1
Renin Inhibitor
The new way for the blood pressure control,
anti-proteinuria, and renal protection
Chang-Chyi Jenq
2010-12-6
2
Renin
Renin Angiotensin
Angiotensin System
System
Renin Angiotensin System Inhibition
Physiologic Effects
Pathophysiologic
Effects
Direct renin inhibitor
Kidney
 Glomerular
vasoconstriction
 Inflammation
 Fibrosis
Angiotensinogen
Renin
Ang I
Heart
Non ACE pathways  Hypertrophy
PRA
PRA
ACE
ACEis
Feedback Loop
Direct renin inhibitor
Aldosterone
Ang II
ARBs
AT1 Receptor
Heart
Target cell
Kidney
(Pro)renin
Na /H2O retention
Vessels
+
 Vasoconstriction
 Remodelling
receptor
 Fibrosis
 Vasoconstriction
Biological effects
Vessels




Hyperplasia hypertrophy
Inflammation
Oxidation
Fibrosis
Brain
Vasoconstriction
 Vasoconstriction
Hypertension
Azizi M et al. 2006; Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006
3
Aliskiren:
the first orally available direct renin inhibitor
CH3O
OH
H
N
H 2N
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
4
Aliskiren binds to the active site of renin
Renin
Aliskiren
Angiotensinogen
Aliskiren binds to
a pocket in the
renin molecule,
blocking
cleavage of
angiotensinogen
to angiotensin I
Adapted from Wood JM, et al. 2003
Aliskiren –
the next generation in antihypertensive treatment

First direct renin inhibitor for hypertension

First major new treatment since the introduction of ARBs in 1994

Uniquely lowers PRA in monotherapy and combination

Effective and sustained monotherapy

Additional BP lowering when combined with other antihypertensives

Sustained 24-hour BP control with prolonged effect after withdrawal

Placebo-like safety and tolerability profile

Potential for improved end-organ protection via optimal suppression of
the renin system
 BNP reduction in heart failure
 LVH regression in hypertensive obesity
 Proteinuria reduction in DM nephropathy
 ASPIRE HIGHER program
5
Unlike ACEIs and ARBs, aliskiren reduces
Ang I, Ang II and PRA
6
Direct renin inhibitor
Angiotensinogen
Renin
Ang I
Heart
Non ACE pathways
Kidney
ACE
Vessels
ACEIs
Feedback Loop
 Vasoconstriction
 Remodelling
Ang II
ARBs
AT1 Receptor
ACEI
ARB
Aliskiren
Ang I
Ang II
Renin
PRA
↑
↑
↓
↓
↑
↓
↑
↑
↑
↑
↑
↓
Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006
7
Elevated PRA may be associated with
increased risk of myocardial infarction
For every 2-unit increase in PRA, there was an overall
25% increase in MI incidence
MI rate/1000 person-years
40
Plasma renin activity (PRA)
High
Normal
Low
30
20
10
0
High risk:
2 additional
risk factors†
†Risk
Moderate risk:
1 additional
risk factor†
factors defined as: smoking, cholesterol
>6.3 mg/dL, or left ventricular hypertrophy
Alderman et al. Am J Hypertens 1997.
Low risk:
No additional
risk factors†
Elevated PRA predicts cardiac events in
patients receiving optimal HF treatment
PRA and cardiac events (n=699, patients on treatment for heart failure)
1.0
PRA <5.48 nmol/L/h (<7.11 ng/mL/h)
0.8
Cumulative survival
n=517
0.6
p<0.001
PRA >5.48 nmol/L/h (>7.11 ng/mL/h)
n=147
0.4
0.2
0
0
500
1000
Follow-up (days)
Vergaro et al. Eur Heart J 2008;29(Suppl.):393 [Abstract]
1500
2000
2500
3000
8
9
Podocyte 足細胞
albumin
Other protein
albumin
細胞骨骼支撐
Fenestrated
endothelium
Tryggvason
et SJ
al. (2006)
(2006)Kidney
N Engl Int
J Med.
Shankland
10
RAS inhibition reduces Proteinuria
• 蛋白尿能預測慢性腎病的進展及心(腦)血管疾病死亡率。
• 使用 ARB/ACEi/DRi 等腎素-血管張力素系統抑制劑，能減低蛋
白尿的嚴重程度，並有效延緩慢性腎衰竭的進展。
• 足細胞的致病機制和蛋白尿的發生機制息息相關。
• 腎絲球若有外來的 stress ，足細胞的RAS會活化以因應 。
• 長期 RAS 過度活化對足細胞的影響：導致足細胞的細胞骨骼重
組變化， 也引起腎絲球過濾選擇性的通透性增加。
• 這個訊息傳導是由血管張力素第一型受體 (AT1R) 傳遞：
– 導致細胞內的 reactive oxygen species (氧化壓力) 上升
– 也導致附著蛋白  actinin-4 的過度消耗及生成減少
– 也導致抗氧化蛋白 Prdx2 生成減少，增加足細胞凋亡
– 持續的 RAS 過度活化會不可逆的傷害並減少足細胞
• 基礎醫學實驗支持 RAS i 是很好的高血壓基礎治療藥物
11
Rasilez® neutralizes the rise in PRA induced
by agents that stimulate renin release
†
Mean change from baseline in PRA after 8 weeks of treatment (%)
160
150
***
111
100
72
50
18
12
0
n= 101
107 186 64
74 75
−50
38 39
51
−44
−44
−75 −72 −75
***
Rasilez® (mg)
150 300 600
300
Other treatment (mg)
Pooled
placebo
10
Rasilez®
10
Ramipril
aPlacebo
from aliskiren/valsartan study
***p<0.0001 vs pooled placebo; †p<0.001, ‡p<0.0001 vs placeboa
Taylor A, et al. J Am Coll Cardiol 2007 (Pooled analysis)
‡
−62
***
*** *** ***
−100
59 61
300
25
300
320 320
25
HCTZ
Placeboa
Valsartan
12
Suppression of PRA is maintained following
discontinuation of aliskiren treatment
Mean change from baseline in PRA (%)
40
Double-blind treatment
Treatment-free
withdrawal
20
0
−20
−40
−60
−80
−100
0
Placebo (n=66)
Aliskiren 150 mg (n=66)
Week
8
10
Aliskiren 300 mg (n=66)
Aliskiren 600 mg (n=66)
Herron J, et al. 2006 (Study 2308)
The ASPIRE HIGHER
clinical study programme
Overview
13
14
15
AVOID
Population and objectives
Study population:

Patients with mild-to-moderate hypertension, type 2 diabetes and
nephropathy (UACR 200–3500 mg/g)
Primary objective:

Change in UACR from baseline to study end with aliskiren when
added to losartan 100 mg once daily and optimal antihypertensive
therapy, compared with placebo
Secondary objectives included:



Proportion of patients with ≥50% reduction in UACR at study end
Effect of treatment on BP
Safety and tolerability
UACR – urinary albumin-to-creatinine ratio
Parving H-H, et al. 2008 (AVOID)
16
Aliskiren in the eValuation of prOteinuria In
Diabetes (AVOID) study
Randomization
Aliskiren 150 mg
Aliskiren 300 mg
Placebo
Placebo
+
Losartan 100 mg + optimal antihypertensive therapy
Open-label
3 months

Double-blind
3 months
All patients continue to receive openlabel losartan 100 mg and optimal
antihypertensive therapy during the
double-blind period


3 months
Patients force-titrated after 3 months
All treatments administered once daily
Parving H-H, et al. 2008 (AVOID)
17
Baseline laboratory variables were similar in the
aliskiren and placebo groups
Optimal antihypertensive
therapy +
Aliskiren
(n=301)
Placebo
(n=298)
Systolic
135 ± 12
134 ± 12
Diastolic
78 ± 8
77 ± 9
Geometric mean UACR, mg/g
513 (463–569)
553 (502–609)
Geometric mean UAER, μg/min
495 (440–557)
520 (469–576)
68.5 ± 25.7
66.8 ± 24.5
Variable
Mean sitting blood pressure, mmHg
Mean eGFR, mL/min/1.73 m2
UAER – urinary albumin excretion rate
eGFR – estimated glomerular filtration rate
Data are presented as mean ± SD, except for UACR and UAER,
which are shown as geometric mean (95% CI)
Parving H-H, et al. 2008 (AVOID)
18
BP remained similar in the aliskiren and placebo groups
throughout the course of the study
Mean sitting BP (mmHg)
140
Systolic
130
120
110
100
90
80
Diastolic
70
60
–2
0
2
4
6
8
10
12
14
16
18
20
22
24
Week
Optimal antihypertensive therapy +
Aliskiren
Placebo
Parving H-H, et al. 2008 (AVOID)
19
Aliskiren provides significantly greater reductions in
UACR compared with placebo
Mean change from baseline§ in UACR at Month 6 (%)
5
2
0
n=289
n=287
−5
20% reduction
in UACR
Vs. placebo
−10
−15
−20
−18
*
Optimal treatment
+ aliskiren 300 mg
Optimal treatment
+ placebo
UACR values – aliskiren 513 pg/mL, placebo 553 pg/mL; baseline
was Week −2 value; data are shown as percentage change in geometric mean
*p<0.001 vs placebo
§Baseline
Parving H-H, et al. 2007 (AVOID)
Parving H-H, et al. 2008 (AVOID)
Significantly more patients achieve ≥50%
reduction in UACR from baseline with aliskiren
than with placebo
20
Patients with ≥50% reduction in UACR from baseline at Month 6 (%)
30
*
24.7
25
20
15
12.5
10
5
0
n=301
n=298
Optimal treatment
+ aliskiren 300 mg
Optimal treatment
+ placebo
*p<0.001 vs placebo
Baseline was Week –2 value
n values represent number of patients randomized to each group
Parving H-H, et al. 2008 (AVOID)
21
Aliskiren provides greater reductions in UACR than
placebo across different patient subgroups
Interaction
p-value
Gender
Males
Females
Interaction
p-value
UACR, mg/g
< median
≥ median
0.63
Race
Caucasian
Non-Caucasian
Age, years
< median
≥ median
eGFR, mL/min/1.73 m2
< median
0.29
≥ median
0.77
SBP, mmHg
< median
≥ median
0.28
0.1
1
Favours
aliskiren
0.89
10
Favours
placebo
Data are shown as geometric mean with 95% CI
for the ratio of the treatment effect for aliskiren:placebo
1.00
0.1
1
Favours
aliskiren
10
Favours
placebo
Parving H-H, et al. 2008 (AVOID)
Aliskiren provides effective BP-lowering
in patients with impaired renal function:
pooled analysis
DBP
0
SBP
eGFR <60
eGFR ≥60
n=26
n=740
n=25
22
n=736
eGFR <60
n=26
n=25
eGFR ≥60
n=740
n=736
5
10
–10.4
–9.4
–11.4
–10.1
–11.2
–11.5
15
–14.7
–14.9
Mean change from baseline in mean sitting BP after 8 weeks (mmHg)
Aliskiren 150 mg
Aliskiren 300 mg
eGFR: estimated glomerular filtration rate (assessed in mL/min/1.73 m2)
Weir MR, et al. 2007 (Pooled analysis)
Addition of Rasilez® to losartan and optimal
antihypertensive therapy was generally well
tolerated during the study
Optimal antihypertensive
therapy +
Rasilez®
(n=301)
Placebo
(n=298)
201 (66.8)
200 (67.1)
Any serious AE, n (%)
27 (9.0)
28 (9.4)
Discontinuations due to AEs, n (%)
17 (5.6)
19 (6.4)
0
2 (0.7)
Any adverse event (AE), n (%)
Deaths, n (%)
AEs reported by ≥5% of patients in either treatment group, n (%)
Headache
18 (6.0)
11 (3.7)
Nasopharyngitis
18 (6.0)
15 (5.0)
Dizziness
15 (5.0)
10 (3.4)
Hyperkalaemia
15 (5.0)
17 (5.7)
Peripheral oedema
13 (4.3)
23 (7.7)
Data are shown for the double-blind period
Parving HH et al. N Eng J Med 2008
23
Effect of study treatments on
laboratory values
24
Optimal antihypertensive
therapy +
Aliskiren
Placebo
(n=299)
(n=297)
Potassium
<3.5 mmol/L, n (%)
15 (5.0)
11 (3.7)
>5.5 mmol/L, n (%)
41 (13.7)
32 (10.8)
≥6.0 mmol/L, n (%)
14 ( 4.7)
5 (1.7)
Creatinine
>2.0 mg/dL, n (%)
37 (12.4)
54 (18.2)
BUN
>40.0 mg/dL, n (%)
65 (21.7)
66 (22.2)
• The incidence of serum potassium >6.0 mEq/L was numerically, but
not significantly greater with aliskiren compared with placebo
(p=0.06)
BUN – blood urea nitrogen
Data are presented as number of patients with pre-specified abnormal
laboratory values at any time during the double-blind period
Parving H-H, et al. 2008 (AVOID)
25
AVOID
Summary



In patients with hypertension, type 2 diabetes and nephropathy,
receiving losartan 100 mg once-daily and optimal
antihypertensive therapy aliskiren 300 mg provided a significant
additional mean reduction in UACR from baseline of 20%
compared with placebo
As differences in BP between the aliskiren and placebo groups
were small and not considered clinically meaningful, the effect of
aliskiren on UACR appears to be independent of the level of BP
control, suggesting a potential renoprotective effect for aliskiren
Aliskiren has tolerability comparable to placebo when
administered to patients with hypertension, type 2 diabetes and
nephropathy, receiving losartan 100 mg and optimal
antihypertensive therapy
26
27
Anti-proteinuric effect of aliskiren in patients with
hypertension and Type 2 diabetes – Study design
28 day washout
28 day treatment
Day 1
Furosemide*
28 day washout
Day 28
Aliskiren 300 mg od
Furosemide
Day 56
Furosemide
Patients with Type 2 diabetes, hypertension and albuminuria received stable
doses of furosemide throughout the study
•
Aims: to investigate the time course of the anti-proteinuric
effect and the antihypertensive effect of aliskiren 300 mg/day
*slow-release furosemide; UACR: urinary albumin-to-creatinine ratio
Persson F, et al. 2008
Aliskiren significantly reduces UACR from
baseline in patients with diabetes and
albuminuria
Geometric mean UACR (mg/g)
200
Treatment phase
Washout phase
*
150
**
100
†
NS
**
44% reduction in UACR from
baseline at Day 28
50
Effect persisted 11 days
0
1
5–7
2–4
11–13 17–19
23–25
29–31
35–37
41–43 47–49
53–54
8–10
14–16
20–22
26–28 32–34
38–40
44–46
50–52
*p=0.04; **p<0.001; †p=0.02 vs baseline;
NS: not statistically significant (p=0.14)
Persson F et al. Kidney Int 2008
Day
28
29
Aliskiren significantly reduces UACR from
baseline in patients with Type 2 diabetes and
albuminuria
0
Days 2–4
Days 8–10
Days 26–28
n=15
n=15
n=15
−10
−20
−30
−40
−17
*
−31
**
−44
**
−50
Mean change from baseline in UACR (%)
Aliskiren 300 mg + furosemide
*p<0.05; **p<0.001 vs baseline
Persson F, et al. 2008
30
Mean (SE)
SBP (mmHg)
Aliskiren significantly reduces 24-h SBP
from baseline in patients with diabetes
and
albuminuria
150
Max. ↓ in av. 24-h SBP on day 14
Reduction persisted for 3 days
after treatment disc.
145
Values are mean±SEM
* p≤0.05 vs baseline
140
*
* *
*
135
130
-1
7
14
21
28
Treatment phase
42
Washout phase
Day
Persson F, et al. Kidney Int 2008
35
49
56
31
comprised of three studies
•
The AVOID2 programme consists of three studies in diabetic and
non-diabetic patients, with and without nephropathy
• Study #1 (SPP100A2243)
• Evaluating the effect of aliskiren monotherapy and
aliskiren/ARB combination therapy on albuminuria
• Study #2 (SPP100A2329)
• Evaluating the effect of aliskiren compared with ACEI or
ARB therapy on renal blood flow and glomerular
filtration rate
• Study #3 (SPP100A2260)
• Evaluating the anti-proteinuric effect of aliskiren, on
top of ACEI therapy and hydrochlorothiazide
Persson F, et al. Diabetes Care 2009 doi:10.2337/dc09-0168 (Study 2243)
Clinicaltrials.gov http://clinicaltrials.gov/ct2/show/NCT00660309 (Study 2329); Data on File 2009 (Study 2260)
32
AVOID2 Study #1
Antiproteinuric effect of aliskiren compared, and in combination,
with irbesartan in patients with Type 2 diabetes, hypertension and
albuminuria – Study design
Placebo
Alis 300
Irb 300
Ali/Irb 300/300
Alis 300
Ali/Irb 300/300
Placebo
Irb 300
Irb 300
Placebo
Ali/Irb 300/300
Alis 300
Ali/Irb 300/300
Irb 300
Alis 300
Placebo
33
Furosemide# 40–60 mg
Run-in
4 weeks
8 weeks
Randomization*
Double-blind
8 weeks
*Patients randomized to one of the treatment sequences
#Furosemide administered to control fluid retention and BP
8 weeks
8 weeks
Persson F, et al. 2008
Aliskiren/irbesartan combination provides
significantly greater reductions in UAER than
either component monotherapy
0
Aliskiren
300 mg
Irbesartan
300 mg
Aliskiren/irbesartan
300/300mg
n=26
n=26
n=26
34
−25
−50
–48%
*
−75
–58%
*
–71%
*‡
−100
Mean change in UAER relative to placebo§ at Week 8 (%)
§Placebo
UAER at baseline: 258 mg/day
*p<0.001 vs placebo
‡p<0.05 vs component monotherapies
Persson F, et al. 2008
35
Aliskiren/irbesartan combination provides numerically
greater reductions in BP than either component
monotherapy
0
–2
–4
–6
SBP
DBP
n=26
n=26
–3.9
–3.6
n=26
n=26
n=26
n=26
*
–8
–10
–7.6
–7.2
*
−12
*
–6.4
*
–11.8
*
−14
Change in mean sitting BP relative to placebo at Week 8 (mmHg)
Aliskiren 300 mg
Placebo BP at endpoint: 135/78 mmHg
*p<0.05 vs placebo
Irbesartan 300 mg
Aliskiren/irbesartan
300/300 mg
Persson F, et al. 2008
Aliskiren neutralises the rise in PRA induced by irbesartan
in patients with Type 2 diabetes, hypertension and
albuminuria
36
Mean change in PRA relative to placebo at Week 8 (%)
**
400
321
200
0
−200
n=26
n=26
n=26
–47
–87
*
**
Aliskiren
300 mg
*p<0.01; **p<0.001 vs placebo
Irbesartan
300 mg
Aliskiren/irbesartan
300/300 mg
Persson F, et al. 2008
37
AVOID2 – Study #2
Effect on renal blood flow and GFR: Design overview
Randomization
Aliskiren 300 mg
Captopril
Wash-out
High sodium
Diet (3 days)
25 mg n=36
High sodium
diet (3 days)
2 weeks
n=18
Irbesartan 300 mg
1 day
single dose
n=18
2 weeks
Open-label treatment period
GFR = glomerular filtration rate
Clinicaltrials.gov http://clinicaltrials.gov/ct2/show/NCT00660309 (Study 2329)
38
39
Effect of aliskiren on renal plasma flow in
healthy volunteers – Study design



Single-blind study in 20 healthy volunteers
 Subjects tested on 3 separate days, separated by 48 hour
intervals
On each day of testing, subjects were assigned to receive a single
dose of aliskiren (75, 150, 300, or 600 mg) or placebo
RPF* assessed using clearance of PAH**
 On each study day, basal RPF determined after which aliskiren
administered as a single dose
*RPF – renal plasma flow
**PAH – para-aminohippurate
Fisher ND, et al. 2008
40
Aliskiren provides dose-dependent
increases in peak RPF
Peak change† from baseline in RPF after a single dose (mL/min/1.73 m2)
250
*
*
200
169
*
150
*
0
†Peak
124
93
100
50
197
33
n=7
n=7
n=15
n=19
n=7
Placebo
75 mg
150 mg
300 mg
600 mg
change determined from hourly assessments
of RPF made over 6 hours post-dose
Baseline RPF – 575 mL/min/1.73 m2; *p<0.05 vs baseline
Aliskiren
Fisher ND, et al. 2008
41
RPF remains above baseline 48 hours after
aliskiren administration
Change in RPF from baseline 48-hours post-dose (mL/min/1.73 m2)
100
*
50
*
*
0
n=3
n=6
Placebo
75 mg
n=15
n=8
150 mg
300 mg
-50
Aliskiren
*p<0.05 vs baseline
Fisher ND, et al. 2008
42
Change in renal plasma flow in response to ACE
inhibition, angiotensin receptor blockade and Direct
Renin Inhibition
Enalapril 5–20 mg1
ACEI
Captopril 25 mg2
ARB
Candesartan 16 mg3
Zankiren 250 mg4
Enalkiren 0.5 mg/kg2
DRI
Enalkiren* 36 mg5
Aliskiren 300 mg6
0
50
100
150
Change in RPF (ml/min/1.73 m2)
*mean dosage based
on patient weight
200
1. Hollenberg et al. 2000; 2. Fisher et al. 1994; 3. Lansang et al. 2000;
4. Fisher & Hollenberg 1995; 5. Cordero et al. 1991; 6. Fisher et al. 2008
Rasilez®/ramipril combination therapy
demonstrates a lower incidence of cough
compared with ramipril monotherapy
Ramipril
monotherapy*
(n=278)
Rasilez®
monotherapy*
(n=282)
Rasilez®
/ramipril
combination
therapy* (n=277)
33.8
32.3
30.0
Serious AEs, (%)
2.2
2.8
1.4
Discontinuation due to AEs, (%)
4.0
3.9
2.2
7.4
6.1
Any AE, (%)
Treatment-related AEs, (%)
11.9
Most frequent AEs (³2% in any group), (%)
Headache
6.1
3.2
2.9
Cough
4.7
2.1
1.8
Nasopharyngitis
1.8
3.2
1.1
Diarrhoea
2.5
1.1
1.1
*Patients received Rasilez® 150 mg, ramipril 5 mg, or Rasilez®/ramipril 150/5 mg od. After 4 weeks, patients
were titrated to Rasilez® 300 mg, ramipril 10 mg or Rasilez®/ramipril 300/5 mg for an additional 4 weeks
Uresin Y, et al. JRAAS 2007
43
44
Rasilez® (Aliskiren) 150-300 mg daily –
new generation in antihypertensive treatment

First direct renin inhibitor for hypertension

Uniquely lowers PRA in monotherapy and combination

Effective and sustained monotherapy

Additional BP lowering when combined with other
antihypertensives

Sustained 24-hour BP control with prolonged effect after
withdrawal

Placebo-like safety and tolerability profile

Potential for improved end-organ protection via optimal
suppression of the renin system
 BNP reduction in heart failure
 LVH regression in hypertensive obesity
 Proteinuria reduction in DM nephropathy