ACUTE HEART FAILURE THE ROAD TO WHERE?Gad Cotter, Momentum-Research Inc

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AHF therapy 1970 - 2010DiuresisReno-protectionVasodilatorsInotropeVasoconstricted(no real criteria)Renal ImpairmentLow output(No real criteria)10-15% of PatientsNitro-vasodilatorsNatriuretic peptidesCongestionLoop Diuretics> 90% of Patients< 5% of patientsLevosimendanDobutamineMilrinone

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AHF Current Treatment Options this is really sad.IV Diuretic72%IV Diuretic + NesiritideIV Diuretic + InotropeIV Diuretic + NitroOther6%4%4%9%1% Nesiritide Alone1% Inotrope Alone

Chart1

0.72IV DiureticIV Diuretic

0.06IV Diuretic + NesiritideIV Diuretic + Nesiritide

0.04IV Diuretic + InotropeIV Diuretic + Inotrope

0.04IV Diuretic + NitroIV Diuretic + Nitro

0.01NesiritideNesiritide

0.01InotropesInotropes

0.09OtherOther

Sheet1

IV DiureticIV Diuretic + NesiritideIV Diuretic + InotropeIV Diuretic + NitroNesiritideInotropesOther

0.720.060.040.040.010.010.09

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AHF therapy 1970 - 2010DiuresisReno-protectionVasodilatationInotropeVasoconstricted(no real criteria)Renal ImpairmentLow output(No real criteria)10-15% of PatientsNitro-vasodilatorsNatriuretic peptidesCongestionLoop Diuretics> 90% of Patients< 5% of patientsLevosimendanDobutamineMilrinone

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

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Dyspnea Improvement in VMACVMAC - NesiritideCritical look minimal dyspnea improvementWith worsening renal function and increased mortality

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AHF therapy 2010 Combination Therapy?DiuresisReno-protectionVasodilatationInotropeVasoconstrictedSys BP > 125 mmHgRenal Impairment(eGFR< 80 cc/min)Low outputSys BP < 125 mmHg# Relaxin ? (phase III)# Direct Soluble GC Activators ? (phase II)Congestion#Low doseLoop Diuretics(Phase III)?# VasopresinAntagonists and low doseLoop 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)

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AHF therapy Beyond 2010 Improve diagnosis by non-invasive CODiuresisReno-protectionVasodilatationInotropeVasoconstrictedIncreased SVRRenal Impairment(eGFR< 80 cc/min)Low outputLow Cardiac PowerCongestion# Relaxin ? (phase III)# Direct Soluble GC Activators ? (phase II)#Low doseLoop Diuretics(Phase III)?# VasopresinAntagonists and low doseLoop 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)

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Some Supportive information

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The Lancet - April 15h 2009

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Relaxin Mechanisms of ActionNaturally occurring peptide Up-regulated in pregnancy and HFVasodilationUpregulation of ETBInduction of NOS II/IIINO, cGMP effectorsbut actually an anti-vasocontrictor - Preferential dilates constricted vesselsAnti-ischemic effects in animal modelsAnti-inflammatoryDown-modulation of inflammatory cytokines linked to outcome in HF (TNF-a, TGF-b)

Relaxin*

*Global Phase 2 in Acute Heart FailureDyspnea (shortness of breath): Serial Likert and VAS to Day 14Other AHF measures - Signs, symptoms, outcomes through Day 14 - 180Safety, including renal dysfunctionChoose dose, endpoints, sample size, sites for pivotal P3 trials

Acute Vascular Failure subset of AHF:Dyspnea requiring hospitalizationBNP/NT-pro-BNP > 350/1400 pg/mLBaseline BP > 125 mmHgRenal dysfunction (CrCl 30-75 mL/min)

Study Endpoints & ObjectivesPatient PopulationPhase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, International StudyRandomized to placebo, 10, 30, 100, 250 g/kg of relaxin (3,2,2,2,2) 48 hr iv infusion, on top of standard of care234 patients, 54 sites, 8 countries

Study Design

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Dyspnea Improvement over Time*

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

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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

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Cardiac OutputL/min

PCWPmmHg BAY 58-2667 after

2h 4h 6h BLFU2h BAY 58-2667 after

2h 4h 6h BLFU2h Proof of Concept Study Hemodynamic Results

Cardiac OutputL/min

PCWPmmHg BAY 58-2667 after

2h 4h 6h BLFU2h BAY 58-2667 after

2h 4h 6h BLFU2h Proof of Concept Study Hemodynamic ResultsCritical 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

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*Rolofylline: Selective Renal Arterial Vasodilator for the Treatment of Acute Heart Failure

*Change in Serum Creatinine

*All-Cause Mortality: 30-Day and 60-DayCritical look (1) Effects only patients at risk for renal impairment many treated for a few to benefit (2) Seizure risk not globally applicable

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Myosin Activators - A Novel Mechanism for Heart Failure TherapySelectivity for cardiac sarcomere versus other muscle typesNo increase in the cardiac myocyte calcium transientEfficacy in large animal model of heart failureLengthens the duration of cardiac contraction rather than the contraction velocityImproves cardiac function and hemodynamics in dose-dependent fashionImproves cardiac efficiency without increasing MV02High oral bioavailability in preclinical species

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CK - 1827452Double blind, placebo controlled phase IIa Study, patients with Chr HF, EF

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Calcium Cycling Mediated by SERCA2a is Key to Cardiac ContractionHeart failure => reduced SERCA2a results in reduced contraction & elevated intracellular Ca2+ Contraction Intracellular Ca2+ increased, binds troponin C and starts contractile machineryRelaxationIntracellular Ca2+ declines via re-uptake into SRSERCA2a removes 70% of the intracellular calcium from the intracellular space in humans

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*XXX Improves Hemodynamics in Myocardial Infarction Model in the Mouse.XXXXXdP/dtmax (mmHg/sec).Hemodynamic ParametersControlXXXXXPmax (mmHg)Contractility Index (sec-1).Cardiac Output (mL/min)..Ejection Fraction (%)2716423710912445366102Stroke Work...1828Stroke Volume (mL).21966010155171Heart Rate (bpm)..476410Vehicle control

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