12/17/16 Disclosures Research Contracts: Amgen, Astra Zeneca, - - PDF document

SLIDE 1

12/17/16 1

Investigational Medical Therapies for Acute and Chronic Heart Failure

John R. Teerlink, M.D.

FACC, FAHA, FESC, FHFSA, FRCP(UK) Professor of Medicine, University of California San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical Center San Francisco, CA, USA

• Research Contracts: Amgen, Astra Zeneca, Bayer,

Bristol Meyer Squibb, Celyad, Cytokinetics, Medtronic, Merck, Novartis, St. Jude, Trevena

• Consultant: Amgen, Astra Zeneca, Bayer, Bristol

Meyer Squibb, Celyad, Cytokinetics, Medtronic, Merck, Novartis, St. Jude, Stealth, Trevena

Disclosures

Investigational Medical Therapies for Acute and Chronic Heart Failure Teaching Old Dogs New Tricks Agents with Vasodilating Properties Getting to the Heart of the Matter

SLIDE 2

12/17/16 2

Teaching Old Dogs New Tricks:

• Diuretics: Torsemide, Subcutaneous diuretics

Investigational Medical Therapies for Acute and Chronic Heart Failure Risk of long-term mortality associated with diuretic treatment

Paren P, et al. ESC 2016 Death N (%) All-Cause Mortality, Unadjusted HR (95% CI) P-value All-cause Mortality, Adjusted for MAGICC score HR (95% CI) P-value No diuretics (n=4,940) 788 (16%) Ref.

• Ref.
• Diuretics

(n=12,579) 4,523 (36%)

2.57

(2.38-2.77)

<0.001

1.42

(1.23-1.64)

<0.001

Torsemide versus Furosemide in Patients With Acute Heart Failure (from the ASCEND-HF Trial)

Mentz RJ, et al. Am J Cardiol 2016;117:404-411.

87% (n=3,620) received furosemide and 13% (n=557) received torsemide

Teaching Old Dogs New Tricks:

• Diuretics: Torsemide, Subcutaneous diuretics
• Angiotensin Receptor Neprilysin Inhibitor (ARNI):

Sacubitril/ Valsartan Investigational Medical Therapies for Acute and Chronic Heart Failure

SLIDE 3

12/17/16 3

LCZ696 – A First-in-Class Angiotensin Receptor Neprilysin Inhibitor (ARNI)

AT1 receptor

Vasoconstriction “ blood pressure “ sympathetic tone “ aldosterone “ fibrosis “ hypertrophy Angiotensinogen (liver secretion) Angiotensin I Angiotensin II

Renin Angiotensin System

Vasodilation ” blood pressure ” sympathetic tone ”aldosterone levels ” fibrosis ” hypertrophy Natriuresis/Diuresis Inactive fragments BNP pro-BNP NT-pro BNP Neprilysin

Natriuretic Peptide System Heart Failure

X X

NH N N N N O OH O O H O N H O O H O

Valsartan Sacubitril (AHU377)

↓

LBQ657 LCZ696

PARADIGM-HF: Main Results

McMurray JJV, et al. N Engl J Med 2014;371:993-1004.

PARAGON: Study design

≥55 yo, LVEF ≥ 45%, LAE or LVH, Symptomatic HF (NYHA II-IV), Diuretics for HF ≥30d AND either 1) Elevated BNP/ NT-proBNP; or 2) HF Hosp within 9 mo Estimated 4,300 patients

Valsartan/Sacubitril: Considerations

Vodovar N, et al. Eur Heart J 2015;36(15):902-5.

SLIDE 4

12/17/16 4

Teaching Old Dogs New Tricks:

• Diuretics: Torsemide, Subcutaneous diuretics
• Angiotensin Receptor Neprilysin Inhibitor (ARNI):

Sacubitril/ Valsartan

• Biased-ligand angiotensin receptor antagonist: TRV027

Investigational Medical Therapies for Acute and Chronic Heart Failure TRV120027, a selective and beta-arrestin-biased AT1R ligand

DeWire SM, et al. Circ Res. 2011;109:205-216

TRV120027, a selective and beta-arrestin-biased AT1R ligand

DeWire SM, et al. Circ Res. 2011;109:205-216

Biased Ligands of the Angiotensin receptor STudy in Acute Heart Failure (BLAST-AHF)

• Phase-2, international,

dose-finding study in

• approx. 500 patients

hospitalized for acute heart failure.

Felker GM, et al. JACC Heart Fail 2015;3:193-201.

AHF$$ Pa'ent$ Randomiza'on$

• 16 hours

48-96 hours Placebo TRV027 @1 mg/hr TRV027 @5 mg/hr TRV027 @25 mg/hr Day$5$$ visit$ Day$30$ visit$ End$of$ Infusion$ Follow up Day$180$ call$

Evalua'on$of$primary$ composite$endpoint$

Equal$ alloca'on$

≥40mg furosemide 1 hr before randomization Each$arm$added$to$ standard$AHF$therapy$

SLIDE 5

12/17/16 5

All Cause Death through day 30 HF re-hospitalization through day 30 Worsening HF through day 5 Length of initial hospital stay

Average Z-score

Change in dyspnea VAS (AUC) through day 5 25 mg/hr (n=125) 5 mg/hr (n=182) 1 mg/hr (n=128)

Negative Z-score favors Placebo Treatment

Z-score Z-score Z-score

• 0.5

0.5

• 0.5

0.5

• 0.5

0.5

Felker GM, et al. ESC Heart Failure 2016.

Teaching Old Dogs New Tricks:

• Diuretics: Torsemide, Subcutaneous diuretics
• Angiotensin Receptor Neprilysin Inhibitor (ARNI):

Valsartan/sacubitril

• Biased-ligand angiotensin receptor antagonist: TRV027
• Mineralocorticoid Receptor Antagonists

Investigational Medical Therapies for Acute and Chronic Heart Failure Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)

Pitt B, et al. N Engl J Med 2014;370:1383-1392.

• Randomized, double-blind, placebo-

controlled, multicenter trial

• Target 3515 pts with ≥1 sign and ≥1 symptom
• f HF, LVEF ≥45%, SBP <140 mm Hg (or ≤160

mm Hg if ≥3 BP meds), serum K <5.0 mmol/L; either HF hosp ≤12 months or BNP ≥100 pg/mL

• r NTproBNP ≥360 pg/mL
• 3445 pts randomized to Placebo or

Spironolactone 15-45 mg qd

• Potassium monitored baseline,

weeks 1 & 4, then q4 months

• Hyperkalemia: Spiro 18.7%, vs. 9.1% Placebo

Hypokalemia: Spiro 16.2%, vs. 22.9% Placebo Worsening renal function: Spironolactone 10.2%, vs. 7.0% in Placebo group; p <0.001.

TOPCAT: Regional Outcomes

Pfeffer MA, et al. Circulation 2015;131:34-42.

SLIDE 6

12/17/16 6

Finerenone: Non-steroidal MRA

Bärfacker L, et al. ChemMedChem 2012;7:1385-1403.

• Current MRAs limited by concerns about renal

failure, hyperkalemia, and progestogenic effect (spironolactone)

• Finerenone has demonstrated superior selectivity

compared with spironolactone and improved affinity for the MR compared with eplerenone

• Pre-clinical studies demonstrated more pronounced

cardiorenal end-organ protection than the steroidal MRAs

• PEARL-HF Pilot study provided preliminary support

for safety and pharmacologic differences

• ARTS provided dosing and safety information

FINESSE-HF: Study Design

Bayer: www.investor.bayer.com/securedl/13158

Also FIDELIO-DKD (4800 pts) and FIGARO-DKD (6400 pts)

Agents with Vasodilating Properties…

Teaching Old Dogs New Tricks: Agents with Vasodilating Properties:

• Natriuretic peptides: Ularitide, Cenderitide

Investigational Medical Therapies for Acute and Chronic Heart Failure

SLIDE 7

12/17/16 7

Urodilatin (Ularitide)

PCWP

• Recently discovered (1988)
• Natriuretic peptide

synthesized in the kidneys.

• N-terminal last 4 amino

acids only difference from ANP, which are maintained from pro-ANP.

• N-terminal prolongation may

be responsible for a higher resistance to endopeptidases with more powerful vasodilating and renal effects.

TRUE-AHF: TRial of Ularitide’s Efficacy and safety in patients with AHF

• 2,157 patients with unplanned hospitalization or ED visit for ADHF with

dyspnea at rest, Radiological evidence of HF on a chest x-ray, BNP > 500 pg/mL

• r NT-proBNP > 2000 pg/mL, Systolic blood pressure (SBP) ≥ 110 mmHg.
• 1° endpoint: Clinical composite at 48°; all cause mortality;

Multiple 2° endpoints

Clinicaltrials.gov NCT01661634 (last updated 02.August, 2016)

TRUE-AHF 1°: Cardiovascular Mortality

32

Placebo

225 deaths

Ularitide

236 deaths HR = 1.03 (96% CI:0.85-1.25) P=0.75

Months After Randomization 6 12 18 24 30 36 0.0 0.2 0.4 0.6 0.8 1.0 Proportion Free From Cardiovascular Death

Packer M, et al. AHA 2016 Late-breaking Clinical Trial.

15 30 45 60

Improved Worse Unchanged

P=0.82

TRUE-AHF 1°: Clinical Composite

% Patients

Packer M, et al. AHA 2016 Late-breaking Clinical Trial.

SLIDE 8

12/17/16 8

TRUE-AHF: Secondary Endpoints

Placebo (n=1069) Ularitide (n=1088) P Value Length of stay (hr) in intensive care during first 120 hours, 69.8 (50.3, 94.3) 68.0 (49.3, 93.6) 0.24 Length of stay (hr) in the hospital during first 30 days, 148.2 (94.0, 216.8) 160.8 (96.0, 228.9) 0.16 Episodes of in-hospital worsening HF during first 120 hr 126 115 0.63 Proportion with in-hospital worsening HF during first 120 hr 94 (8.8%) 90 (8.3%) 0.70 Rehospitalization for HF within 30 days

• f hospital discharge

74 (7.0%) 75 (7.1%) 1.00 Duration (hours) of IV therapy for HF during index admission, 68.9 (44.6, 115.5) 70.5 (42.7, 115.4) 0.53 All-cause mortality or CV hospitalization at 6 months 398 (37.2%) 443 (40.7%) 0.10

Packer M, et al. AHA 2016 Late-breaking Clinical Trial.

Teaching Old Dogs New Tricks: Agents with Vasodilating Properties:

• Natriuretic peptides: Ularitide, Cenderitide
• Soluble Guanylate Cyclase (sGC) Stimulator: Vericiguat

Investigational Medical Therapies for Acute and Chronic Heart Failure Vericiguat: sGC Stimulation as a Novel Mechanism with a Dual Mode of Action

cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; sGC, soluble guanylate cyclase Stasch, et al. Nature 2001;410:212–215; Evgenov, et al. Nature Rev Drug Discov 2006;5:755–768; Stasch JP & Evgenov OV, Handb Exp Pharmacol 2013;218:279–31.

Soluble Guanylate Cyclase Stimulator in Heart Failure Studies (SOCRATES) Program

Symptomatic HF (NYHA II-IV); Hospitalized for Worsening HF; Elevated BNP/ NT-proBNP REDUCED: LVEF <45% PRESERVED: LVEF ≥45%, LAE by echo Pieske B, et al. Eur J Heart Fail 2014;16:1026–1038.

SLIDE 9

12/17/16 9

SOCRATES-REDUCED: NT-proBNP

Gheorghiade M, et al. JAMA 2015;314:2251-2262. 1° Endpoint P=NS 456 patients randomized

VerICiguaT: glObal study in patients with heart failure and Reduced ejectIon frAction(VICTORIA)

• Clinically stable patients with CHF with LVEF

<45% on SoC therapy

• HF hospitalization within 6 months or IV diuretic

treatment for HF within 3 mo

• NT-proBNP / BNP criteria (increased)
• Patients with concurrent or anticipated use of

long-acting oral nitrates or PDE type 5 inhibitors are excluded 1° Endpoint: Time to first occurrence of the composite of CV death and HF hosp 2° Endpoints: Time to CV death, Time to first HF hosp, Time to total HF hosp (first and recurrent), Time to all-cause death and HF hospitalizations, Time to all-cause death

Teaching Old Dogs New Tricks: Agents with Vasodilating Properties:

• Natriuretic peptides: Ularitide, Cenderitide
• Soluble Guanylate Cyclase (sGC) Stimulator: Vericiguat
• Serelaxin

Investigational Medical Therapies for Acute and Chronic Heart Failure

*Selective dilation of pre-constricted vessels; AHF=acute heart failure; ECM=extracellular matrix; ET-1=endothelin-1; GFR=glomerular filtration rate; NO=nitric oxide; RBF=renal blood flow; SVR-systemic vascular resistance

Serelaxin has potential multi-mechanistic effects which may address the pathophysiology of AHF

Serelaxin

Adapted from Du XJ, et al. Nat Rev Cardiol 2010;7:48–58

Remodeling ↓ Fibrosis ↑ ECM remodeling

3

↑ Matrix metalloproteinases ↓ Vessel stiffness ↓ Collagen synthesis ↑ Collagen breakdown

↑Tissue healing ↓ Inflammation ↑ Cell survival

↑ Cell preservation

2

↓ Inflammatory cell infiltration ↓ Oxidative stress ↑ Angiogenesis ↑ Stem cell survival ↓ Oxidative stress ↓ Apoptosis ↓ Ca2+ overload ↓ Infarct size

Vasorelaxation*

↓ Myocardial overload; ↑

Renal function

1

↑ Endothelial NO* ↓ SVR, ↑ RBF, ↑ GFR ↓ ET-1 Volume redistribution

SLIDE 10

12/17/16 10

RELAX-AHF: 1° Endpoint: (VAS AUC Composite)

Teerlink JR, et al. Lancet 2013; 381:29-39.

5 10 15 20 25 30 35

1 2 3 4 5

AUC with placebo, 2308 ± 3082 AUC with serelaxin, 2756 ± 2588 p=0.0075 Change from baseline (mm) 19.4% increase in AUC with serelaxin from baseline through day 5 (Mean difference of 448 mm-hr)

Days

6

Serelaxin Placebo

12 hrs

1,161 patients hospitalized for AHF, randomized to:

• Placebo (n=580)
• Serelaxin 30 µg/kg/d (n=581)

Entry Criteria:

• Dyspnea, Congestion on CXR,

Elevated BNP/ NT-proBNP

• SBP >125 mmHg
• eGFR 30-75 ml/min 1.73m2
• ≥40 mg IV furosemide

Excluded:

• Acute Coronary Syndrome
• High dose nitrates

Cumulative proportion of worsening heart failure to Day 5 (%)

Worsening of Heart Failure

Kaplan-Meier estimate D14 for time to WHF (%)

11 3 16 4 31 10 44 17 57 25 64 69 37 36 573 570

**HR 0.7 (0.51, 0.96); p=0.024

(Numbers of subjects with WHF shown for each time point) Worsening Heart Failure (WHF) was defined as worsening signs and/or symptoms of HF that required an intensification of IV therapy for heart failure or mechanical ventilatory or circulatory support.

n= 573 570 *p<0.001 through Day 5 *p value by Wilcoxon test **p value by log rank test for Serelaxin vs. Placebo; HR estimate by Cox model, HR<1.0 favors Serelaxin

Teerlink JR, et al. Lancet 2013; 381:29-39.

All-cause mortality in the RELAX-AHF program

1.00 0.98 0.96 0.94 0.92 0.90 0.88 0.86 0.84 0.82 Survival probability 20 40 60 80 100 120 140 160 180 Study Day

Pre-RELAX-AHF: Placebo Pre-RELAX-AHF: Serelaxin RELAX-AHF: Placebo RELAX-AHF: Serelaxin Combined: Placebo Combined: Serelaxin

HR (95%CI), P value

• Pre-RELAX: 0.53 (0.22,1.30), p = 0.16
• RELAX-AHF: 0.63 (CI 0.43, 0.93); p=0.020
• Combined: 0.62 (0.43-0.88), p=0.0076

Metra M, et al. J Am Coll Cardiol 2013;61:196-206.

Variable TRUE-AHF RELAX-AHF CV Mortality 1°: N.S. HR 1.03 (96% CI:0.85-1.25) P=0.75 2° (180 day): HR 0·63 (95% CI 0·41–0·96) p=0·028 Clinical Composite (5d) 1°: N.S. p=0.82 1°: Dyspnea composite: 19.4% improvement; p=0.007) Worsening HF (5d) N.S. p=0.63 30% reduction; p<0.001 LOS ICU in 5d N.S. p=0.24

• 0.3 d; p=0.03

LOS in 30d N.S. p=0.16

• 0.9 d; p=0.04

Change in troponin 2d N.S. p=0.70 p<0.05 Change in NT-proBNP Decreased p<0.001 p<0.001 Change in Creatinine INCREASED p<0.001 Hypotension 22.4% Ularitide/ 10.1% Placebo 5% Serelaxin/ 4% Placebo

TRUE-AHF and RELAX-AHF

SLIDE 11

12/17/16 11

Post-discharge evaluation period Placebo (n~3400) Serelaxin 30 µg/kg/d (n~3400) 6 12 24 48 h 5 d 14 d 60 d 180 d 48 h study drug infusion period Screening Double-blind, randomized treatment and follow up period Presentation <16 h

Target ~6,600 patients hospitalized for AHF

RELAX-AHF-2: Study design

Teerlink JR and Metra M, et al. Submitted.

Standard HF therapy During study investigators free to use any concomitant medications incl. nitrates according to clinical judgment

Entry Criteria:

• Dyspnea, Congestion on CXR,

Elevated BNP/ NT-proBNP

• SBP >125 mmHg
• eGFR 20-75 ml/min 1.73m2
• ≥40 mg IV furosemide

Excluded:

• Acute Coronary Syndrome
• High dose nitrates

1° Endpoints:

• Cardiovascular mortality at 180 days
• Worsening Heart Failure within 5 days

Investigational Therapies for Acute and Chronic Heart Failure Teaching Old Dogs New Tricks: Agents with Vasodilating Properties: Getting to the Heart of the Matter:

• Cardiac myosin activators: Omecamtiv mecarbil

Investigational Therapies for Acute and Chronic Heart Failure Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator

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 Mechanochemical Cycle of Myosin

Malik FI, et al. Science 2011; 331:1439-43. Shen YT, et al. Circ Heart Fail 2010;3:522-7.

SLIDE 12

12/17/16 12

Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure

• Multi-center, randomized, double-blind,

placebo-controlled study

• Phase 2 Pharmacokinetic/

Pharmacodynamic dosing study

• 3 sequential cohorts (~200 subjects per

cohort) with ascending targets (1: ~115 ng/mL; 2: ~230 ng/mL; 3: ~310 ng/mL)

• Randomized 1:1 to 48-hour IV placebo
• r omecamtiv mecarbil (OM).
• Admitted for AHF with history of heart

failure, LVEF ≤ 40%, dyspnea at rest or with minimal exertion, and biomarker evidence of congestion, randomized within 24 hours of initial IV furosemide therapy

Teerlink JR, et al. J Am Coll Cardiol 2016; 67:1444–55.

Primary Efficacy Endpoint: Dyspnea Response through 48h (Likert Scale)

Response Rate Ratio 1.02 1.02 1.41 95% CI (0.74, 1.42) (0.76, 1.37) (1.02, 1.93)

Response rate ratio: ratio of response rate to Placebo within each cohort

Cohort 1 OM OM OM 42% 41% Cohort 2 47% 46% Cohort 3 Placebo 51% 37% Dyspnea Response Rate (% Responders) 5 10 15 20 25 30 35 40 45 50 55 Placebo Placebo

p = NS p = NS p = 0.03 Primary analysis versus Pooled Placebo: Overall p-value = 0.33

Teerlink JR, et al. J Am Coll Cardiol 2016; 67:1444–55. Objectives

• To select an oral modified release (MR) formulation and dose of OM for

chronic dosing in subjects with HF and left ventricular systolic dysfunction

• To characterize its pharmacokinetics (PK) and pharmacodynamics over 20

weeks of chronic therapy Patient Population

• Male/female ≥ 18 and ≤ 85 years of age with chronic HF
• n stable, optimal pharmacological therapy
• LVEF ≤ 40%
• NT-proBNP ≥ 200 pg/mL (≥ 1200 pg/mL if atrial fibrillation)
• Expansion phase: NYHA class II-III and screening echo

Chronic Oral Study of Myosin activation to Increase Contractility in Heart Failure

Teerlink JR, et al. Lancet 2016;388:2895–903.

Randomization 1:1:1 2 Time (wk) 20 Screening 30 Days 8 16 Study drug administration PK sampling Echo Placebo (n = 149) 25 mg BID à50 mg BID (PK-titration; n = 149) 25 mg BID (n = 150) End of IP Administration 24 End of Study Visit Dose adjustment 12

Intensive PK sampling Echo, echocardiographic parameters; IP, investigational product

Dose Expansion Phase

Dose escalation from 25 mg BID to 50 mg BID based

• n OM trough concentration at Week 2

Titration was blinded

Teerlink JR, et al. Lancet 2016;388:2895–903.

SLIDE 13

12/17/16 13

Cardiac Troponin I

Number of increased troponin events adjudicated by CEC for MI = 0/278

• cTnI > 0.04 ng/mL (99%URL) when prior undetectable OR
• cTnI > 0.03 ng/mL (10%CoV) greater than prior when prior detectable

a Excludes 3 patients that were not dosed

Troponin I — ng/mL

• No. (%)

Placebo (n = 149) Omecamtiv Mecarbil 25 mg BID (n = 150) Omecamtiv Mecarbil Titration Group (n = 146) a Change to Week 20, median (Q1,Q3) 0·000 (-0·007, 0·004) 0·001 (0·000, 0·012) 0·006 (0·000, 0·024) Maximum change from baseline, median (Q1, Q3) 0·010 (0·000, 0·020) 0·016 (0·003, 0·034) 0·020 0·005, 0·038) Change to Week 24, median (Q1,Q3) 0·000 (-0·006, 0·008) 0·000 (-0·002, 0·009) 0·000 (-0·003, 0·010)

Teerlink JR, et al. Lancet 2016;388:2895–903.

Efficacy of Omecamtiv Mecarbil

Teerlink JR, et al. Lancet 2016;388:2895–903.

Teaching Old Dogs New Tricks: Agents with Vasodilating Properties: Getting to the Heart of the Matter:

• Cardiac myosin activators: Omecamtiv mecarbil
• Nitroxyl donors: CXL-1427

Investigational Therapies for Acute and Chronic Heart Failure

Ica, L-type calcium current; CONT, control; AS, Angeli’s Salt; SR, sarcoplasmic reticulum; NCX, Na-Ca exchanger; RyR, ryanodine receptor

HNO enhances myofilament calcium sensitivity3,4:

• Formation of disulfide bonds in

Actin, Myosin light chain, and Tropomyosin HNO enhances SERCa activity2,5,6:

• Formation of disulfide bonds

between Phospholamban monomers

• S-glutathiolation of SERCa at

cysteine 674

References:

• 1. Kohr, et al., Front Biosci, 2009
• 2. Tocchetti, et al., Circ Res, 2007
• 3. Dai, et al., J Physiol, 2007
• 4. Murray et al., JMCC, 2009
• 5. Froehlich, et al., Biochem, 2008
• 6. Lancel, et al., Circ Res, 2009

HNO enhances RyR activity2:

• Open probability of RyR increased
• Molecular target(s) to be

determined Adapted from Tochchetti, et. al., Antioxid Redox Signal 2011.

Cardiomyocyte

HNO Enhances Myocardial Contractility and Relaxation via a Unique Mechanism

SLIDE 14

12/17/16 14

CXL-1427-02: Study Design

• Randomized, double-blind, placebo-controlled,

sequential cohort study

• 6-hour infusions with 3:1 randomization active to

placebo

• First cohort dose 3 µg/kg/min; subsequent cohort

doses determined by Dose-Escalation Review Committee based on safety and tolerability were 5, 7 and 12 µg/kg/min 8 pts 8 pts 8 pts 8 pts

Up to 16

3 µg/kg/min 5 µg/kg/min 7 µg/kg/min 12 µg/kg/min Confirmation of hemodynamics

Mitrovic V, et al. HF2016 Late-breaking Clinical Trial Key inclusion criteria

• Hospitalized for advanced heart failure
• CIa ≤2.5 L/min/m2
• PCWP ≥20 mmHg
• Left ventricular ejection fraction (LVEF) ≤40%
• Not requiring i.v. or oral vasoactive medication

for 10 hours

• Have indwelling PA catheter

Key exclusion criteria

• HR <50 bpm or >110 bpm
• Screening SBP >150 or <95 mmHgb
• Treated with IV inotropes, vasodilators,

pressors within 4–8 hours

• Hospitalized for acute coronary syndrome

within 90 days aBy estimated Fick or thermodilution method

b<100 mmHg (if PCWP ≥20 but <22 mmHg)

CXL-1427-02: CXL-1427 Significantly Reduces PCWP

Time-averageda reduction in PCWP Time course of PCWP reductions during and after infusion

n=11 n=6 n=9 n=12 n=7

Placebo 3 5 7 12

• 8
• 6
• 4
• 2

2 Mean (SEM) change from baseline (mmHg) CXL-1427 (µg/kg/min) p=0.0059 p=0.0001 p=0.0062 p=0.0086 2 4 6 8

• 10
• 5

5 Mean (SEM) change from baseline (mmHg) Time course (hours) CXL-1427 (µg/kg/min)

Placebo

3 5 7 12

aAverage of values at 2, 4 and 6 hours

Mitrovic V, et al. HF2016 Late-breaking Clinical Trial

CXL-1427-02: Hemodynamic Dataa

aAverage of values at 2, 4 and 6 hours bFick calculated using an assumed oxygen consumption value of 125 mL/min per m2 of body surface area

Fick CI performed in all patients; thermodilution CI performed in a subset of patients

100 90

Cardiac Index (NICaS)

• 10

20 Mean (SEM) change from baseline (%) CXL-1427 (µg/kg/min) Placebo 3 5 7 12 p=0.1093 p=0.1060 p=0.0347 p<0.0001 10 30 40 50 60 70 80

n=11 n=6 n=9 n=12 n=7

Mitrovic V, et al. HF2016 Late-breaking Clinical Trial

20

• 20
• 40

CXL-1427 (µg/kg/min) Mean (SEM) change from baseline (%) Placebo 3 5 7 12 p=0.0108 p=0.0179 p=0.0026 p=0.0038 Total peripheral resistance (NICaS) n=11 n=6 n=9 n=12 n=7 Systolic blood pressure

• 12.5
• 10.0
• 7.5
• 5.0
• 2.5

2.5 Mean (SEM) change from baseline (mmHg) CXL-1427 (µg/kg/min) Placebo 3 5 7 12 p=0.2499 p=0.8281 p=0.4121 p=0.8592

n=11 n=6 n=9 n=12 n=7

25

Estimated Cardiac Index (Fickb)

• 25
• 15
• 5

5 15 Mean (SEM) change from baseline (%) CXL-1427 (µg/kg/min) Placebo 3 5 7 12

n=11 n=6 n=9 n=12 n=7

p=0.4241 p=0.4035 p=0.8308 p=0.1180 20 10

• 10
• 20

Teaching Old Dogs New Tricks: Agents with Vasodilating Properties: Getting to the Heart of the Matter:

• Cardiac myosin activators: Omecamtiv mecarbil
• Nitroxyl donors: CXL-1427
• Partial A1 Adenosine Receptor Agonist: BAY 1067197

Investigational Therapies for Acute and Chronic Heart Failure

SLIDE 15

12/17/16 15

Partial A1 Adenosine Receptor Agonism

Greene SJ, et al. Heart Fail Rev 2016;21:95–102. Selective Partial Adenosine A1 Receptor Agonist

• Partial agonism selectively addresses beneficial physiological

effects avoiding side effects of full agonism

• Fast and sustained improvement of cardiomyocyte energetics

(mitochondrial fxn, energy metabolism) & calcium handling

• Current therapies do not address energetic imbalance and demand in HF
• “Silent” on blood pressure*
• First results showing improvement of skeletal muscle energetics
• Counteracting sympathetic over-activation
• Cardioprotection
• Prevention of cardiac fibrosis & remodeling
• Normalization of SERCA2a expression and Ca2+-handling
• Renal protection in animal models
• Decrease of free fatty acids (FFA) with potential positive

metabolic effects in IGT and Diabetes

Neladenoson bialanate –

A Selective Partial Adenosine A1 Receptor Agonist*

A novel Mode of Action for the Treatment of Heart Failure

• Improvement of disturbed

mitochondrial function in HF

• Restoring ATP synthesis
• Reduction of mPTP1 opening
• Normalization of mitochondrial

uncoupling proteins and glucose transporters

• Restoration of SERCA2a expression

leading to improved contraction/ relaxation ratio

• Improved Ca 2+ handling

Without affecting hemodynamics (BP, HR) on top of SoC

• Normalization of GLUT-1 and
• 4 glucose transporter

proteins

• Reduction in free fatty acid

plasma levels

• Reduction in interstitial

fibrosis

• No increase of hypertrophy

due to activation of viable but not functional myocardium (no positive inotropy)

• Inhibition of adenyl cyclase/

reduction of cAMP and partial inhibition of L-type calcium channels

• Activation of PKC modulates

mitochondrial KATP channels, improving mitochondrial fxn

• Inhibition of excessive

catecholamine release,

• pposes sympathetic
• verdrive

The failing heart is characterized by abnormal mitochondrial structure and function, reduced rate of ATP synthesis, and dysfunctional changes in energetics and calcium handling. Neladenoson bialanate, a selective partial adenosine A1R agonist, improves outcomes in both, HFpEF and HFrEF, by activating A1Rs resulting in: Improving dysfunction of cardiac and skeletal muscle Correcting imbalances in substrate utilization Reversing cardiac remodeling Anti-ischemic cardioprotective effects

Investigational Medical Therapies for Acute and Chronic Heart Failure Teaching Old Dogs New Tricks Agents with Vasodilating Properties Getting to the Heart of the Matter

MULTIPLE other directions…

• Neuregulin
• Caspase-1 inhibition
• TTR-inhibition
• MAP-kinase inhibition
• TRPV4 inhibition
• SGLT2-inhibitiors
• IL-antagonism
• Elamipretide
• Chymase inhibition
• AVP antagonism
• i.v. Iron
• Endothelin antagonism
• etc., etc., etc.!!!

Courtesy of Prof. Adriaan Voors, Marco Metra and others.

SLIDE 16

12/17/16 16

Von Lueder TG, Krum H. Nat Rev Cardiol 2015;12:730-740.

Investigational Therapies for Acute and Chronic Heart Failure

Heart Failure Society of America

www.hfsa.org

San Francisco Veterans Affairs Medical Center

Thank you!