ACUTE HEART FAILURE –
THE ROAD TO WHERE?
Gad Cotter, Momentum-Research Inc
AHF therapy 1970 - 2010
Vasoconstricted
(no real criteria)
Congestion
Renal
Impairment
Vasodilators
Diuresis
Renoprotection
Low output
(No real criteria)
Inotrope
10-15% of Patients
Nitro-vasodilators
Natriuretic peptides
Loop Diuretics
> 90% of
Patients
< 5% of patients
Levosimendan
Dobutamine
Milrinone
IV Diuretic + Nesiritide
IV Diuretic + Inotrope
6%
IV Diuretic
72%
4%
4%
9%
IV Diuretic + Nitro
1% Nesiritide Alone
1% Inotrope Alone
Other
AHF Current Treatment Options – this is really sad….
AHF therapy 1970 - 2010
Vasoconstricted
(no real criteria)
Congestion
Renal
Impairment
Vasodilatation
Diuresis
Renoprotection
Low output
(No real criteria)
Inotrope
10-15% of Patients
Nitro-vasodilators
Natriuretic peptides
Loop Diuretics
> 90% of
Patients
< 5% of patients
Levosimendan
Dobutamine
Milrinone
Critical look: Some improved symptoms, some
prevention of in hospital Worsening HF but….
VMAC Nesiritide
Critical look – minimal
dyspnea improvement
With worsening renal
function and increased
mortality
Dyspnea Improvement in VMAC
AHF therapy 2010 – Combination
Therapy?
Vasoconstricted
Sys BP > 125 mmHg
Vasodilatation
Congestion
Renal Impairment
(eGFR< 80 cc/min)
Diuresis
Low output
Sys BP < 125 mmHg
Renoprotection
Inotrope
# Relaxin ?
(phase III)
# Direct Soluble
GC Activators ?
(phase II)
#Low dose
Loop Diuretics
(Phase III)?
# Vasopresin
Antagonists and
low dose
Loop diuretics
(phase II)?
Adenosine A1
Antagonists
(Rolofyline)?
(phase III - II)
Low dose
Natriuretic
Peptides?
(Phase II)
# Cardiac Myosin
Activators?
(Phase II)
# SERCA2A
Activators?
(phase I)
AHF therapy Beyond 2010 – Improve
diagnosis by non-invasive CO
Vasoconstricted
Increased SVR
Vasodilatation
Congestion
Renal Impairment
(eGFR< 80 cc/min)
Diuresis
Low output
Low Cardiac Power
Renoprotection
Inotrope
# Relaxin ?
(phase III)
# Direct Soluble
GC Activators ?
(phase II)
#Low dose
Loop Diuretics
(Phase III)?
# Vasopresin
Antagonists and
low dose
Loop diuretics
(phase II)?
Adenosine A1
Antagonists
(Rolofyline)?
(phase III - II)
Low dose
Natriuretic
Peptides?
(Phase II)
# Cardiac Myosin
Activators?
(Phase II)
# SERCA2A
Activators?
(phase I)
Some Supportive information
The Lancet - April 15h 2009
Relaxin Mechanisms of Action
Relaxin



Naturally occurring peptide
Up-regulated in pregnancy and HF
Vasodilation…






Upregulation of ETB
Induction of NOS II/III
NO, cGMP effectors
…but actually an anti-vasocontrictor
- Preferential dilates constricted
vessels
Anti-ischemic effects in animal
models
Anti-inflammatory

Down-modulation of inflammatory
cytokines linked to outcome in HF
(TNF-a, TGF-b)
11
Global Phase 2 in Acute Heart Failure
Study Design
 Phase 2/3, Multicenter, Randomized, Double-Blind, PlaceboControlled, International Study
 Randomized to placebo, 10, 30, 100, 250 μg/kg of relaxin (3,2,2,2,2) –
48 hr iv infusion, on top of standard of care
 234 patients, 54 sites, 8 countries
 “Acute Vascular Failure” subset of AHF:
Patient
Population
- Dyspnea requiring hospitalization
- BNP/NT-pro-BNP > 350/1400 pg/mL
- Baseline BP > 125 mmHg
- Renal dysfunction (CrCl 30-75 mL/min)
 Dyspnea (shortness of breath): Serial Likert and VAS to Day 14
Study Endpoints
& Objectives
 Other AHF measures - Signs, symptoms, outcomes through Day 14
- 180
 Safety, including renal dysfunction
 Choose dose, endpoints, sample size, sites
12 for pivotal P3 trials
Dyspnea Improvement over Time
p=0.06
p=0.05
10000
9000
p=0.16
Dyspnea (AUC; mm*hr)
8000
7000
6000
5000
4000
3000
p=0.11
p=0.15
p=0.16
2000
1000
0
Placebo
10
30
100
250
Relaxin (mcg/kg/d)
Day 5
Placebo
10
30
100
250
Relaxin (mcg/kg/d)
Day 14
13
Kaplan-Meier Event-free Survival (%)
CV Death or Heart/Renal Failure
Re-hospitalizations to Day 60
Relaxin 30 mcg/kg/d
(p<0.05)
1
Cardiovascular Deaths to Day
180
Relaxin 30 mcg/kg/d
(p<0.05)
1
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d
0.95
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d
0.95
Relaxin 250 mcg/kg/d
0.9
Placebo
0.85
0.8
0
30
60
90
Days
120
150
180
Relaxin 250 mcg/kg/d
0.9
Placebo
0.85
0.8
0
30
60
90
120
150
Days
Critical look – Too good to be true? Lack of clear mechanism of action?
180
soluble Guanylate Cyclase (sGC) Stimulators
and sGC Activators
NO
sGC Stimulator
sGC Fe(II) heme
sGC Activator
sGC Fe(III) heme
Oxidative
Stress
cGMP
sGC Activator
Stasch/as/3
sGC Stimulator
 Amplifies protective effects of NO in the
cardiovascular system
 NO-independent mode of action
 Selective dilation of diseased or
oxidative
stress impaired blood vessels
Proof of Concept Study – Hemodynamic Results
Cardiac Output
PCWP
7
L/min
mmHg
30
24,7
25
6,04
6
5,59
5,04
20,7
20
18,2
15
10
19,0
2h
4h
5
16,9
4,35
4
BAY 58-2667 after
BL
5,37
6h
FU
2h
BAY 58-2667 after
BL
3
2h
4h
6h
FU
2h
Critical look – (1) By bypassing the endothelium, drug also bypases know control
pathways? Hence may increase risk of hypotension
(2) Will need very careful titration and patient selection, but for some
patients especially with endothelial dysfunction – may be very
helpful
Proof of Concept Study – Hemodynamic Results
Cardiac Output
PCWP
7
L/min
mmHg
30
24,7
25
6,04
6
5,59
5,04
20,7
20
18,2
15
10
19,0
2h
4h
5
16,9
4,35
4
BAY 58-2667 after
BL
5,37
6h
FU
2h
BAY 58-2667 after
BL
3
2h
4h
6h
FU
2h
Rolofylline: Selective Renal Arterial Vasodilator for the
Treatment of Acute Heart Failure
Thiazides
1. Inhibits sodium reabsorption in
the proximal tubule  enhances
diuresis
2. Blocks adenosine-mediated
vasoconstriction of afferent
arteriole  maintains glomerular
filtration rate (GFR).
1
Interstitial
2
Na+
Proximal Tubule
Adenosine-mediated
Vasoconstriction
Blocked Adenosine-mediated
Vasoconstriction
Afferent
Arteriole
Smooth
Muscle
Cells
MD
Cells
A1 Receptor
Adenosine
Distal
Tubule
Furosemide
MK-7418
MD
Cells
A1 Receptor
Adenosine
Distal
Tubule
20
Mean change in serum creatinine, mg/dL
Change in Serum Creatinine
0.35
Placebo (n=78)
0.3
10 mg (n=74)
20 mg (n=75)
0.25
30 mg (n=74)
0.2
0.15
0.1
0.05
0
-0.05
Day 2
Day 3
Day 7
Day 14
21
% subjects
All-Cause Mortality: 30-Day and 60-Day
18
Placebo (n=78)
16
20 mg (n=75)
14
30 mg (n=74)
10 mg (n=74)
12
10
8
6
4
2
0
30-Day
60-Day
Critical look – (1) Effects only patients at risk for renal impairment – many treated
for a few to benefit
(2) Seizure risk – not globally applicable
22
Myosin Activators - A Novel Mechanism for
Heart Failure Therapy
• Selectivity for cardiac sarcomere versus other muscle
types
• No increase in the cardiac myocyte calcium transient
• Efficacy in large animal model of heart failure
• Lengthens the duration of cardiac contraction rather than the
contraction velocity
• Improves cardiac function and hemodynamics in dose-dependent
fashion
• Improves cardiac efficiency without increasing MV02
• High oral bioavailability in preclinical species
CK - 1827452
Methods
Double blind, placebo controlled phase IIa Study, patients with
Chr HF, EF<40%. Dose escalating and time escalating from 2 48 hours of infusion.
Results
Critical look – shortens diastole while lengthening systole – myocardial perfusion?
Calcium Cycling Mediated by SERCA2a is Key to Cardiac
Contraction


Heart failure => reduced SERCA2a
results in
reduced contraction &
elevated intracellular Ca2+
Contraction


Intracellular Ca2+ increased, binds
troponin C and starts contractile
machinery
Relaxation

Intracellular Ca2+ declines via reuptake into SR

SERCA2a removes 70% of the
intracellular calcium from the
intracellular space in humans
26
26
XXX Improves Hemodynamics in
Myocardial Infarction Model in the
Mouse.
27
Vehicle control
Hemodynamic Parameters
Control
XXXXX
XXXXX
Pmax (mmHg)…………………
51
71
dP/dtmax (mmHg/sec)……….
2716
4237
Contractility Index (sec-1)…….
109
124
Cardiac Output (mL/min)……..
4536
6102
Ejection Fraction (%)…………
18
28
Stroke Work…………………...
219
660
Stroke Volume (mL)………….
10
15
Heart Rate (bpm)……………..
476
410