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
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