Acute Heart Failure – The road to where

1. ACUTE HEART FAILURE –
THE ROADTO WHERE?
Gad Cotter, Momentum-Research Inc

2. AHF therapy 1970 - 2010
Diuresis
Reno-
protection
Vasodilators
Inotrope
Vasoconstricted
(no real criteria)
Renal
Impairment
Low output
(No real criteria)
10-15% of Patients
Nitro-vasodilators
Natriuretic peptides
Congestion
Loop
Diuretics
> 90% of
Patients
< 5% of patients
Levosimendan
Dobutamine
Milrinone

3. AHF Current Treatment Options – this is really sad….
IV Diuretic 72%
IV Diuretic + Nesiritide
IV Diuretic + Inotrope
IV Diuretic + Nitro
Other
6%
4%
4%
9%
1% Nesiritide Alone
1% Inotrope Alone

4. AHF therapy 1970 - 2010
Diuresis
Reno-
protection
Vasodilatation
Inotrope
Vasoconstricted
(no real criteria)
Renal
Impairment
Low output
(No real criteria)
10-15% of Patients
Nitro-vasodilators
Natriuretic peptides
Congestion
Loop
Diuretics
> 90% of
Patients
< 5% of patients
Levosimendan
Dobutamine
Milrinone

5. Critical look: Some improved symptoms, some
prevention of in hospital Worsening HF but….

6. Dyspnea Improvement in VMAC
VMAC -
Nesiritide
Critical look – minimal
dyspnea improvement
With worsening renal
function and increased
mortality

7. AHF therapy 2010 – Combination
Therapy?
Diuresis
Reno-
protection
Vasodilatation
Inotrope
Vasoconstricted
Sys BP > 125 mmHg
Renal Impairment
(eGFR< 80 cc/min)
Low output
Sys BP < 125 mmHg
# Relaxin ?
(phase III)
# Direct Soluble
GC Activators ?
(phase II)
Congestion
#Low dose
Loop Diuretics
(Phase III)?
# Vasopresin
Antagonists
and low dose
Loop diuretics
(phase II)?
# Cardiac Myosin
Activators?
(Phase II)
# SERCA2A
Activators?
(phase I)
Adenosine
A1
Antagonists
(Rolofyline)?
(phase III - II)
Low dose
Natriuretic
Peptides?
(Phase II)

8. AHF therapy Beyond 2010 – Improve
diagnosis by non-invasive CO
Diuresis
Reno-
protection
Vasodilatation
Inotrope
Vasoconstricted
Increased SVR
Renal Impairment
(eGFR< 80 cc/min)
Low output
Low Cardiac PowerCongestion
# 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)

9. Some Supportive information

10. The Lancet - April 15h 2009

11. Relaxin Mechanisms of Action
 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)
Relaxin
11

12. 12
Global Phase 2 in Acute Heart Failure
 Dyspnea (shortness of breath): Serial Likert and VAS to Day 14
 Other AHF measures - Signs, symptoms, outcomes through Day 14
- 180
 Safety, including renal dysfunction
 Choose dose, endpoints, sample size, sites for pivotal P3 trials
 “Acute Vascular Failure” subset of AHF:
- Dyspnea requiring hospitalization
- BNP/NT-pro-BNP > 350/1400 pg/mL
- Baseline BP > 125 mmHg
- Renal dysfunction (CrCl 30-75 mL/min)
Study Endpoints
& Objectives
Study Endpoints
& Objectives
Patient
Population
Patient
Population
 Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, 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
Study DesignStudy Design

13. Dyspnea Improvement over Time
13
Day 5 Day 14
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
Dyspnea(AUC;mm*hr)
p=0.11
p=0.05
p=0.06
Placebo 10 30 100 250
Relaxin (mcg/kg/d)
Placebo 10 30 100 250
Relaxin (mcg/kg/d)
p=0.16
p=0.16p=0.15

14. CV Death or Heart/Renal Failure
Re-hospitalizations to Day 60
0 .8
0 .8 5
0 .9
0 .9 5
1
0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0
D a y s
P la c e b o
R e la x in 1 0 m c g /k g /d
R e la x in 1 0 0 m c g /k g /d
R e la x in 2 5 0 m c g /k g /d
R e la x in 3 0 m c g /k g /d
(p < 0 .0 5 )
Cardiovascular Deaths to Day
180
0 .8
0 .8 5
0 .9
0 .9 5
1
0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0
Kaplan-MeierEvent-freeSurvival(%)
D a y s
P la c e b o
R e la x in 1 0 m c g /k g /d
R e la x in 1 0 0 m c g /k g /d
R e la x in 2 5 0 m c g /k g /d
R e la x in 3 0 m c g /k g /d
(p < 0 .0 5 )
Critical look – Too good to be true? Lack of clear mechanism of action?

15. soluble Guanylate Cyclase (sGC) Stimulators
and sGC Activators
sGC Fe(III) hemesGC Fe(II) heme
sGC StimulatorsGC Stimulator sGC ActivatorsGC Activator
Oxidative
Stress
cGMP
NONO
sGC Activator
 NO-independent mode of action
 Selective dilation of diseased or
oxidative
stress impaired blood vessels
sGC Stimulator
 Amplifies protective effects of NO in the
cardiovascular system
Stasch/as/3

16. 4,35
5,04
5,59
6,04
5,37
3
4
5
6
7
Cardiac Output
L/min
PCWP
mmHg
BAY 58-2667 after
2h 4h 6hBL
FU
2h
BAY 58-2667 after
2h 4h 6hBL
FU
2h
Proof of Concept Study – Hemodynamic
Results
24,7
20,7
18,2
16,9
19,0
10
15
20
25
30

17. 4,35
5,04
5,59
6,04
5,37
3
4
5
6
7
Cardiac Output
L/min
PCWP
mmHg
BAY 58-2667 after
2h 4h 6hBL
FU
2h
BAY 58-2667 after
2h 4h 6hBL
FU
2h
Proof of Concept Study – Hemodynamic
Results
24,7
20,7
18,2
16,9
19,0
10
15
20
25
30
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

20. 20
Rolofylline: Selective Renal Arterial Vasodilatorforthe
Treatment of Acute Heart Failure
1. Inhibits sodium reabsorption in
the proximal tubule  enhances
diuresis
2. Blocks adenosine-mediated
vasoconstriction of afferent
arteriole  maintains glomerular
filtration rate (GFR).
MK-7418
Distal
Tubule
Smooth
Muscle
Cells
A1 Receptor
Adenosine
MD
Cells
Proximal Tubule
Na+
Afferent
Arteriole
Distal
Tubule
A1 Receptor
Adenosine
MD
Cells
Interstitial
Furosemide
Thiazides
Adenosine-mediated
Vasoconstriction
Blocked Adenosine-mediated
Vasoconstriction
1
2

21. 21
Change in SerumCreatinine
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Day 2 Day 3 Day 7 Day 14
Meanchangeinserumcreatinine,mg/dL
Placebo (n=78)
10 mg (n=74)
20 mg (n=75)
30 mg (n=74)

22. 22
All-Cause Mortality: 30-Day and 60-Day
0
2
4
6
8
10
12
14
16
18
30-Day 60-Day
%subjects
Placebo (n=78)
10 mg (n=74)
20 mg (n=75)
30 mg (n=74)
Critical look – (1) Effects only patients at risk for renal impairment – many treated
for a few to benefit
(2) Seizure risk – not globally applicable

24. Myosin Activators - ANovelMechanism
forHeart FailureTherapy
• 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

25. CK- 1827452
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
Methods
Critical look – shortens diastole while lengthening systole – myocardial perfusion?

26. 26
26
CalciumCycling 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
re-uptake into SR
 SERCA2a removes 70% of
the intracellular calcium from
the intracellular space in
humans

27. 27
XXX Improves Hemodynamics
in Myocardial Infarction Model in
the Mouse.
XXXXX
dP/dtmax (mmHg/sec)……….
Hemodynamic Parameters
Control XXXXX
Pmax (mmHg)…………………
Contractility Index (sec-1
)…….
Cardiac Output (µL/min)……..
Ejection Fraction (%)…………
2716 4237
109 124
4536 6102
Stroke Work…………………...
18 28
Stroke Volume (µL)………….
219 660
10 15
51 71
Heart Rate (bpm)…………….. 476 410
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