La neuromodulazione

Michele SenniDirettore

Cardiologia 1

LCZ696: sacubitril valsartan sodiumA first in class angiotensin receptor – neprilysin inhibitor

Gu et al. J. Clin. Pharmacol. 2010;50:401-414Feng et al. Tetrahedron Let. 2012;53:275-276

LCZ696 PLASMA

First pass esterase

AHU377pro-drug

(t1/2 = 1.1h)

LBQ657drug

(t1/2 = 11.1h)

ValsartanARB

(t1/2 = 11.7h)

Plasma AHU377 VAL Valsartan

AUC equivalent 97 mg 103 mg 160 mg

LCZ696 200 mg oral Dose

LCZ696 is a salt complex that comprises

the two active moieties:2,3

–sacubitril (AHU377) – a pro-drug; further

metabolized to the neprilysin inhibitor

LBQ657, and

–valsartan – an AT1 receptor blocker

in a 1:1 molar ratio

LCZ696 – Mechanism of Action

3

Vasodilation

blood pressure

sympathetic tone

aldosterone levels

fibrosis

hypertrophy

Natriuresis/Diuresis

Inactive

fragments

BNP, ANP, CNP

NP systemRAAS

pro-BNP

Pre-proBNP

Inert NT-pro BNP

XNeprilysin

(degrades)

Natriuretic Peptide System

AT1 receptorX

Vasoconstriction

blood pressure

sympathetic tone

aldosterone

fibrosis

hypertrophy

Angiotensinogen

(liver secretion)

Angiotensin I

Angiotensin II

Renin

Renin Angiotensin System

NH

N

N

N

N

O

OH

O

OH

ONH

O

OH

O

valsartanAHU377

↓

LBQ657

HF

Heart Failure

↓Vasoconstrictor/

anti-natriuretic

/pro-mitotic

Mediators

↑ Vasodilator/

natriuretic/

anti-mitotic

Mediators

Natriuretic

peptides

ACEi and ARBs

Beta-blockers

Aldosterone

antagonists

Heart Failure: a state of “neurohumoral imbalance”

A “paradigm shift”: from “neurohumoral

inhibition” to “neurohumoral modulation”

Natriuretic

peptides

Bradykinin

Substance

P

Adreno-

medullinAng II

Ang I

Endothelin-1

Vasoactive peptides affecting

neurohormonal balance in heart failure

D’Elia E…Senni M, Eur J Heart Fail 2017

Neprilysin has many substrates that are metabolized

ANP, CNP

ANG II

ANG I

ADM

SP

BK

ET

BNP

Aff

init

y f

or

nep

rily

sin

Re

ma

inin

g s

ub

stra

te

follo

win

g d

eg

rad

atio

n

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

Overall effect is

dependent upon the

net effect on NEP

metabolism of

individual substrates

D’Elia E…Senni M, Eur J Heart Fail 2017

PARADIGM-HF Study Design

2 weeks ~ 21 to 43 months (event-driven)

Randomization

(N = 8,399 patients)

Enalapril 10 mg bid

LCZ696 200 mg bid

LCZ696

200 mg bid

On top of standard heart failure therapy (excluding ACEIs and ARBs)

Primary endpoint: CV death or HF hospitalization

Testing tolerability to target doses of

enalapril and LCZ696*

LCZ696

100 mg bid

Enalapril

10 mg bid‡

1-2 weeks 2-4 weeks

Single-blind run-in period

Double-blind randomized treatment period

|

PARADIGM-HF:

Baseline Characteristics

PARADIGM trial: Results

# VASODILATORS : V-HeFT I, PROFILE, FIRST

# ACE INHIBITORS : CONSENSUS, V-HeFT II, SAVE, SOLVD TREAT/PREV, NETWORK, ATLAS

# AII R ANTAGONISTS: ELITE, RESOLVD, ELITE II, VAL-HeFT

# Ca ANTAGONISTS : PRAISE, V-HeFT III, MACH-1

# DIGITALIS : CAPTOPRIL-DIGOXIN MRG, CADS,RADIANCE, DIG

# INOTROPES : PROMISE, VEST, PRIME II

# AMIODARONE : GESICA, CHF-STAT

# BETA-BLOCKERS : XAMOTEROL, MDC, CIBIS I, CIBIS II, ANZ, US CARVEDILOL, MERIT, BESTCOPERNICUS, CAPRICORN

# MISCELLANEOUS :WASH, RALES, MUSTIK, SHIFT, EPHESUS

RANDOMIZED CLINICAL TRIALS in HFrEF

(N=38) 1988-2014

Drugs reducing mortality

CONSENSUS enalapril 1987

RALES spironolactone 1999

CIBIS-2 bisoprolol 1999

PARADIGM LCZ696 2014

PARADIGM first trial proposing a substitution rather than

an “add-on” strategy in HFrEF patients.

1. Simpson et al. Effect of the angiotensin receptor neprilysin

inhibitor LCZ696 compared with enalapril according to baseline

risk in PARADIGM-HF. Poster presented at ESC-HF 2015.

CV death or HF hospitalization across

MAGGIC risk-score quintiles

The effect of LCZ696 over enalapril for CV death or HF hospitalization was consistent

across the spectrum of risk1

LCZ696 and more symptomatic/higher risk

patients

PARADIGM-HF Effects on recurrent hospitalizations

Packer et al. Circulation 2015

LCZ696 improve the vulnerable period

Desai AS et al. JACC 2016

Importance to reach and keep

the target dose

Vardeny O et al. Eur J Heart Fail 2016

Primary endpoint according to background treatment

Okumura N et al. Circ Heart Fail. 2016

82.6%

73.6%

83.8% 84.9%

0

20

40

60

80

100

p = 0.0302

High RASi Low RASi

Pro

po

rtio

n o

f p

ati

en

ts, %

p = 0.7827

Treatment success

Treatment success: proportion of patients who achieved and maintained LCZ696 200 mg BID

without any dose interruption or down-titration over 12 weeks

• Hypotension was more

common in Low RASi

compared to High RASi

(14.3% vs 4.9, p= 0.016)•

Conservative, N=236*

High / Low RASi* = 117 / 119

Condensed, N=230*

High / Low RASi = 109 / 121

TITRATION STUDY? which is the best up-titration modality

Senni M et al. Eur J Heart Fail 2016

Targets for Heart Failure Therapy“The Swinging Pendulum”

Heart Failure DigitalisHydralazine – Isosorbide dinitrateMinoxidilDobutamine - DopamineMilrinone – EnoximoneIvabradine

1970 - … Hemodynamic improvement

LCZ696BendaviaChymase inhibitorAdenosine partial A1 agonistStem cellsGene therapy

2015 - …

Myocite (e.g. Mitochondria)InterstitiumMicrocirculationMetabolic abnormalities

HeartNeurohumoral

modulation

DigitalisACE-inhibitorsAngiotensin Receptor BlockersBeta-BlockersMineralocorticoid Receptor AntagonistsLCZ696

1990 - 2015

NPS RAASSNS

Senni M et al. Eur J Heart Fail 2015