Improving Cardiac Function: Reconsidering Concept of ... · Worsening Heart Failure (WHF)...

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