Direct Renin Inhibition - Aliskiren

A new way of targeting the Renin System

 THE RENIN SYSTEM PLAYS A CENTRAL ROLE
IN REGULATION OF BP

Renin is released
into the vasculature

Juxtaglomerular cells

Glomerulus

2
 RENIN SECRETION IS REGULATED
BY 4 MECHANISMS
Distal tubule

1
Pressure in the
afferent arteriole

3
 RENIN SECRETION IS REGULATED
BY 4 MECHANISMS
Sympathetic nerve
2 stimulation of the beta1 Distal tubule
receptor in the JGA

4
 RENIN SECRETION IS REGULATED
BY 4 MECHANISMS
Distal tubule
3 Na+ at the macula densa

5
 RENIN SECRETION IS REGULATED
BY 4 MECHANISMS
Negative feedback by Ang II
Distal tubule

6
 7

Aliskiren binds to the active site of renin

Renin

Aliskiren
Aliskiren binds to
a pocket in the
Angiotensinogen renin molecule,
blocking
cleavage of
angiotensinogen
to angiotensin I

Adapted from Wood JM, et al. 2003

 CLASSIC UNDERSTANDING OF THE RENIN SYSTEM

Angiotensinogen

Renin
Ang I

ACE

Ang II Aldosterone
AT1 Receptor

Vasoconstriction
Na+/H2O retention Hypertension
8
Gibbons GH. 1998; Adapted from: Mller DN & Luft FC. 2006
 ACEIS AND ARBS CAUSE
COMPENSATORY RISES IN PRA
Kidney
Glomerular
vasoconstriction
Inflammation
Angiotensinogen Fibrosis

Renin` Heart
Ang I Hypertrophy
Non ACE pathways Fibrosis
Vasoconstriction
PRA ACE
ACEIs Vessels
Feedback Loop Hyperplasia
Ang II hypertrophy
ARBs Inflammation
Oxidation
AT1 Receptor
Fibrosis

Brain
Biological effects Vasoconstriction

9
Adapted from: Mller DN & Luft FC. 2006
 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
Angiotensinogen Fibrosis

Renin Heart
Ang I Hypertrophy
Non ACE pathways Fibrosis
PR Vasoconstriction
A ACE

Feedback Loop Vessels

Hyperplasia
Ang II hypertrophy
Inflammation
Oxidation
AT1 Receptor
Fibrosis

Brain
Biological effects Vasoconstriction
 11

Unlike ACEIs and ARBs, aliskiren reduces

Ang I, Ang II and PRA
Direct renin inhibitor

Angiotensinogen

Renin
Ang I
Non ACE pathways

ACE

Feedback Loop ACEIs

Ang II
ARBs
AT1 Receptor

Ang I Ang II Renin PRA

ACEI
ARB
Aliskiren
Azizi M et al. 2006; Adapted from: Mller DN & Luft FC. 2006
 A RECEPTOR FOR RENIN AND PRORENIN
WAS RECENTLY IDENTIFIED
Expression of prorenin receptor
The (pro)renin
receptor: High levels Low levels

A cell surface Brain

receptor that binds
Heart
renin and prorenin Liver
has been identified Pancreas

Receptor is a 350 Placenta Kidney

amino acid protein

with a single
transmembrane
domain
12
Nguyen et al. 2002.
 ALISKIREN MONOTHERAPY PROVIDES DOSE-
DEPENDENT REDUCTIONS IN DBP AND SBP
Irbesartan Irbesartan
Aliskiren (mg) (mg) Aliskiren (mg) (mg)
Placebo 150 300 600 150 Placebo 150 300 600 150
0
n=130 n=127 n=130 n=129 n=133 n=130 n=127 n=130 n=129 n=133

5
5.3
6.3
10 9.3 8.9
** 11.8 11.5 * 11.4
12.5
15 *** *** *** ***
p=0.01 15.8 15.7
20 p=0.005 *** ***
DBP SBP
Mean change from baseline in mean sitting BP (mmHg)

*p<0.02 vs placebo; **p<0.005; ***p<0.0005 vs placebo Gradman AH, et al. 2005 (Study 2201) 13
 ALISKIREN REDUCES DBP EFFECTIVELY IN BOTH
YOUNG AND ELDERLY PATIENTS
Aliskiren Aliskiren
Placebo 150 mg 300 mg Placebo 150 mg 300 mg
0
n=637 n=975 n=1243 n=139 n=205 n=360

5
3.9 5.8
5.8
3.6 4.2
10 8.1
9.7
11.6 11.7 12.3
15
***
*** *** ***
20 <65 years 65 years
Mean change from baseline in mean sitting DBP (mmHg)

***p<0.0001 vs placebo
Values under bars represent least square mean reductions standard error of the
mean; values in arrows represent placebo-subtracted reductions 14
Dahlf B, et al. 2007 (Pooled analysis)
 ALISKIREN PROVIDES EFFECTIVE DBP-LOWERING
IN PATIENTS WITH OBESITY: POOLED ANALYSIS
Aliskiren (mg) Aliskiren (mg)
Placebo 150 300 Placebo 150 300
0
n=275 n=434 n=630 n=776 n=1180 n=1603

5
6.1 6.2

10
10.0 10.1
*** 11.1 *** 11.8
*** ***
15 Patients with obesity All patients
Mean change from baseline in mean sitting DBP
after 812 weeks (mmHg)

***p<0.001 vs placebo Prescott MF, et al. 2007 (Pooled analysis) 15

HYPERTENSION STUDIES RESULTS
Efficacy in monotherapy
Efficacy in comparative and add-on
studies
24-hour BP control
Long-term efficacy
Persistence of effect
Safety
Effects on components of the Renin
System
16
SIGNIFICANT REDUCTIONS IN MEAN AMBULATORY
BP SUSTAINED OVER 24 HOURS
Placebo (n=53)
Aliskiren 150 mg (n=52)
Mean change from baseline in mean Aliskiren 300 mg (n=56)
ambulatory DBP (mmHg) Aliskiren 600 mg (n=55)
5

10

15
08:00 12:00 16:00 20:00 0:00 04:00
Clock hour
Trough to peak ratio:
aliskiren 150 mg 0.64
aliskiren 300 mg 0.98
aliskiren 600 mg 0.86 Mitchell J, et al. 2006 (Study 2308) 17
 SUSTAINED >24-HOUR BP CONTROL
SUMMARY
Aliskiren once daily provides persistent and smooth
24-hour BP reduction
Aliskiren once daily demonstrates >24-hour blood
pressure control, with a trough-to-peak ratio of 98%
with the 300 mg dose
Adding aliskiren to valsartan provides significantly
greater reductions in mean 24-hour ambulatory BP
compared with either component monotherapy
Even during the early morning BP surge, aliskiren
maintains sustained BP reductions
With a half-life of 40 hours, aliskiren demonstrates
sustained BP reductions at every time point over 24
hours 18
ALISKIREN OBSERVATION OF HEART FAILURE TREATMENT
(ALOFT) STUDY DESIGN OVERVIEW

Randomization

Placebo once-daily
Placebo
Aliskiren 150 mg once-daily

+
Standard therapy for HF continued throughout study in all patients,
which could include an ACEI or ARB, but not both

2 weeks 12 weeks
single-blind double-blind

Clinicaltrials.gov; 2007: NCT00219011

McMurray JJV. ESC 2007 (ALOFT) 19
 ALISKIREN DECREASES PRA
COMPARED WITH PLACEBO IN PATIENTS WITH HF
Standard HF therapy +
Aliskiren 150 mg Placebo
0
n=145 n=137
1
0.97
2
3
4
5
6
5.71
7 ***
Mean change from baseline in PRA at Week 12 (ng/mL/h)

***p<0.0001 vs placebo
PRA, plasma renin activity McMurray JJV. ESC 2007 (ALOFT) 20
 ALOFT Summary
In patients receiving standard therapy
for HF:
Aliskiren has a placebo-like tolerability
profile
Aliskiren significantly reduces BNP and
NT-proBNP compared with placebo
Aliskiren reduces urinary aldosterone
compared with placebo
Aliskiren provides significant reductions
in PRA compared with placebo
McMurray JJV. ESC 2007 (ALOFT) 21
 KESIMPULAN
Aliskerin efektif untuk menurunkan tekanan darah sistol
maupun diastol sama seperti obat antihipertensi yang lain
Dengan dosis 150 sampai 300 mg dapat menurunkan tekanan
darah sampai 24 jam
Kombinasi aliskerin dengan obat anti hipertensi yang lain
dapat menurunkan tekanan darah lebih baik lagi.
Dari percobaan binatang, aliskerin dapat mengurangi LVH dan
proteinura
Studi ALOFT menunjukkan aliskerin dapat mengurangi gagal
jantung (menurunkan BNP, Aldosteron dan PRA)
Studi AVOID menunjukkan aliskerin dengan losartan dapat
mengurangi proteinuria 20% lebih besar dari losartan saja.
Studi yang lain, pd usia lanjut, ACS, Post MI, resiko tinggi
belum selesai.

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