Aliskiren - Gastaldi Congressi

Renin inhibitors:
the last challenge in the RAAS blockade
Alberto Morganti
U.O. Medicna Generale e Centro Ipertensione Arteriosa
Ospedale San Giuseppe
Unversità degli Studi di Milano
Tenth International Symposium Heart Failure
Milan April, 9-10 2010
1464 Mo
Different Levels of Pharmacological Blockade of
the Renin-Angiotensin System
Liver
Kidney, Adrenals,
Retina, Ovaries, Testis
Angiotensinogen
Asp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu-Val…
Renin
Angiotensin(1,9)
ACE2
Prorenin
Angiotensin I
Bradykinin
Asp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu
ACE
ACE
Angiotensin(1,7)
ACE2
Angiotensin II
ACE
Inactive peptides
Asp-Arg-Val-Tyr-Lle-His-Pro-Phe
Mas
AT2
-
1948 Mo
AT1
-
+
Kidney: Na retention, fibrosis
Heart: Hypertrophy (?), fibrosis
Adrenals: Aldosterone release
Vessels: Constriction, hypertrophy
Brain: SNS activation, ADH release, thirst, salt appetite
(Pro)renin receptors
??
+
Antagonism of the RAAS has been Proven Effective in:
Essential hypertension
Renovascular hypertension
Pheochromocytoma
Primary hyperaldosteronism?
Acute and chronic heart failure
Acute MI
Cardiac arrhythmias
Ischemic heart disease
Stroke and TIA
Dementia?
Diabetic and nondiabetic nephropathy
Proteinuria and non-proteinuric renal insufficiency
Portal hypertension
943 Mo
Residual risk: morbidity and mortality remains high,
despite treatment with ACEIs and ARBs
20
15
10
5
00
0.5 1.0 1.5 2.0 2.5 3.0 3.5
0.20
0.15
0.10
0.5
00
500
Time (years)
Time (months)
1Pfeffer
14.6%
relative risk
reduction
1,500
Val-HeFT4: freedom from combined endpoint
Event-free probability (%)
16
Atenolol
14
Losartan
12
10
8
6
4
2
00 6 12 18 24 30 36 42 48 54 60 66
1,000
Days of follow-up
Residual
Risk
Proportion of patients
with first event (%)
LIFE3: CV death, stroke and MI
22%
relative risk
reduction
Placebo
Ramipril
Residual
Risk
25
12%
relative risk
reduction
100
Valsartan
Placebo
90
Residual
Risk
Placebo
Candesartan
Population of patients
30
HOPE2: CV death, stroke and MI
Residual
Risk
Proportion died (%)
CHARM-Overall1: CV death
80
13.2%
relative risk
reduction
70
00
3
6
9
12 15 18 21 24
Time post-randomization (months)
et al. Lancet 2003;362:759–66; 2Yusuf et al. N Engl J Med 2000;342:145–53; 3Dahlöf et al. Lancet 2002;359:995–1003; 4Cohn et al. N Engl J Med 2001;345:1667–75
ACEIs and ARBs cause
compensatory rises in PRA
Kidney
 Glomerular
vasoconstriction
 Inflammation
 Fibrosis
Angiotensinogen
Renin
Heart
Ang I
Non ACE pathways
PRA
ACE
 Hypertrophy
 Fibrosis
 Vasoconstriction
ACEIs
Feedback Loop
Vessels
Ang II
ARBs
AT1 Receptor




Hyperplasia hypertrophy
Inflammation
Oxidation
Fibrosis
Brain
Biological effects
 Vasoconstriction
Adapted from: Müller DN & Luft FC. 2006
High PRA is associated with an increase in the incidence
of events across the CVD continuum
%
= increased risk of event for high versus low PRA
Alderman1:
280%
MI/CAD
HYPERTENSION
Bair ACC 20092: 40%
Time points:
Alderman: 3.6 years (mean)
SAVE: 38 months (mean)
Bair ACC: >5 years
Val-HeFT6: 23 months (mean)
Vergaro: 23 months (mean)
DEATH
*Hospitalization for CHF; ACC: American College of Cardiology
SAVE: Survival and Ventricular Enlargement study; Val-HeFT:
Valsartan Heart Failure Trial
SAVE3: 100%
Bair ACC 20092: 106%*
DEATH or
CHF
Val-HeFT4: 30%
Vergaro5: 50%
1Alderman
CV EVENTS
et al. Am J Hypertens 1997;10:1–8
et al. J Am Coll Cardiol 2009;53:A383 [Abstract]
3Rouleau et al. J Am Coll Cardiol 1994;24:583–91
4Latini et al. Eur Heart J 2004;25:292–9
5Vergaro et al. Eur Heart J 2008;29(Suppl.):393 [Abstract]
6Cohn et al. N Engl J Med 2001;435:1667–75
2Bair
Nonproteolytic Activation of Prorenin Bound to
the (Pro)renin Receptor
AOG
Ang I
Prorenin
Ang II
Renin
PRR
ACEI
PRR
Nucleus
 Fibronectin
 Collagen I
1741 Mo
Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 129-133
Ricerca farmacologica e sviluppo dei DRIs
Glaxo Wellcome
BMS
Harvard
Merck
Astra
Searle
SKB
Dainippon
Sankyo
Zeneca
Kissei
Parke Davis
Pfizer
Aliskiren
P&U
Sanofi
Abbott
Fujisawa
HMR
Merck KGaA
Roche
Yamanouchi
1988
1989
1990
1991
1992
1993
1994
1995
1996
BI/Bio-Mega
Wyeth-Ayerst
Speedel
Serie SPP800
Serie SPP1148
SPP635
Vitae/GSK
Plexxikon/Servier
Actelion/Merck
1997
2007
Aliskiren: the first orally available direct renin inhibitor
CH3O
OH
H
N
H2N
O
CONH2
O
CH3O
 Molecular weight = 609.8
 High solubility in water and biological fluids
 Non-peptide drug suitable for oral administration
Wood JM, et al. 2003
Aliskiren si lega alla tasca secondaria S3sp
della renina
La tasca secondaria S3sp
distingue la renina dalle altre
aspartil proteasi.
Il legame di aliskiren alla tasca
secondaria S3sp della renina
(alloggiandovi la catena
secondaria metossialcossilica
dell’inibitore) è alla base della
sua specificità per la renina
umana rispetto alle altre
aspartil proteasi.
Adattato da: Wood JM et al, 2003
Direct renin inhibition acts at the point of activation of the
Renin System and neutralizes the PRA rise
Direct renin inhibitor
Kidney
 Glomerular
vasoconstriction
 Inflammation
 Fibrosis
Angiotensinogen
Renin
Heart
Ang I
Non ACE pathways
PRA
ACE
 Hypertrophy
 Fibrosis
 Vasoconstriction
Feedback Loop
Vessels
Ang II
AT1 Receptor




Hyperplasia hypertrophy
Inflammation
Oxidation
Fibrosis
Brain
Biological effects
 Vasoconstriction
Adapted from: Müller DN & Luft FC. 2006
Inibitori Diretti della Renina
Caratteristiche Farmacologiche di Aliskiren
Potente e specifico inibitore non peptidico della renina umana
(IC50 = 0.6 nmol/L)
Lunga emivita plasmatica (30-40 ore)
Assorbimento rapido ma scarso e variabile; migliore a digiuno
Binding alle proteine plasmatiche 50%
Bassa biodisponibilità (2.6%)
Lunga persistenza nei tessuti (specie nel rene)
Escrezione prevalentemente per via fecale (90%)
1683 Mo
Concentration of Aliskiren in the Circulation
Aliskiren conc. (ng/ml)
120
80
40
0
Time
(min):
Dose:
1824 Mo
0
120 300
Placebo
24
h
0
120 300
75 mg
0
120 300
150 mg
24
h
0
120 300
300 mg
24
h
0
120 300
24
h
48
h
600 mg
Fisher NDL et al., Circulation 2008; 117: 3199-3205
Plasma Renin, Aliskiren/Renin Concentration Ratio,
Percentage Renin Inhibition, PRA and Plasma AII
Following Exposure to Escalating Doses of Aliskiren on Separate Study Days
Renin
[Aliskiren]/[renin]
(ng/l)
400
200
0
100
(%)
20
(thousands)
600
10
0
0
75
150
300
600
0
75
150
300
600
3
0
75
300
600
150
300
600
AII
20
15
(pg/ml)
(ng AII l/ml.h)
50
0
PRA
4
2
1
10
5
0
0
0
2202 Mo
Renin inhibition
75
150
300
600
0
75
150
Danser JAH et al., Hypertension Research 2010; 34: 4-10
Change in PRA in Patients Treated with
Various Antihypertensives and Combination RAS Blockade
700
650
PRA increase (%)
600
500
380
400
300
200
100
143
178
205
58
0
-70
-100
2100 Mo
-44.3
CCB
ACEI
HCTZ
ARB
ARB/
HCTZ
ACEI/
ARB
DRI
DRI/
ACEI
Amlodipine
Ramipril
HCTZ
Irbesartan
Valsartan/
HCTZ
Benazepril/
valsartan
Aliskiren
Aliskiren/
ramipril
Epstein BS et al., Expert Rev Cardiovasc Ther 2009; 7: 1373-1384
Renal Partitioning and Localization Pattern of Aliskiren
12
Plasma
Kidney
Aliskiren (M)
10
8
Glomeruli
6
4
2
0
Aliskiren: 10 mg/kg
Non-diabetic
1839 Mo
3 mg/kg
10 mg/kg
Diabetic
Renal cortical artery
Feldman DL et al., Hypertension 2008; 52: 130-136
Percentage of (pro)renin that is Aliskiren-bound in the Cell Lysates,
Culture Medium, and Stimulation Medium of HMC-1 Cells
after Incubation of Cells in the Absence or Presence of Aliskiren
Cell lysate
Culture medium
Stimulation medium
100
100
80
80
60
60
60
40
40
40
20
20
20
0
0
0
100
% aliskiren-bound
Renin
Prorenin
80
-10
-9
-8
-7
-6
-10
-9
-8
-7
-6
-10
-9
-8
-7
-6
log [aliskiren] (mol/l)
1934 Mo
Krop M et al., Hypertension 2008; 52: 1076-1083
Potential Inhibition of Receptor-bound Activated Prorenin and of Renin
and Receptor Interaction by Renin Inhibitor Blocking the Active Site of
Renin and Modifying Its Conformation
Mature renin
Prorenin
Renin inhibitor
Ang I
?
?
ERK1/2
Nucleus
1742 Mo
Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 129-133
Changes in Systolic and Diastolic BP with Aliskiren
according to Gender and Body Mass Index
Mean change in SBP
Aliskiren
150 mg
(mmHg)
0
Aliskiren
300 mg
Aliskiren
150 mg
BMI
Men Women Men Women < 30
n=468 n=298 n=438 n=326 n=512
BMI
≥ 30
n=250
Mean change in DBP
Aliskiren
300 mg
BMI
BMI
< 30
≥ 30
n=491 n=269
Aliskiren
150 mg
0
-5
-5
-10
-10
-15
-15
-20
-20
Placebo
2213 Mo
Aliskiren
300 mg
Aliskiren
150 mg
BMI
Men Women Men Women < 30
n=468 n=298 n=438 n=326 n=512
Aliskiren 150 mg
BMI
≥ 30
n=250
Aliskiren
300 mg
BMI
BMI
< 30
≥ 30
n=491 n=269
Aliskiren 300 mg
Jarugula V et al., J Clin Pharm, March 2010
Change in Sitting Systolic and Diastolic BP
with Aliskiren Monotherapy in Women, Analysed by Age
Mean change in msSBP
Aliskiren 150 mg
(mmHg)
n=
0
< 50 y
148
50-55 y
100
> 55 y
244
Mean change in msDBP
Aliskiren 300 mg
< 50 y
170
50-55 y
147
> 55 y
388
Aliskiren 150 mg
n=
0
-5
-5
-10
-10
< 50 y
148
50-55 y
100
-10.8
-10.7
> 55 y
244
Aliskiren 300 mg
< 50 y
170
-15
-13.9
> 55 y
388
-10.6
-11.4
-12.4
-13.6
50-55 y
147
-12.9
-15
-15.0
-16.0
-17.0
-17.8
-20
2206 Mo
-20
Gradman AH et al., J Human Hypertens, March 2010
Effect of Aliskiren Monotherapy and in Combination with
Other Antihypertensive Agents in AGELESS Study
Mean change in msSBP
Week 12
Ali- Ramiskiren pril
Mean change in msDBP
Week 22
Week 36
Week 12
Ali Rami
± HCTZ
Ali Rami
± HCTZ
± Amlo
Ali- Ramiskiren pril
0
-5
Week 22
Week 36
Ali Rami
± HCTZ
Ali Rami
± HCTZ
± Amlo
0
-5
-3.6
(mmHg)
-5.1
-10
-10
P < 0.01
-11.6
-15
-17.1
-18.1
-19.6
2210 Mo
P = 0.02
P = 0.14
-8.2
P = 0.03
-15
-14.0
-20
-25
-7.0
-7.3
-8.2
P = 0.03
-20
-20.0
P = 0.07
-25
Duprez A et al., J Human Hypertens, December 2009
Systolic and Diastolic Blood Pressure during the
Post-active-controlled-treatment with Aliskiren and Ramipril
SBP
mmHg
DBP
mmHg
150
100
145
95
140
90
135
85
130
80
26
27
28
29
30
26
27
Week
Aliskiren (n = 170)
2103 Mo
28
29
30
Week
Aliskiren placebo (n = 163)
Ramipril (n = 165)
Ramipril placebo (n = 177)
Andersen K et al., J Renin Angiotensin Aldosterone Syst 2009; 10: 157-167
Aliskiren provides significant reductions in
PRA compared with placebo
0
Optimal HF therapy +
Aliskiren 150 mg
Optimal HF therapy +
Placebo
n=145
n=137
−0.97
−2
−4
−6
−5.71
*
−8
Mean change from baseline in PRA at Week 12 (ng/mL/h)
*p<0.0001 vs placebo
McMurray JJV. ESC 2007 (ALOFT)
Aliskiren provides significant reductions in urinary
aldosterone levels compared with placebo
0
Optimal HF therapy +
Aliskiren 150 mg
Optimal HF therapy +
Placebo
n=141
n=128
–2
–4
–6
–8
–7.0
–9.2
–10
*
Mean change from baseline in urinary aldosterone at Week 12 (nmol/day)
*p=0.015 vs placebo
McMurray JJV. ESC 2007 (ALOFT)
Aliskiren provides significant reductions in
BNP levels compared with placebo
0
−10
Optimal HF therapy +
Aliskiren 150 mg
Optimal HF therapy +
Placebo
n=148
n=137
−12.2
−20
−30
−40
−50
−60
−61.0
p=0.0160
−70
Mean change from baseline in BNP at Week 12 (pg/mL)
Baseline BNP concentration = 291 pg/mL
McMurray JJV. ESC 2007 (ALOFT)
Changes in Albumin Excretion Rate in Patients with Diabetes and Hypertension
Treated with Losartan Alone or in Combination with Aliskiren
Urinary
albumin-to-creatinine ratio
Urinary albumin
excretion rate
Mean sitting
blood pressure
%
%
mmHg
10
20
140
S
10
0
120
0
-10
100
-10
-20
D
80
-20
-30
-30
-2 0
2 4
6
8 10 12 14 16 18 20 22 24
Week
60
-2 0
2 4
6
8 10 12 14 16 18 20 22 24
Week
Aliskiren
1832 Mo
-2 0
2 4
6
8 10 12 14 16 18 20 22 24
Week
Placebo
Parving HH et al., NEJM 2008; 358: 2433-2446
Conclusioni
Aliskiren è il primo di una nuova classe di farmaci che antagonizzano
l’attività del SRAA inibendo direttamente l’attività enzimatica della
renina
Aliskiren è l’unico farmaco che inibisce i meccanismi di
controregolazione che possono limitare l’efficacia degli altri bloccanti
del SRAA (ACEI/ARB)
In studi controllati la riduzione della pressione arteriosa indotta da
aliskiren è uguale o superiore a quella di alcuni ACEI/ARB
Grazie alla elevata concentrazione a livello renale e alla interferenza
del binding di renina e prorenina agli specifici recettori, aliskiren
potrebbe esercitare effetti locali di protezione d’organo indipendenti
dall’effetto antipertensivo
1684 Mo