Acute Heart Failure – The road to where?

1. Acute Heart Failure – The road to where? Gad Cotter, Momentum-Research Inc

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

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

4. AHF therapy 1970 - 2010 Vasoconstricted (no real criteria) Congestion Renal Impairment Low output (No real criteria) Vasodilatation Diuresis Reno-protection Inotrope 10-15% of Patients Nitro-vasodilators Natriuretic peptides 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. VMAC - Nesiritide Dyspnea Improvement in VMAC Critical look – minimal dyspnea improvement With worsening renal function and increased mortality

7. AHF therapy 2010 – Combination Therapy? Vasoconstricted Sys BP > 125 mmHg Congestion Renal Impairment (eGFR< 80 cc/min) Low output Sys BP < 125 mmHg Vasodilatation Diuresis Reno-protection Inotrope #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) # Relaxin ? (phase III) # Direct Soluble GC Activators ? (phase II) # Cardiac Myosin Activators? (Phase II) # SERCA2A Activators? (phase I)

8. AHF therapy Beyond 2010 – Improve diagnosis by non-invasive CO Vasoconstricted Increased SVR Congestion Renal Impairment (eGFR< 80 cc/min) Low output Low Cardiac Power Vasodilatation Diuresis Reno-protection Inotrope #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) # Relaxin ? (phase III) # Direct Soluble GC Activators ? (phase II) # Cardiac Myosin Activators? (Phase II) # SERCA2A Activators? (phase I)

9. Some Supportive information

10. The Lancet - April 15h 2009

11. 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 Mechanisms of Action Relaxin

12. Global Phase 2 in Acute Heart Failure • 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 Design • “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) Patient Population • 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 Study Endpoints & Objectives

13. Dyspnea Improvement over Time

14. CV Death or Heart/Renal Failure Re-hospitalizations to Day 60 Cardiovascular Deaths to Day 180 Critical look – Too good to be true? Lack of clear mechanism of action?

15. NO sGC Stimulator sGC Activator sGC Fe(II) heme sGC Fe(III) heme Oxidative Stress Stimulation Activation cGMP • sGC Stimulator • Amplifies protective effects of NO in the cardiovascular system soluble Guanylate Cyclase (sGC) Stimulators and sGC Activators • sGC Activator • NO-independent mode of action • Selective dilation of diseased or oxidative stress impaired blood vessels

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

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

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

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

22. 18 16 14 12 10 % subjects 8 6 4 2 Placebo (n=78) 0 10 mg (n=74) 30-Day 60-Day 20 mg (n=75) 30 mg (n=74) All-Cause Mortality: 30-Day and 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

24. 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

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

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

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