angiotensin receptor neprilysin + valsartan
TRANSCRIPT
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