This document summarizes information about LCZ696, an angiotensin receptor neprilysin inhibitor (ARNI). It provides mechanisms of action, summarizes clinical trial results, and discusses the potential of LCZ696 as a new treatment for heart failure. Key points include: 1) LCZ696 provides both neprilysin inhibition to increase natriuretic peptides and blockade of the renin-angiotensin-aldosterone system through AT1 receptor blockade. 2) In clinical trials, LCZ696 reduced blood pressure more than valsartan alone and reduced cardiovascular death and heart failure hospitalization more than enalapril in heart failure patients. 3) LCZ696 may offer

1. ARNI
Angiotensin Receptor
Neprilysin + Valsartan
Dr. Jai Parekh, Dr. Ramesh Dargad

2. Metabolism ofANP 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 natriuretic
peptide degradation

3. Structure and Known Functions of
the Natriuretic Peptide Receptors (NPRs)
Source: Gardner, D. G. et al. Hypertension 2007;49:419-426
3

4. Dual NEP / ACE inhibitors

5. Omapatrilat (vasopeptidase inhibitor): Dual
ACE-NEP inhibition
Omapatrilat
ACE Neprilysin
Aminopeptidase
(APP)

6. LCZ696
LCZ696: Angiotensin Receptor Neprilysin Inhibition
Angiotensin
receptor blocker
Inhibition of
neprilysin

7. 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

8. Dual angiotensin receptor blockade and NEP inhibition
Counter-regulatory systems
Vasodilation
blood pressure
sympathetic tone
aldosterone levels
fibrosis
hypertrophy
Natriuresis/Diuresis
Symptoms /
disease
progression
Natriuretic peptides Angiotensin II
AT1Xreceptor
Vasoconstriction
blood pressure
sympathetic tone
aldosterone
fibrosis
hypertrophy
XNEP
Inactive
fragments
Dual NEP/RAAS
blockade
LCZ696

9. Mechanism of LCZ696 acting on the RAAS and
natriuretic peptide systems
Waeber and Feihl. Lancet, 2010

10. LCZ696 dose-dependently enhances ANP levels
and reduces BP
dTGR hypertensive rat model‡Rats infused with ANP*
220
200
180
160
140
120
100
8-htime-weightedaverage
[ANPir](%baseline)
Vehicle
0
–10
–20
–30
–40
–50
–60
Vehicle
24-htime-weightedaverage
∆MAP(mmHg)
LCZ696 dose (mg/kg) 2
6 20 60
2 6 20 60
LCZ696 dose (mg/kg)

11. • Healthy volunteers received once-daily oral LCZ696 50, 200, 600 or 900 mg
or placebo for 14 days
• cGMP measured as a biomarker of NEP inhibition andAng II as a measure of
AT1 receptor blockade
LCZ696 900 mg
Effects of LCZ696 on biomarkers of NEP inhibition
and AT1 receptor blockade
0 4
0.8
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
Changefrombaseline(n-fold)
Time (h)
10
*
*
*
* * *
0 4 12 24
*
*
* *
*
*
*
* *
*
*
*
*
*
1.2
1
1.0
Changefrombaseline(n-fold)
* *
*

12. LCZ696 in mild-to-moderate hypertension
Placebo
run-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 QD
Valsartan 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

13. 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
Changeinplacebo-subtractedBPfrom
baselinetoweek8(mmHg)
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 Val
200 100 80 200 160 400 320
154 163 168 163 170 163
AHU LCZ Val LCZ Val LCZ Val
200 100 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

14. -4.4
-4.9
-8.6
-12
-16
-8
-4
0
AHU
200
p < .0001
p = 0.011
p = 0.696
-2.3
p=0.059
vs 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
ValsartanLCZ696
160 mg 200 mg
Valsartan LCZ696
320 mg 400 mg
Changeinplacebo-subtractedBPfrom
baselinetoweek8(mmHg)

15. 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
Changefrombaselineinmeansitting
pulsepressure(mmHg)
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

16. Systolic BP

17. Diastolic BP

18. LCZ696 in mild-to-moderate hypertension
Compared with RAAS inhibition with valsartan
alone, LCZ696:
• Provided complementary pharmacological effects
(additional BP reduction) in patients with
hypertension
• Well tolerated at all doses
• No increased risk of angioedema was observed

19. Heart failure: a state of “neurohumoral
imbalance”
↑Vasoconstrictor/
anti-natriuretic
/pro-mitotic
Mediators
↓ Vasodilator/
natriuretic/
anti-mitotic
mediators
ACEi and ARBs
Beta-blockers
Aldosterone antagonists

20. A paradigm shift ... from “neuro-humoral
inhibition” to “neuro-humoral modulation”?
↓Vasoconstrictor/
anti-natriuretic
/pro-mitotic
Mediators
↑ Vasodilator/
natriuretic/
anti-mitotic
mediators
Natriuretic
peptides
ACEi and ARBs
Beta-blockers
Aldosterone antagonists

21. 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 tolerability
to target doses of
enalapril and LCZ696
LCZ696 LCZ696
100 mg bid 200 mg bid
Enalapril
10 mg bid‡
2 weeks 1–2 weeks 2–4 weeks
Double-blind randomized treatment
Single-blind run-in
LCZ696 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

22. 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

23. 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

24. PARAMOUNT: Phase 2 study in HF-PEF
Prospective comparison of ARNI with ARB on exaMination Of heart
failUre with preserved ejectioN fracTion
Secondary
endpoints
 Echocardiographicparametersof diastolicfunction, cardiacfillingpressuresandstructure
 QoL– KCCQ
 Patient global symptomassessment/NYHAclass
 Biomarkers(BNP,ANP, cGMP, aldosterone, collagen/fibrosisbiomarkers)
 Renal function
 Arterial stiffness(substudy)
Population Approximately300patientswith CHF(NYHA II-IV),LVEF ≥45%,baselineNT-proBNP>400pg/mL,
symptoms of HF, diuretic therapyrequired
LCZ696
100mgBID
LCZ696
50mgBID
Valsartan
40mgBID
10weeks2weeks
Primary endpoint
Placeborun-in
DiscontinueACEI or
ARB therapyoneday
priortorandomization
LCZ696200mgBID
Valsartan
80mgBID
Valsartan160mgBID
PriorACEi/ARBusediscontinued
1–2wks 1–2wks
ReductioninNT-proBNP
6monthextension
Clinicaltrials.gov; http://clinicaltrials.gov/ct2/show/NCT00887588

25. LCZ696: potential new treatment paradigm
 Angiotensin Receptor Neprilysin Inhibitor (ARNI)
– Potential for added neurohormonal modulation –
potentiation of natriuretic peptides
– Proven neurohormonal RAAS blockade – antagonism of
angiotensin II
 Potential for treatment in heart failure and other
cardiovascular disorders in which vasoconstriction,
volume overload and neurohormonal activation
play a role