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HFrEF and NeurohormonalSystems
Richard Troughton
CSANZ Breakfast Symposium
15 June 2018
Vasoconstrictor
Salt and H2O
retaining
Normal Control of the Circulation:
Neurohumoral Balance
Endothelin
Angiotensin II
Aldosterone
Norepinephrine
BNP
ANP
Urocortin
Adrenomedullin
Vasodilator
Diuretic
Adapted from Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2–S6.
Neurohormonal Imbalance in Heart Failure
Endothelin
Aldosterone
Vasopressin
Angiotensin II
Norepinephrine
Excess v
asoconstric
tion
Compensation
Excess vasodilation
BNP
ANP
Urocortin
Adrenomedullin
• HF is characterized by heightened sympathetic tone
• Imbalances in baroreceptor reflexes and AngII-dependent SNS activation play an important role in adverse haemodynamic and cardiac responses
• Stimulation of SNS in HF results in
• Heart rate
• Contractility
• Na reabsorption
• Renal and peripheral vascular resistance
• Direct myocardial toxicity
Ach=acetylcholine; AngII= angiotensin II; CV=cardiovascular; E=epinephrine; HF=heart failure; NE=norepinephrine; SNS=sympathetic nervous system
Floras, JACC, 2009, 34: 375-85. Lymperopoulos et al. Circ Res 2013;113:739–53.
Sympathetic Nervous System: Role in the pathophysiology of HF
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*Studies ongoing; not approved for treatment of HFACE=angiotensin-converting enzyme; ACEI=angiotensin-converting-enzyme inhibitor; ADH=antidiuretic hormone; ARB=angiotensin receptor blocker; MRA=mineralocorticoid receptor antagonist; RAAS=renin-angiotensin-aldosterone system
Zaman et al. Nat Rev Drug Discov 2002;1:621–36; Schrier and Abraham. N Engl J Med 1999;341:577–85; Brewster et al. Am J Med Sci 2003;326:15–24; Schmieder. Am J Hypertens 2005;18:720–30; McMurray et al. Eur Heart J 2012;33:1787–847 Francis et al.
Ann Intern Med 1984;101:370–7; Von Lueder et al. Circ Heart Fail 2013;6:594–605.
RAAS: Initially compensatory and subsequently pathological in HF
Angiotensinogen
Ang I
Ang II
ACE
Renin
AT1 receptor
Biological actions
Signalling
cascade
Direct renin
inhibitors*
ACEIs
ARBs
Hypertrophy
Fibrosis
Vasoconstriction
hypertrophy
Aldosterone
secretion
Na+/H2O
retention
ADH
Secretion
Norepinephrine release
Sympathetic tone
Cardiac remodeling
Myocyte necrosis
Blood
Pressure Blood volume Heart rate
Contractility
MRAs
•ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names
•1. SOLVD Investigators. N Engl J Med 1991;325:293–302 2. MERIT-HF study group, Lancet, 1999, 353:2001-7 3. Granger et al. Lancet 2003;362:772−6 4. McMurray et al. Lancet
2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85 6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004 8 CIBIS-II
Investigators. Lancet 1999;353:9–13
Landmark trials in HFrEF
MERIT-HF2 (1999)3991 patients
Metoprolol vs placebo:
• 34% all-cause mortality
EMPHASIS-HF6 (2011)2,737 patients
Eplerenone (MRA) vs
placebo:
• 37% CV mortality or HF
hospitalization
SHIFT5 (2010)6,558 patients
Ivabradine (If inhibitor) vs
placebo:
• 18% CV death or HF
hospitalization
SOLVD-T1 (1991)2,569 patients
Enalapril (ACEI) vs placebo:
• 16% all-cause mortality
CHARM-Alternative3 (2003)2,028 patients
Candesartan (ARB) vs
placebo:
• 23% CV mortality or HF
hospitalization
CHARM-Added4 (2003)2,548 patients
Candesartan (ARB) vs
placebo:
• 15% CV mortality or HF
hospitalization
1990s 2000s 2010s
CIBIS-II8 (1999)2,647 patients
Bisoprolol (BB) vs placebo:
• 34% all-cause mortality
Combination ACEI, -Blocker and MRA are now the cornerstone of therapy for HFrEF
ACEI
ARB
BB
ACEI + BB
ACEI + ARB
ARB + BB
ACEI +MRA
ACEI + ARB +BB
ACEI +BB + MRA
0.83 (0.66, 1.01)
0.88 (0.61, 1.26)
0.57 (0.33, 0.94)
0.57 (0.41, 0.72)
0.83 (0.51, 1.24)
0.47 (0.23, 0.86)
0.57 (0.35, 0.91)
0.52 (0.31, 0.80)
0.44 (0.26, 0.66)
HR (95% credible interval) for treatment vs. placebo*
0 0.5 1 1.5
*HR<1 favors treatment
Results are based on random-effects network meta-analysis using Bayesian models2
Studies included: 57 RCTs, Phase II/III (Jan 1987- April 2015) assessing guideline-recommended drug classes for HFrEF
Patient population: Patients (aged ≥18 years) with chronic HFrEF (LVEF <45%) and NYHA class II–IV of varying etiology presenting in the
outpatient department were included
1. McMurray et al. Eur Heart J 2012;33:1787–847;.2. Burnett H et al. Circ Heart Fail. 2017;10:e003529 Adapted from Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2–S6.
Neurohormonal Imbalance in Heart Failure
Endothelin
Aldosterone
Vasopressin
Angiotensin II
Norepinephrine
Excess v
asoconstric
tion
Compensation
Excess vasodilation
BNP
ANP
Urocortin
Adrenomedullin
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The Natriuretic Peptide Family
H2 N
H2 N
H2 N
HOOCHOOC
HOOC
ANP BNP CNP
Courtesy of Dr Ruskoaho
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension 2007;49:419–26; 3. Yamahara et al., PNAS, 2003, 100:3404-09. 4. Yamamoto et al. ,AJP,
1997, 273: H2406-14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6. Kasama et al., Eur. Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016: 130:57-77. 8. Levin et al. N
Engl J Med 1998;339;321–8.
Effects of the Natriuretic Peptides
NPR-A
GTP
ANP and BNP
NPR-C
Internalization
Degradation
of NPs7
Receptor
recycling
Cardiomyocytes1
cGMP
⚫ Vasodilation1,2
⚫ Antihypertrophy1,2
⚫ Antiproliferation2
⚫ Vascular regeneration3
⚫ Myocardial relaxation4,5
⚫ Diuresis, natriuresis1,2
⚫ Antiapoptosis6
⚫ Anti-aldosterone1,2
⚫ Renin secretion inhibition7
⚫ Reduced sympathetic tone8
⚫ Lipolysis7
NPR-B
CNP
Endothelial cells1
GTPcGMP
⚫ Vasodilation1,2
⚫ Antihypertrophy1,2
⚫ Antiproliferation2
⚫ Vascular regeneration1
⚫ Venodilation1
⚫ Antifibrosis1
Natriuretic peptide degradation and clearance
Effect of Short Term Augmentation of BNP and Adrenomedullin Levels in HFrEF.
Lainchbury et al. Hypertension. 1999;34:70-75
Short term NP infusion not associated with
improvements in mortality or hospitalisation
Longer term infusion or S/C treatment not feasible
Inhibition of Clearance a potential therapeutic target
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; cGMP=cyclic guanosine monophosphate; GTP=guanosine triphosphate; NPR=neprilysin receptor
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al. Hypertension 2007;49:419–26; 3. Yamahara et al., PNAS, 2003, 100:3404-09. 4. Yamamoto et al. ,AJP, 1997, 273: H2406-
14. 5. Clarkson et al., Clin Science 1995: 88: 159-64. 6. Kasama et al., Eur. Heart. J. 2008: 29:1485-94. 7.Volpe et al., Clin Science, 2016: 130:57-77. 8. Levin et al. N Engl J Med
1998;339;321–8;.
Natriuretic peptides are cleared via NPR-C and degraded by the protease, neprilysin
NPR-A
GTP
ANP and BNP
NPR-C
Endocytosis
Inactivation
of NPs7
Receptor
recycling
Cardiomyocytes1
cGMP
NPR-B
Endothelial cells1
GTPcGMP
⚫ Vasodilation1,2
⚫ Antihypertrophy1,2
⚫ Antiproliferation2
⚫ Vascular regeneration1
⚫ Venodilation1
⚫ Antifibrosis1
ANP
BNP
CNP Inactive
cleavage
productsCNP
Natriuretic peptide degradation and clearance
NEPNeprilysin
Natriuretic peptide signaling and effects
⚫ Vasodilation1,2
⚫ Antihypertrophy1,2
⚫ Antiproliferation2
⚫ Vascular regeneration3
⚫ Myocardial relaxation4,5
⚫ Diuresis, natriuresis1,2
⚫ Antiapoptosis6
⚫ Anti-aldosterone1,2
⚫ Renin secretion inhibition7
⚫ Reduced sympathetic tone8
⚫ Lipolysis7
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Antoni Bayes-Genis et al. JACC 2016;68:639-653
Neprilysin / Neutral Endopeptidase
NEP is 749-AA, membrane-bound, zinc-dependent endopeptidase
Found in epithelia, fibroblasts and neutrophils and in soluble form
in the circulation, urine and CSF
Widely present in kidneys, heart, brain, gut and lungs
Neprilysin Cleavage Sites
• ANP and CNP are degraded by neprilysin with similar levels of enzymatic efficiency
• BNP is also degraded by neprilysin, but at a slower rate than ANP and CNP
Antoni Bayes-Genis et al. JACC 2016;68:639-653
Lainchbury et al, J Clin Endocrinol Metab. 1999;84(2):
Short-term NEP Inhibition in HFrEFOral NEP inhibition elevates NP levels in patients with HF
Single oral doses of candoxatril increase ANP and BNP levels in seven patients with chronic HF1#
Dose of candoxatril
Before treatment
Pla
sm
a B
NP
(p
mol/L)
Pla
sm
a A
NP
(p
mol/L)
50
40
30
20
10
0
100
80
60
40
20
00 mg 10 mg 50 mg 200 mg
Dose of candoxatril
*
*
**
**
After treatment
0 mg 10 mg 50 mg 200 mg
#Seven patients (mean age 65) with chronic HF NYHA II–III were given candoxatril 10, 50, 200 mg or placebo as a
single dose in a four-way crossover study. Values as mean and SEM; *p<0 05 vs 0 mg (placebo) (ANOVA);
Candoxatril - an orally active inhibitor of neprilysin
1. Lang et al. Lancet 1991;338:255
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• Candoxatril showed minimal hemodynamic effects compared with placebo in patients with HFrEF1-3
•Westheim et al. J Am Coll Cardiol 1999;34:1794–801; 2. Cleland and Swedberg. Lancet 1998; 351:1657–83 3. MaDowell and
Nicholls, Cardiovasscular drug reviews, 2000; 18: 259-70
Oral NEP inhibitor monotherapy failed to demonstrate clinical efficacy in HFrEF1
Left and right
atrial pressures
(reduced)
Arterial pressures
(no change)Heart rate
(no change)
Cardiac index
(no change after
exercise)
Systemic or
pulmonary
vascular
resistance
(no change)
▪ Another neprilysin inhibitor, ecadotril, led to numerically more deaths, as well as no evidence of clinical efficacy compared with placebo in patients with HF2
▪ Consequently, the development of both candoxatril and ecadotril for HF was discontinued2
⚫opposing actions of multiple neprilysin substrates
⚫increased Ang II levels offsetting beneficial effects of enhancing the NP system
⚫systemic vasoconstrictor rather than vasodilator effects (in part due to increased levels of the potent vasconstrictor ET-1)
•1. Westheim et al. J Am Coll Cardiol 1999;34:1794–801; 2. Kimmelstiel et al. Cardiology 1996;87:46–53; 3. Kentsch et al. Eur J Clin Pharmacol 1996;51:269–72; •4. McDowell et al. Br J Clin Pharmacol 1997;43:329–32; 5. Ando et al. Hypertension 1995;26:1160–6; 6. Von Lueder et al. Pharmacol Ther 2014;144: 41–9;
•7. Langenickel and Dole. Drug Discov Today:Ther Strateg 2012;9:e131–9.
Rationale for lack of efficacy with NEP inhibitor monotherapy in HFrEF1
Natriuretic peptides
Endothelin
Substance P
Bradykinin
Angiotensin II
Adrenomedullin
Angiotensin I
NEP
Inactive
fragments
or metabolites
⚫ Neprilysin metabolizes Ang I and Ang II 1,2
⚫ Inhibition of neprilysin alone is associated with an increase in Ang II levels, counteracting the potential benefits of neprilysin inhibition2
⚫ Neprilysin inhibition must be accompanied by simultaneous RAAS blockade
•1. Von Lueder et al. Circ Heart Fail 2013;6:594–605;
•2. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9.
Neprilysin inhibition must be accompanied by simultaneous RAAS blockade
Angiotensinogen
Ang I
Ang II
AT1 receptor
Biological actions
Norepinephrine release
↑ Sympathetic tone
Vasoconstriction
Hypertrophy
Na+/H2O retention
Aldosterone release
Hypertrophy
Fibrosis
Signaling
cascade
Ang-(1–7)
Renin
ACE
Inactive
fragments
Neprilysininhibitor
Neprilysin
Neprilysin
Neprilysininhibitor • The IMPRESS study, tested the efficacy and safety of omapatrilat compared with the
ACEi lisinopril in 573 patients with HFrEF over 24 weeks*
•1. Rouleau et al. Lancet 2000;356:615–20
Vasopeptidase inhibitors (dual NEP and ACE inhibition) showed promise in HFrEF
Pro
port
ion w
ith e
vent
0.15
0.10
0.05
01801501209060300
Death or admission for heart failure
Lisinopril
Omapatrilat
p=0.052
0.15
Death, admission for heart failure, or
discontinuation of treatment
p=0.035
0.10
0.05
01801501209060300
Lisinopril
Omapatrilat
Pro
port
ion w
ith e
vent
Time from randomization (days)Time from randomization (days)
*A randomized, double-blind, parallel trial in patients with chronic HF NYHA class II–IV, LVEF ≤40%, and receiving an ACEI. Omapatrilat 40 mg (n=289) or lisinopril
20 mg (n=284)
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• Omapatrilat was compared with enalapril in 5,770 patients with HFrEF
•Packer et al.Circulation 2002;106:920–6
OVERTURE study showed trends towards efficacy with dual NEPi/ACEi but raised significant safety concerns
Event-
free s
urv
ival (%
)
1.0
0.8
0.6
0211815630
Time to death or HF hospitalization
Omapatrilat
Enalapril
p=0.187
Months
0.4
0.2
249 12
▪ Omapatrilat discontinued due to:
• Lack of efficacyattributed to sub-optimal neprilysin and ACE inhibition over 24 hours due to the once-daily dosing regimen
• Safety concernunacceptable risk of angioedema (24 patients [0.8%] vs 14 patients [0.5%] for omapatrilat and enalapril, respectively)., attributed to dual neprilysin and ACE inhibition leading to elevated bradykinin levels,
• Bradykinin is a substrate of neprilysin, ACE and other vasopeptidases
• Simultaneous inhibition of ACE and neprilysin results in elevated levels of bradykinin leading to higher risk of cough and angioedema1,2
• A selective neprilysin inhibitor coupled with an ARB can enhance beneficial effects of NP system while inhibiting RAAS with minimal effect on bradykinin degradation1
•1. McMurray et al. Eur J Heart Fail 2014;16:817–25; 2. Gu et al. J Clin Pharmacol 2010;50: 401–14;
Co-inhibition of neprilysin and AT1-receptor: better efficacy with lower angioedema risk?
Active
bradykinin
Inactive
bradykinin
Omapatrilat inhibits
ACE, APP and NEP2
Bradykinin breakdown
Active
bradykinin
Inactive
bradykinin
Selective NEP and
ARB inhibition
ACE APP NEP DPP-4
• Sacubitril/Valsartan is a salt complex comprised of two active components in a 1:1 molar ratio
•sacubitril (AHU377) – a pro-drug metabolised to the neprilysin inhibitor sacubitrilat
•valsartan – an AT1 receptor blocker
Sacubitril/Valsartan a first in class dual neprilysin inhibitor and AT1 receptor blocker
1. Bloch and Basile. J Clin Hypertens 2010;12:809–12; 2. Gu et al. J Clin Pharmacol 2010;50:401–14; 3. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9.
3D sacubitril/valsartan structure2
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•ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names
•1. SOLVD Investigators. N Engl J Med 1991;325:293–302 2. MERIT-HF study group, Lancet, 1999, 353:2001-7 3. Granger et al. Lancet 2003;362:772−6 4. McMurray et al. Lancet
2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85 6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004 8 CIBIS-II
Investigators. Lancet 1999;353:9–13
Landmark trials in HFrEF
MERIT-HF2 (1999)3991 patients
Metorprolol vs placebo:
• 34% all-cause mortality
EMPHASIS-HF6 (2011)2,737 patients
Eplerenone (MRA) vs
placebo:
• 37% CV mortality or HF
hospitalization
SHIFT5 (2010)6,558 patients
Isvabradine (If inhibitor) vs
placebo:
• 18% CV death or HF
hospitalization
PARADIGM-HF7
(2014)
8,442 patients
Sacubitril/valsartan
(ARNI) vs enalapril:
SOLVD-T1 (1991)2,569 patients
Enalapril (ACEI) vs placebo:
• 16% all-cause mortality
CHARM-Alternative3 (2003)2,028 patients
Candesartan (ARB) vs
placebo:
• 23% CV mortality or HF
hospitalization
CHARM-Added4 (2003)2,548 patients
Candesartan (ARB) vs
placebo:
• 15% CV mortality or HF
hospitalization
1990s 2000s 2010s
CIBIS-II8 (1999)2,647 patients
Bisoprolol (BB) vs placebo:
• 34% all-cause mortality
Sacubitril/valsartan development timelines in HFrEF
1. de Bold AJ et al. Life Sci 1981;28:89–94; 2. Brauwald E et al, J Am Coll Cardiol
2015;65:1029–41
1998-2000:
Omapatrilat
and
Angioedema
1981-1983:
ANP is
discovered
1988-1992:
NEP
inhibitor
research
2005-2006:
Sacubitril/
valsartan
is born
2008-2014:
PARADIGM-HF
study. Trial
stopped early
2015: Sacubitril/
valsartan
approval in US
and EU
The future
Through its action of ANP
hydrolysis, NEP inhibition
leads to natriuresis and diuresis
First in class oral dual NEP and
ACE inhibitors discovered but
discontinued due to significant angioedema cases
Largest HF trial in history
compares sacubitril/valsartan
to ACEi enalapril in HFrEF patients
ANP released by
heart under
stress conditions lowers the blood
pressure
Both ESC-HF and US guidelines
give a recommendation of class IB
and replacement of ACEi/ARB with sacubitril/valsartan in all
symptomatic HFrEF patients
Novartis develops a unique, well-defined crystalline
salt complex comprising valsartan and sacubitrilat
along with sodium ions and water. A proof of concept human study of sacubitril/valsartan in
hypertension gives positive results
20 Jan 2016
TGA Approval
Sacubitril/valsartan
(Entresto®) receives
Australian TGA approval and is listed on the ARTG
Sacubitril/
valsartan is
available on the PBS
1 June 2017
PBS Listing
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•ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT1R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system
•1. McMurray et al. Eur J Heart Fail 2013;15:1062–73; 2. Minguet et al., Exp. Opin.Pharamacother, 2015, 16:435-46;,
•Figure references: Levin et al. N Engl J Med 1998;339:321–8
Sacubitril/valsartan: Neprilysin inhibition combined with RAAS blockade is an alternative to an ACEI or ARB in patients with HFrEF1
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 activity
VasopressinHeart rate
Contractility
Neprilysin
inhibitors
RAAS inhibitors
(ACEI, ARB, MRA)
β-blockers
Sacubitril/valsartan
Neprilysin degrades other vasoactive peptides substrates including
Ang II
AT1 receptor
Signaling
cascades
NPR-A NPR-B
GTP GTP
cGMP
ANP
BNP CNP
Vasodilation
Cardiac fibrosis/hypertrophy
Natriuresis/diuresis
Ang II
Vasoconstriction
Cardiac fibrosis/hypertrophy
Sodium/water retention
NPR-C
Receptor
recyclingEndocytosis
ANP
BNP
CNP
ANP
BNP
CNP
Inactive
cleavage
products
Neprilysin
Ang II
Ang I
AdrenomedullinBradykinin
ET-1
Substance P
Inactivation
of NPs1,2,5
⚫ Neprilysin metabolizes Ang I and Ang II 1,2
⚫ Inhibition of neprilysin alone is associated with an increase in AngII levels, counteracting the potential benefits of neprilysininhibition2
⚫ Neprilysin inhibition must be accompanied by simultaneous RAAS blockade
•1. Von Lueder et al. Circ Heart Fail 2013;6:594–605;
•2. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9.
Neprilysin inhibition must be accompanied by simultaneous RAAS blockade
Angiotensinogen
Ang I
Ang II
AT1 receptor
Biological actions
Norepinephrine release
↑ Sympathetic tone
Vasoconstriction
Hypertrophy
Na+/H2O retention
Aldosterone release
Hypertrophy
Fibrosis
Signaling
cascade
Ang-(1–7)
Renin
ACE
Inactive
fragments
Neprilysininhibitor
Neprilysin
Neprilysin
Neprilysininhibitor
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