Prognostic Circulating Neprilysin and Therapeutic

Prognostic Circulating Neprilysin and

Therapeutic Neprilysin Inhibition

Antoni Bayes-GenisChair, Heart Institute

Hospital Univesitari Germans Trias i Pujol

Badalona, Barcelona, Spain

HF Epidemic… in the WORLD

…. In US and Western Europe

1 in 5 individuals > 40 years will develop HF

HF unmet needs?

Excessive mortality despite neurohormonal blockade

HF progresses and mortality remains high

despite optimal neurohormonal blockade

McMurray. Eur J Heart Fail. 2011;13:929–36

Sudden death accounts for 50% of HF mortality

MERIT-HF Study Group. Lancet. 1999;353:2001-7

Too many HF admissions and readmissions

Centers for Medicare & Medicaid Services. Medicare Provider Utilization and Payment Data: Inpatient. 2013

… and poor quality of life

HT diabetes arthritis COPD angina HF Better

worse

McMurray J. Eur Heart J 1998; 19 (supp. P): P9

New Mechanism of action: Neprilysin inhibition

Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365-71;

Schrier et al. Kidney Int 2000;57:1418-25; Schrier & Abraham N Engl J Med 1999;341:577–85; Boerrigter & Burnett. Expert Opin Invest Drugs 2004;13:643–

52; Ferro et al. Circulation 1998;97:2323–30; Brewster et al. Am J Med Sci 2003;326:15–24

SNS

RAAS

VasoconstrictionBlood pressure

Sympathetic toneAldosteroneHypertrophy

Fibrosis

Ang II AT1R

HF SYMPTOMS&

PROGRESSION

INACTIVE

FRAGMENTS

NP system

VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

NPRs NPs

Epinephrine

Norepinephrineα1, β1, β2

receptors

VasoconstrictionRAAS activityVasopressin

Heart rateContractility

Neprilysin

inhibitors

RAAS inhibitors

(ACEI, ARB, MRA)

β-blockers

CALLA(common acute

lymphocytic leukemia antigen)

Neprilysin (NEP)

Membrane Metallopeptidase

variant 1

Neutral Endopeptidease

24.11

CD 10Enkephalinase

Kerr MA, Kenny AJ. 1973; 137: 477-488.

Neprilysin: a long journey

Short NT Intracellular domain (27 aa)

Large CT Extracellular domain (55-750 aa)with a Zn atom at the active site

A single transmembrane helix

Mangiafico S, et al. Eur Heart J. 2013; 34: 886-893.

NEP: a “ubiquitous” transmembrane receptor

Primary sites of cleavage by NEP

on human ANP, BNP and CNP

Bayes-Genis A, Barallat J, Richards MR. J Am Coll Cardiol 2016;68:639-53

Interaction of individual NPs with neprilysin

Bayes-Genis A, Barallat J, Richards MR. J Am Coll Cardiol 2016;68:639-53

Endogenous vasoactive peptides

Vasodilators: NPs, adrenomedullin, bradykinin.

Vasoconstrictors: angiotensin I- II, endothelin 1.

Inactive metabollites

Other peptides

Opioids, substance P, gastrin, β-amyloid

NEP: a «promiscuous» transmembrane receptor

Bayes-Genis A, Barallat J, Richards MR. J Am Coll Cardiol 2016;68:639-53

Neprilysin has many substrates that are metabolized with differing levels of affinity

Metabolism of vasoactive peptides by NEP

ANP y CNP

Endothelin

Sustance P

Bradikinin

Ang II

Adrenomedullin

Ang I

Implications for NEP

inhibition

NEP substrates can have

opposing biological actions

Overall effect is dependent

upon the net effect on NEP

metabolism of individual

substrates

Benefits in enhancing NP

system may be offset by

increased Ang II

Needs to be complemented

by simultaneous RAAS

suppression

BNP

NEP

Inactive fragments ormetabolites

Relative

affinity

for NEP

NEP inhibition alone increases NPs and AT-II

AT1 receptor

Neprilysin(NEP)

Signaling cascades

Gene expression; ↑ protein synthesis; ↑ cell proliferation

NPR-A NPR-B

GTP GTP

cGMP

ANP BNP CNP

ANP/CNP

BNP

Internalization

Inactive peptides

Receptor recycling

Vasodilation

Cardiac fibrosis/hypertrophy

Natriuresis/diuresis

AT-IIInactive NP

fragmentsANP/CNP

BNP

Vasoconstriction

Cardiac fibrosis/hypertrophy

Sodium/water retention

NPR-C

Inactive AT-II

fragmentsAT-II

Neprilysin(NEP)

AT1 receptorNeprilysin

Signaling

cascades

Gene expression; ↑ protein

synthesis; ↑ cell proliferation

NPR-A NPR-B NPR-C

GTP GTP

cGMP

ANPBNP CNP

ANP/CNP/BNP

Internalization

Inactive peptides

Vasodilation

Cardiac fibrosis/hypertrophy

Natriuresis/diuresis

Vasoconstriction

Cardiac fibrosis/hypertrophy

Sodium/water retention

Inactive NP

fragments ANP/CNP

LCZ696

ValsartanSacubitril

Ang II

Enhancing the natriuretic peptide system

Supressingthe RAAS

Receptor

recyclingSignaling

cascades

Gene expression; ↑ protein

synthesis; ↑ cell proliferation

Vasoconstriction

Cardiac fibrosis/hypertrophy

Sodium/water retention

Sac/Val in the Angiotensin pathway

LCZ696

Vasodilation

Anti-fibrosis

Anti-proliferation

Natriuresis

Death from CV causes or first hospitalization for HF

Hazard ratio = 0.80 (95% CI: 0.73–0.87)

p<0.001

Days since randomization

Cu

mu

lati

ve p

rob

ab

ilit

y1.0

0.6

0.4

0.2

0

0 180 360 540 720 900 1080 1260

Enalapril

LCZ696

McMurray et al. N Engl J Med. 2014;37:993-1004

20% Reduction

Sudden Death

Desai et al. Eur Heart J. 2015;36:1990–7

20% Reduction

30- and 60-day HF readmissions

Desai et al. J Am Coll Cardiol 2016;68:241-8

Is it safe?

Hypotension Renal impairment HyperkalaemiaAny adverse event

LCZ696 (n=4187)

Enalapril (n=4212)

0

5

10

15 p=0.03

p=0.38 p=0.002p=0.56

0.70.91.4

0.7 0.40.3

12.3

10.7

stu

dy

dru

g d

isco

nti

nu

ed

(%

)

McMurray et al. N Engl J Med. 2014;37:993-1004

Active

bradykinin

Inactive

bradykinin

ACE APP NEP DPP-4

Bradykinin breakdown

Omapatrilat

Sac/Val Active

bradykinin

Inactive

bradykinin

What about biomarkers?

YES

cleaved by NEP

NOT

cleaved by NEP

Bayes-Genis A et al. J Am Coll Cardiol 2016;68:639-53; Ichiki & Burnett. Circulation 2010;122:229–32

400

600

1,000

1,400

1,600

1,200

800

***

***

LCZ696Enalapril

NT-p

roB

NP, p

g/m

L

LCZ696 significantly reduced levels of NT-proBNP

Packer et al. Circulation 2015;131:54–61;

1,000 pg/mLEnalapril LCZ696

***p<0.0001

V2/2aPrior to enalapril

run-in

V5Randomization

V7

4 weeks

V10

8 months

V3After enalapril run-in/

prior to LCZ696 run-in

Sustained BNP reflects NEP inhibition with LCZ696

Packer et al. Circulation 2015;131:54–61

50

100

150

200

250***

***

***p<0.0001

V2/2aPrior to enalapril

run-in

V5

Randomization

V7

4 weeks

V10

8 months

V3After enalapril run-in/

prior to LCZ696 run-in

Enalapril LCZ696

BN

P,

pg/m

L

LCZ696Enalapril

...So, what NP should I use: BNP or NT-proBNP?

NT-proBNP: remains a good biomarker for diagnosis, prognosis, monitoring

BNP: changes its role from biomarker to biotarget

NEP may be found as a circulating peptide: sNEP

NEP extracellular domain, Human 55-750

Large CT Extracellular domain (55-750 aa)

with a Zn atom at the active site

Rho 0.49, p<0.001

Is sNEP catalytically active?

Bayes-Genis A, et al. J Heart Lung Transpl 2016;35:684-5.

sNEP and prognosis in chronic HF

Bayes-Genis A, et al. J Am Coll Cardiol. 2015; 65: 657.

Composite Primary Endpoint Cardiovascular Death

HR 95% CI P value HR 95% CI P value

sNEP 1.18 1.07 - 1.31 0.001 1.18 1.05 - 1.32 0.006

18% Increased Risk

sNEP vs. NTproBNP: eGFR and BMI

Bayes-Genis A, et al. Rev Esp Cardiol 2015; 68:1075-84

sNEP in Acute HF

Bayés-Genís A, et al. JACC Heart Failure 2015;3:641-4.

• High sNEP in AHF with prognostic value argues in favour of initiating LCZ696 within hospital admission

Clinical studies using sNEP for HF prognostication

Bayes-Genis A, Barallat J, Richards MR. J Am Coll Cardiol 2016;68:639-53

Performance of the marketed sNEP assays

Bayes-Genis A, Barallat J, Richards MR. J Am Coll Cardiol 2016;68:639-53

Take-home message

Bayes-Genis A, Barallat J, Richards MR. J Am Coll Cardiol 2016;68:639-53