Myocyte Ca++)
Mitotropes
(Energetics)
Psotka MA JACC 2019;73:2345
Back to the Future: Inotropic Agents
• Assumption - Central problem of CHF with LV Dysfunction is Low Cardiac Output
• Goal increased cardiac contractility BUT
• Precision Approach – Target Sarcomere
• Use Clinical Dose Response Assessment to avoid
toxicity
• Use Surrogate Endpoints to Assess Potential
Clinical Benefits of Enhancing Sarcomere
Mechanics
Cardiac muscle cell & sarcomere
Anatomic and Molecular Details of Cardiomyocyte
Contractile Unit – the Sarcomere
The cardiac sarcomere, highlighting protein products of genes involved in hypertrophic
cardiomyopathy.
Kyla E. Dunn et al. Circ Cardiovasc Genet. 2013;6:118-131
Copyright © American Heart Association, Inc. All rights reserved.
Myosin Activators –
Mechanism of Action
Teerlink EuHeartJ 2011;32:1838
Myosin Activators –
Increase the efficiency of
interaction between
Actin and Myosin – more
sustained crosslinking
process which prolongs
contraction for same
level of energy provided
Omecamtiv – Mechanistic Precision Medicine –Target Actomyosin ATPase Cycle – Dual Binding Sites
Planeeles-Herrero VJ, Malik F, Houdusse Nat Commun 2017;8:190
OM-PPS
Inactive
State
OM-PPS PR
Active
State
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 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
Omecamtiv – Myosin Activator – Ca++ Homeostasis Unchanged – No Inc Ca++
Malik FI Science 2011;331:1439
Omecamtiv – Experimental Hemodynamic
Effects – Normal and CHF
Malik FI Science 2011;331:1439
Omecamtiv – Pilot Study in CHF Pts
Teerlink JR Lancet 2011;32:667
Omecamtiv – Positive Effects LV Function
Teerlink JR Lancet 2011;32:667
Omecamtiv Plasma Conc - Change in SET
Cleland J Lancet 2011;32:667
SET =
Systolic
Time
Interval
A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel Cardiac Myosin Activator,
In Patients With Acute Heart Failure
John R. Teerlink, G. Michael Felker, John J. V. McMurray, Piotr Ponikowski, Marco Metra, Gerasimos S. Filippatos, Kenneth Dickstein, Justin A. Ezekowitz, John G. Cleland,
Jae B. Kim, Lei Lei, Beat Knusel, Andrew A. Wolff, Fady I. Malik and Scott M. Wasserman
on behalf of the ATOMIC-AHF Investigators and Patients
Study Design: Sequential Dosing Cohort
Cohort 1 Cohort 2 Cohort 3
Omecamtiv
Placebo
1:1 Randomization (n≈200)
Omecamtiv
Placebo1:1 randomization (n≈200)
Placebo
Omecamtiv1:1 randomization (n≈200)
DMC DMC
Cohort 1 Cohort 2 Cohort 315 mg/hr @ 0-4 hr3 mg/hr @ 4-48 hrTarget: 230 ng/mL
Cmax: 75-500 ng/mLSET: ~8-55 msec
20 mg/hr @ 0-4 hr4 mg/hr @ 4-48 hrTarget: 310 ng/mL
Cmax: 125-700 ng/mLSET: ~14-78 msec
7.5 mg/hr @ 0-4 hr1.5 mg/hr @ 4-48 hrTarget: 115 ng/mL
Cmax: 30-250 ng/mL SET: ~3-28 msec
Pharmacokinetic simulations
Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.
Study DesignP
rese
nta
tio
n f
or
AH
F
Ran
do
mis
atio
n*
1:1
Placebo IV
0 72484Time (hrs)
M A N D A T O R Y I N - H O S P I T A L S T A Y
Day 30EOS
Scre
en
ing
LoadingDose
Omecamtiv mecarbil IV
Month 6
* Randomisation within 24 hours of initial IV diuretic (Amendment 2)
Randomised, double-blind, placebo-controlled, sequential cohort study
6 15 24 Day 6/DC
Vit
al S
tatu
s (p
ho
ne
cal
l)
Study drug administration
1⁰ EP dyspnoea response
PK samplingall subjectsPK/PD sub-study
Echo (PK/PD sub-study)
MaintenanceDose
96
Cardiac troponin/CK-MB
Within 7 days of IP initiation
Pooled Placebo
(N = 303)
Cohort 1OM
(N = 103)
Cohort 2OM
(N = 99)
Cohort 3OM
(N = 101)
Death or WHF*
Yes - n(%) 52 (17) 13 (13) 9 (9) 9 (9)
Relative risk 0.67 0.54 0.54
(95% CI) (0.38, 1.18) (0.28, 1.04) (0.27, 1.08)
p-value 0.151 0.054 0.067
WHF*
Yes - n(%) 51 (17) 13 (13) 8 (8) 9 (9)
Relative risk 0.68 0.49 0.55
(95% CI) (0.38, 1.21) (0.24, 0.98) (0.28, 1.09)
p-value 0.179 0.034 0.075
Secondary Efficacy Endpoint: Worsening Heart Failure (WHF)
*Worsening heart failure is defined as clinical evidence of persistent or deteriorating heart failure requiring at least one of the following treatments:• Initiation, reinstitution or intensification of IV vasodilator• Initiation of IV positive inotropes, or IV vasopressors• Initiation of ultrafiltration, hemofiltration, or dialysis• Initiation of mechanical ventilatory or circulatory support
Preferred TermPatient Incidence, n (%)
PooledPlacebo
(N = 303)
Pooled OM
(N = 303)
Cohort 1OM
(N = 103)
Cohort 2OM
(N = 99)
Cohort 3OM
(N = 101)
Number of subjects reporting AEs of
Supraventricular or Ventricular
Tachyarrhythmia
34 (11.2) 26 (8.6) 13 (12.6) 5 (5.1) 8 (7.9)
Supraventricular Tachyarrhythmias 20 (6.6) 10 (3.3) 6 (5.8) 0 (0.0) 4 (4.0)
Atrial Fibrillation or Atrial Flutter 15 (5.0) 6 (2.0) 3 (2.9) 0 (0.0) 3 (3.0)
Atrial Tachycardia 3 (1.0) 1 (0.3) 1 (1.0) 0 (0.0) 0 (0.0)
Sinus Tachycardia 1 (0.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Supraventricular Tachycardia 2 (0.7) 4 (1.3) 3 (2.9) 0 (0.0) 1 (1.0)
Ventricular Tachyarrhythmias 18 (5.9) 17 (5.6) 8 (7.8) 5 (5.1) 4 (4.0)
Ventricular Arrhythmia 4 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Ventricular Extrasystoles 1 (0.3) 2 (0.7) 1 (1.0) 1 (1.0) 0 (0.0)
Ventricular Fibrillation 2 (0.7) 1 (0.3) 0 (0.0) 1 (1.0) 0 (0.0)
Ventricular Tachyarrhythmia 0 (0.0) 1 (0.3) 1 (1.0) 0 (0.0) 0 (0.0)
Ventricular Tachycardia 11 (3.6) 13 (4.3) 7 (6.8) 3 (3.0) 3 (3.0)
Extrasystoles 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 1 (1.0)
Supraventricular and Ventricular Tachyarrhythmias
-0.05
-0.04
-0.03
-0.02
-0.01
-1E-16
0.01
0.02
0.03
HR4 HR15 HR24 HR48 Day 4 Day 6
Troponin-I Change from Baseline (ng/mL) Compared with Pooled Placebo
Baseline TnI (ng/mL)PooledPlacebo Cohort 1 Cohort 2 Cohort 3
Median 0.044 0.060 0.044 0.056
(Q1, Q3) 0.023, 0.080 0.028, 0.141 0.030, 0.084 0.026, 0.092
4 hours 15 hours 24 hours 48 hours Day 4 Day 6
Time
Tro
po
nin
Ch
ange
fro
m B
ase
line
(n
g/m
L)
Q3
Median
Q1
0.03
0.02
0.01
0.00
–0.01
–0.02
–0.03
–0.04
–0.05
Omecamtiv Mecarbil Concentrations vs. Troponin-I Maximal Change from Baseline
Red lines represent linear regression line and its +/- SE. Baseline troponin-I is adjusted.
Omecamtiv mecarbil Cmax Omecamtiv mecarbil AUC0-48
p=0.83p=0.95
Ma
x T
rop
on
inC
ha
ng
e f
rom
Bas
eli
ne
(ng
/mL
)
Ma
x T
rop
on
in
Ch
an
ge f
rom
Bas
eli
ne
(ng
/mL
)
OM Cmax (ng/mL)
OM Cmax (ng/mL)
OM AUC0-48 (ng*hr/mL)
OM AUC0-48 (ng*hr/mL)
0 200 400 600 800 1000 1200 1400-40
-20
0
20
40
60
80
100
0 200 400 600 800 1000 1200 1400-4
-2
0
2
4
0 10000 20000 30000 40000-40
-20
0
20
40
60
80
100
0 10000 20000 30000 40000-4
-2
0
2
4
COSMIC-HF STUDY DESIGN
• Two-phased, Multicenter, Randomized,
Double-blind, Placeo-controlled
• Outpatients, HFrEF LVEF ≤40, Optimal Rx
• NT-proBNP ≥ 200 pg/mL or ≥ 1200 pg/mL AF
• Two cohorts – dose escalation, extension
• Extension 3 arm, Placebo, 25 mg BID or PK-
based escalation to 50 mg BID
Presented Late-Breaking AHA 2015
COSMIC-HF Expansion Phase
COSMIC
Trial:Change in
SET,
LVEDV,
HR, LVESV
LVEF, SV,
NT-proBNP
Terrlink J et al Lancet 2016;388:2895
Sequential Changes HR and proBNP
A Position on Omecamtiv Development
for HFrEF for Discussion
• Strong basic data for novel MOA
• ATOMIC-HF showed potential
• COSMIC-HF provides evidence of benefit
based on LV Fx and NT-proBNP – classic
surrogates of favorable remodeling of LV
• Troponin findings should be addressed in
larger scale outcome trials but not delay
moving forward
Follow-up to COSMIC - GALACTIC-HF
Major Outcomes Trial
• Multicenter, Randomized, Double-blind, Placeo-
controlled, Dose Monitored, N=8,000
• Out-In Patients, HFrEF LVEF ≤35, Optimal Rx
• Elevated NT-proBNP – NSR ≥ 400 AF ≥ 1200
• Hospitalization or ED Visit for Urgent CHF ≤ 1 yr
• Primary EP = CE Time to CV Death CHF Hosp
• Event Driven – 90% Power for CV Death
Clinical Trials.gov - NCT02929329
Mitochondrial Function in Health and CHF
Microtubule Structure in Working Myocyte –
Key Role of Tyrosine Bound Tubulin
More Complex View of Sarcomere Mechanics –
Microtubules Influence contraction and relaxation
Resistance to
Sarcomere UNIT
Shortening and
Stretch Depends
– In part - on the
State of
Microtubular
Function which in
Turn is Regulated
by Degree of
Tyrosine Binding
the Tubulin
Protein
Current Thoughts – Novel Enhancers of
LV Function • Limitations of Current Drugs that Improve LV function are
well recognized. Novel MOA are needed that don’t depend
on augmenting Ca++
• Omecamtiv unique MOA that is Ca++ independent acting on
Myosin Function Directly – Dec EDV/ESV and proBNP
• OMA Late Stage Development – Outcome Data 2020?
• Cardiac energetics are substantially depressed in CHF
related to mitochondrial dysfunction that may reverse w Rx
• At the structural level, microtubules appear to alter
sacromere mechanics in failing hearts – offering potential
new therapeutic target to improve LV FX
Essential Role of Mitochondrial Function –
ATP Generation
• Humans produce and consume roughly their body
weight in ATP (about 65 kg) every single day. The
heart accounts for only ~0.5% of body weight, but
roughly 8% of ATP use.
• This high energy flux is dynamic: the heart stores
only enough energy to support pumping for a few
heart beats, turning over the entire metabolite pool
approximately every 10 seconds even at resting
heart rates.
Essential Role of Mitochondrial Function
• As the most metabolically active organ in the body,
the heart possesses the highest content of
mitochondria of any tissue. Mitochondria comprise
25–30% of cell volume across mammalian species,
with only the myofilaments being more densely
packed within cardiac myocytes.
• The high mitochondrial content of cardiomyocytes is
needed to meet the enormous energy requirement
for contraction and relaxation. About 90% of cellular
ATP is utilized to support the contraction–relaxation
cycle within the myocardium.
Essential Role of Mitochondrial Function
• ATP-dependent release of actin from myosin is
required for both contraction (as myosin heads
cycle through cross-bridges with actin) and
relaxation.
• Cellular sequestration of calcium back into the
sarcoplasmic reticulum during diastole also
requires a tremendous amount of ATP.
• Cells sustain the energy requirements necessary
to support cardiac function through remarkable
metabolic supply–demand matching.
Essential Role of Mitochondrial Function
• Bioenergetic homeostasis is accomplished almost
exclusively through an ‘energy grid’ comprised of a
mitochondrial network and their associated
phosphate- transfer couples.
• Cardiac mitochondria must operate at high
efficiency levels to respond instantaneously to the
energetic needs of contractile units, a demand that
is ever-changing and necessitated by the body’s
dynamic requirements for oxygen-bearing blood.
Mitochondrial
Dysfunction
in Heart
Failure
relates to
disruption of
electron chain
activity and
accumulation
of reactive
oxygen
species which
are toxic the
myocyte
Mitochondrial Dysfunction May Effect
Extracardiac Organ Function
Mitochondrial Dysfunction – Limits Current Rx
Potential New
Therapeutic
Agent the
Mitochondrial
Modulator
Elamipretide
interacts with
Cardiolipin to
Improve
Mitochondrial
Function
Treatment with Elamipretide Improves
Mitochondrial Function - Basic Model of HF
Elamipretide Improves CV Biomarker Profile
in Basic Model HF
Chronic Elamipretide Improves Cardiac
Function in Basic Model HF
Surprisingly Acute Elamipretide Improves
Cardiac Function in Basic Model HF
Acute Elamipretide
Improves Cardiac
Function in Human
HF
Microtubule
mechanics in
Normal Working
Cardiac
Myocyte at rest
and during
contraction C+D
Removal of
Tyrosine
Disrupts Normal
Microtubular
Function E =
less resistance
to stretch and
shortening
Modifiers of Microtubule
Mechanics – Parthenolide
(PTL) inhibits Tubulin
Carboxypeptide which
removes Tryposine and
Tubulin Tryosine Ligase
(TTL) catalyzes the
addition of Tryosine
Reducing Microtubular Fx Improves Failing
Cardiomyctes in HFrEF and HFpEF
Reduction in Microtubular Function Improves
Contractilitye in Failing Cardiomyocytes
PTL Treatment
Nl vs Failing
Myoctyes
Colchcine Rx
Nl vs Failing
Myoctyes
Therapeutic Role of Altering Microtubule
Mechanics
• Currently available inotropes, such as dobutamine and milrinone, are palliative therapy, at least partly due to increased metabolic cost and arrhythmia risk associated with chronically augmenting Ca2+.
• Destabilizers of a dense microtubular cytoskeletal network may represent a new class of energetically neutral inotropes, which do not force the cell to burn more ATP or augment intracellular calcium flux.
• Reducing microtubular function lowers the resistance the myocyte must work against to improve both systolic and diastolic performance.
Myosin Activators –
Mechanism of Action
Teerlink EuHeartJ 2011;32:1838
Myosin Activators –
Increase the efficiency of
interaction between
Actin and Myosin – more
sustained crosslinking
process which prolongs
contraction for same
level of energy provided
Modifier
Myosin Activators –
Mechanism of Action
Teerlink EuHeartJ 2011;32:1838
Myosin Activators – Increase the
efficiency of interaction between
Actin and Myosin – more
sustained crosslinking process
which prolongs contraction for
same level of energy provided
Early Approach to Inotropic Agents
• Goal of Drug Development was to identify agents
that increased cardiac contractility
• No Concern for “Too much of a good thing”
• Clinical Adverse Effect – Proarrhythmia
• Signals of Disease Progression – Worsening LV
function and LV Size In Early Studies
• Signal of Poorer Clinical Outcomes