ARNIAngiotensin ReceptorNeprilysin + Valsartan

Dr. Jai Parekh, Dr. Ramesh Dargad

Metabolism of ANP and other peptide hormones by NEP

ProEndothelin Endothelin Degradation

ANP

GMP cGMP

NPR-A

Guanylate cyclase

Ang II Bradykinin

Adrenomedullin

NPR-C

Diuresis Natriuresis

Vasodilation Antiproliferative/ antihypertrophic

NEP

Neprilysin (NEP) is responsible for natriureticpeptide degradation

Structure and Known Functions ofthe Natriuretic Peptide Receptors (NPRs)

Source: Gardner, D. G. et al. Hypertension 2007;49:419-426

3

Dual NEP / ACE inhibitors

Omapatrilat (vasopeptidase inhibitor): Dual ACE-NEP inhibition

Omapatrilat

ACE Neprilysin

Aminopeptidase(APP)

LCZ696

LCZ696: Angiotensin Receptor Neprilysin Inhibition

Angiotensinreceptor blocker

Inhibition of neprilysin

Introduction

Dual-acting compounds that augment the activity of natriuretic peptides while inhibiting RAAS activity may offer benefits for the treatment of cardiovascular disease

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that provides neprilysin (NEP) inhibition and blockade of the AT1 receptor

Dual angiotensin receptor blockade and NEP inhibitionCounter-regulatory systems

Vasodilationblood pressuresympathetic tone aldosterone levels fibrosis hypertrophy Natriuresis/Diuresis

Symptoms / disease

progression

Natriuretic peptides Angiotensin II

AT1Xreceptor

Vasoconstrictionblood pressuresympathetic tonealdosterone fibrosis hypertrophy

X NEP

Inactive fragments

Dual NEP/RAAS blockade LCZ696

Mechanism of LCZ696 acting on the RAAS andnatriuretic peptide systems

Waeber and Feihl. Lancet, 2010

LCZ696 dose-dependently enhances ANP levelsand reduces BP

dTGR hypertensive rat model‡Rats infused with ANP*

220

200

180

160

140

120

100

8-h

time-

wei

ghte

d av

erag

e[A

NP

ir] (%

bas

elin

e)

Vehicle

0

–10

–20

–30

–40

–50

–60

Vehicle

24-h

tim

e-w

eigh

ted

aver

age

∆MA

P (m

m H

g)

LCZ696 dose (mg/kg)

2 6

20 60

2 6 2060

LCZ696 dose (mg/kg)

• Healthy volunteers received once-daily oral LCZ696 50, 200, 600 or 900 mgor placebo for 14 days

• cGMP measured as a biomarker of NEP inhibition and Ang II as a measure of AT1 receptor blockade

LCZ696 900 mg

Effects of LCZ696 on biomarkers of NEP inhibitionand AT1 receptor blockade

0 40.8

1.4

cGMP

2.0

1.8

1.6

12 24

Time (h)

0.1

Placebo LCZ696 50 mg LCZ696 200 mg LCZ696 600 mg

Ang II

100

Cha

nge

from

bas

elin

e (n

-fold

)

Time (h)

10*

*

*

* * *

0 4 12 24

* *

* **

* *

* *

* *

** *

1.21

1.0

Cha

nge

from

bas

elin

e (n

-fold

)

* **

LCZ696 in mild-to-moderate hypertension

Placeborun-in period

Washout period

Unmasked run-in period

A randomized, double-blind, placebo-controlled, active-comparator study in 1,328 patients with mild-to-moderate hypertension

Double-blind randomized treatment

period LCZ696 100 mg QD

LCZ696 200 mg QD

LCZ696 200 mg/400 mg

QD* Valsartan 80 mg QD

Valsartan 160 mg QDValsartan 160 mg/320 mg QD*

AHU377 200 mg QD

Placebo

2 weeks 2 weeks 8 weeks

*1 week on lower dose followed by 7 weeks on higher dose; †Mean sitting DBP of 90–109 mmHg after antihypertensive washout, or 95–109 mmHg for untreated patients

SBP reduction (placebo-subtracted) DBP reduction (placebo-subtracted)

Placebo effect = –7.72 mmHg Placebo effect = –6.78 mmHg

0

–4

–6

–8

–10

–12

–14

–4.20

–6.02

–4.72

–11.00

–5.69

–12.50

–6.44

p=0.40

p=0.0006

p<0.0001

Cha

nge

in p

lace

bo-s

ubtra

cted

BP

from

base

line

to w

eek

8 (m

mH

g)

164

–2.99 –3.19

–2–2.36

–6.34

–3.17

–6.85

–4.15

p=0.40

p=0.0023 p=0.0055

AHU LCZ Val LCZ Val LCZ Val200 100 80 200 160 400 320

154 163 168 163170 163

AHU LCZ Val LCZ Val LCZ Val200 100 80 200 160 400 320

164 154 163 168 163 170 163

LCZ696 in mild-to-moderate hypertension:Complementary effects of NEP inhibition and AT1 receptor blockade

mg

-4.4-4.9

-8.6-12

-16

-8

-4

0

AHU 200

p < .0001

p = 0.011

p = 0.696

-2.3p=0.059vs pbo

Placebo effect = -2.9 mmHg

n = 48 to 61/group

LCZ696 in mild-to-moderate hypertension:24-hr mean ambulatory SBP (placebo subtracted)

Valsartan LCZ696 80 mg

100 mg

Valsartan LCZ696 160 mg 200 mg

Valsartan LCZ696 320 mg

400 mg

Cha

nge

in p

lace

bo-s

ubtra

cted

BP

from

base

line

to w

eek

8 (m

mH

g)

LCZ696 in mild-to-moderate hypertension:Dose-related reductions in mean sitting pulse pressure

–2.85–2.38

–4.78

–2.52

–5.57

–2.25

p=0.0439 p=0.003

Cha

nge

from

bas

elin

e in

mea

n si

tting

puls

e pr

essu

re (m

mH

g)

0

–1

–2

–3

–4

–5

–6

p=0.68

Placebo effect = –0.94 mmHg

LCZ696 Valsartan 100 mg

80 mg

n=154 n=163

LCZ696 Valsartan 200 mg

160 mg

n=168 n=163

LCZ696 Valsartan 400 mg

320 mg

n=170 n=163

Systolic BP

Diastolic BP

LCZ696 in mild-to-moderate hypertension

Compared with RAAS inhibition with valsartanalone, LCZ696:

• Provided complementary pharmacological effects (additional BP reduction) in patients with hypertension

• Well tolerated at all doses

• No increased risk of angioedema was observed

Heart failure: a state of “neurohumoralimbalance”

↑Vasoconstrictor/ anti-natriuretic

/pro-mitoticMediators

↓ Vasodilator/ natriuretic/ anti-mitotic mediators

ACEi and ARBs Beta-

blockersAldosterone antagonists

A paradigm shift ... from “neuro-humoralinhibition” to “neuro-humoral modulation”?

↓Vasoconstrictor/ anti-natriuretic

/pro-mitotic Mediators

↑ Vasodilator/ natriuretic/ anti-mitotic mediators

Natriureticpeptides

ACEi and ARBs Beta-

blockersAldosterone antagonists

PARADIGM-HF: Study Design

~ 21 to 43 months (event-driven)

N = 7,980 patients

Enalapril 10 mg bid

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

Primary outcome: CV death or heart failure hospitalization(event driven: 2,410 patients with primary events)

Testing tolerabilityto target doses ofenalapril and LCZ696

LCZ696 LCZ696100 mg bid 200 mg bid

Enalapril 10 mg bid‡

2 weeks 1–2 weeks

2–4 weeks

Double-blind randomized treatment

Single-blind run-inLCZ696 200 mg bid

21

‡ Enalapril 5 mg bid for 1–2 weeks followed by enalapril 10 mg bid as an optional starting run-in dose for those pts who are treated with ARBs or with low dose of ACEI

In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril:

LCZ696 was more effective than enalapril in . . .• Reducing the risk of CV death and HF hospitalization• Reducing the risk of CV death by incremental 20%• Reducing the risk of HF hospitalization by incremental 21%• Reducing all-cause mortality by incremental 16%• Incrementally improving symptoms and physical limitations

LCZ696 was better tolerated than enalapril . . .• Less likely to cause cough, hyperkalemia or renal impairment• Less likely to be discontinued due to an adverse event• More hypotension, but no increase in discontinuations• Not more likely to cause serious angioedema

PARADIGM-HF: Summary of Findings

PARADIGM-HF: key efficacy outcomes

23

Primary outcome measure:• Time to first occurrence of either CV mortality or HF

hospitalization

Secondary outcomes measures:• HF symptoms and physical limitations measured by the

clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ)

• All-cause mortality• Renal progression assessed by first occurrence of 50% decline

in eGFR, >30 mL/min/1.73m2, or reaching end-stage renal disease

PARAMOUNT: Phase 2 study in HF-PEFProspective comparison of ARNI with ARB on exaMination Of heartfailUre with preserved ejectioN fracTion

Secondary endpoints

Echocardiographic parameters of diastolic function, cardiac filling pressures and structure

QoL – KCCQPatient global symptom assessment/NYHA classBiomarkers (BNP, ANP, cGMP, aldosterone, collagen/fibrosis biomarkers)Renal functionArterial stiffness (substudy)Populatio

nApproximately 300 patients with CHF (NYHA II-IV), LVEF ≥45%, baseline NT-proBNP >400 pg/mL, symptoms of HF, diuretic therapy required

LCZ696100 mg BID

LCZ69650 mg BID

Valsartan 40 mg BID

10 weeks

2 weeks

Primary endpoint

Placebo run-in

Discontinue ACEI or ARB therapy one day prior to randomization

LCZ696 200 mg BID

Valsartan 80 mg BID

Valsartan 160 mg BID

Prior ACEi/ARB use discontinued

1–2 wks 1–2 wks

Reduction in NT-proBNP

6 month extension

Clinicaltrials.gov; http://clinicaltrials.gov/ct2/show/NCT00887588

LCZ696: potential new treatment paradigm

Angiotensin Receptor Neprilysin Inhibitor (ARNI)– Potential for added neurohormonal modulation –

potentiation of natriuretic peptides

– Proven neurohormonal RAAS blockade – antagonism ofangiotensin II

Potential for treatment in heart failure and other cardiovascular disorders in which vasoconstriction, volume overload and neurohormonal activation play a role

Thank You