1

Renin Inhibitor Renin Inhibitor

The new way for the blood pressure control, The new way for the blood pressure control,

anti-proteinuria, and renal protectionanti-proteinuria, and renal protection

Chang-Chyi JenqChang-Chyi Jenq

2010-12-62010-12-6

2

Renin Angiotensin System Inhibition

Renin Angiotensin SystemRenin Angiotensin SystemPathophysiologic EffectsPathophysiologic Effects

ACEACE

ReninRenin

NaNa++/H/H22O retentionO retentionVasoconstrictionVasoconstrictionHypertensionHypertension

ATAT11 Receptor Receptor

AldosteroneAldosterone

AngiotensinogenAngiotensinogen

Ang IAng I

Ang IIAng II

Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006

GlomerularGlomerularvasoconstrictionvasoconstriction

InflammationInflammation Fibrosis Fibrosis

KidneyKidney

HypertrophyHypertrophy FibrosisFibrosis VasoconstrictionVasoconstriction

HeartHeart

VasoconstrictionVasoconstriction

BrainBrain

Hyperplasia hypertrophyHyperplasia hypertrophy InflammationInflammation OxidationOxidation Fibrosis Fibrosis

VesselsVessels

Biological effectsBiological effects

ACEisACEis

Non ACE pathwaysNon ACE pathways

ARBsARBs

PRAPRA

Direct renin inhibitorDirect renin inhibitor

PRAPRA

(Pro)renin(Pro)reninreceptorreceptor

Target cellTarget cell

VasoconstrictionVasoconstriction RemodellingRemodelling

VesselsVessels

KidneyKidney

HeartHeart

Direct renin inhibitorDirect renin inhibitor

Azizi M et al. 2006;

Feedback LoopFeedback Loop

Renin Angiotensin SystemPhysiologic Effects

3

Wood JM, et al. 2003

Aliskiren: Aliskiren: the first orally available direct the first orally available direct

renin inhibitorrenin inhibitor

Molecular weight = 609.8Molecular weight = 609.8 High solubility in High solubility in water water and biological and biological

fluidsfluids Non-peptide drug Non-peptide drug suitable for oral suitable for oral

administrationadministration

O

NH

CONH2

OH

H2N

CH3O

O

CH3O

4

Angiotensinogen

Aliskiren binds to the active Aliskiren binds to the active site of reninsite of renin

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

Renin

Aliskiren

Adapted from Wood JM, et al. 2003

5Aliskiren –Aliskiren – the next generation in the next generation in

antihypertensive treatmentantihypertensive treatment First direct renin inhibitor for hypertensionFirst direct renin inhibitor for hypertension

First major new treatment since the introduction of ARBs First major new treatment since the introduction of ARBs in 1994in 1994

Uniquely lowers PRA in monotherapy and combinationUniquely lowers PRA in monotherapy and combination Effective and sustained monotherapyEffective and sustained monotherapy Additional BP lowering when combined with other Additional BP lowering when combined with other

antihypertensivesantihypertensives Sustained 24-hour BP control with prolonged effectSustained 24-hour BP control with prolonged effect after after

withdrawalwithdrawal Placebo-like safety and tolerability profilePlacebo-like safety and tolerability profile Potential for improved Potential for improved end-organ protection end-organ protection viavia optimal optimal

suppression of the renin systemsuppression of the renin system BNP reduction in heart failureBNP reduction in heart failure LVH regression in hypertensive obesity LVH regression in hypertensive obesity Proteinuria reduction in DM nephropathyProteinuria reduction in DM nephropathy ASPIRE HIGHER program ASPIRE HIGHER program

6Unlike ACEIs and ARBs, aliskiren Unlike ACEIs and ARBs, aliskiren reducesreduces

Ang I, Ang II and PRAAng I, Ang II and PRA

↓↑↓↓Aliskiren

↑↑↑↑ARB

↑↑↓↑ACEI

PRAReninAng IIAng I

Feedback Loop

AT1 Receptor

ReninAng I

Angiotensinogen

Ang II

Direct renin inhibitor

ARBs

ACE

Non ACE pathways

ACEIs

Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006

Vasoconstriction Remodelling

Vessels

Kidney

Heart

7Elevated PRA may be associated Elevated PRA may be associated with increased risk of with increased risk of myocardial infarctionmyocardial infarction

†Risk factors defined as: smoking, cholesterol >6.3 mg/dL, or left ventricular hypertrophy

MI rate/1000 person-years40

10

20

30

Low risk:No additionalrisk factors†

Moderate risk:1 additional risk factor†

High risk:2 additionalrisk factors†

Plasma renin activity (PRA)HighNormalLow

Alderman et al. Am J Hypertens 1997.

For every 2-unit increase in PRA, there was an overall 25% increase in MI incidence

0

8Elevated PRA predicts cardiac Elevated PRA predicts cardiac events in patients receiving events in patients receiving

optimal HF treatmentoptimal HF treatment

1.0

0.8

0.6

0.4

0.2

0Cu

mu

lati

ve s

urv

ival

Follow-up (days)

0 500 1000 1500 2000 2500 3000

PRA >5.48 nmol/L/h (>7.11 ng/mL/h)

PRA <5.48 nmol/L/h (<7.11 ng/mL/h)

p<0.001

n=147

n=517

Vergaro et al. Eur Heart J 2008;29(Suppl.):393 [Abstract]

PRA and cardiac events (n=699, patients on treatment for heart failure)

9

Tryggvason et al. (2006) N Engl J Med.

Podocyte Podocyte 足細足細胞胞

GBMGBM

Fenestrated Fenestrated endothelium endothelium

Shankland SJ (2006) Kidney Int

albumin

albumin

細胞骨骼支撐細胞骨骼支撐

Other protein

10

RAS inhibition reduces Proteinuria 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 Rasilez® neutralizes the rise in PRA induced by agents that PRA induced by agents that

stimulate renin releasestimulate renin release

Taylor A, et al. J Am Coll Cardiol 2007 (Pooled analysis)

−50

50

150

Rasilez® (mg)

Other treatment (mg)

−100

n=

Mean change from baseline in PRA after 8 weeks of treatment (%)

100

0101

12

−75 −72 −75

111***

aPlacebo from aliskiren/valsartan study***p<0.0001 vs pooled placebo; †p<0.001, ‡p<0.0001 vs placeboa

Pooled placebo

Rasilez®

150 300 600

107 186 64

72

38

HCTZ

25

39

−62

25

300

***

75

−44

74

Ramipril

300

10 10

****** *** ***

18

51

Placeboa

320

Valsartan

320300

160

59

†

61

−44‡

12

40

0

−20

−80

−100

−60

−40

20

Suppression of PRA is maintained Suppression of PRA is maintained following discontinuation of following discontinuation of

aliskiren treatmentaliskiren treatment

Herron J, et al. 2006 (Study 2308)

Mean change from baseline in PRA (%)

Week100 8

Placebo (n=66)

Aliskiren 150 mg (n=66)

Aliskiren 300 mg (n=66)

Aliskiren 600 mg (n=66)

Double-blind treatmentTreatment-free

withdrawal

13

The ASPIRE HIGHER The ASPIRE HIGHER clinical study programmeclinical study programme

OverviewOverview

14

15AVOIDAVOID Population and Population and

objectivesobjectivesStudy population:Study population: Patients with mild-to-moderate hypertension, type 2 Patients with mild-to-moderate hypertension, type 2

diabetes and nephropathy (UACR 200–3500 mg/g)diabetes and nephropathy (UACR 200–3500 mg/g)

Primary objective:Primary objective: Change in UACR from baseline to study endChange in UACR from baseline to study end with with

aliskiren when added to losartan 100 mg once daily aliskiren when added to losartan 100 mg once daily and optimal antihypertensive therapy, compared with and optimal antihypertensive therapy, compared with placeboplacebo

Secondary objectives included:Secondary objectives included: Proportion of patients with Proportion of patients with ≥≥50% reduction in UACR at 50% reduction in UACR at

study endstudy end Effect of treatment on BPEffect of treatment on BP Safety and tolerabilitySafety and tolerability

UACR – urinary albumin-to-creatinine ratio Parving H-H, et al. 2008 (AVOID)

16

Aliskiren in the eValuation of Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) prOteinuria In Diabetes (AVOID)

studystudy

All patients continue to receive All patients continue to receive open-label losartan 100 mg and open-label losartan 100 mg and optimal antihypertensive therapy optimal antihypertensive therapy during the double-blind periodduring the double-blind period

Patients force-titrated after 3 Patients force-titrated after 3 monthsmonths

All treatments administered once All treatments administered once dailydaily

3 months

Placebo

Aliskiren 150 mg

+

3 months 3 months

Placebo

Aliskiren 300 mg

Randomization

Open-label Double-blind

Losartan 100 mg + optimal antihypertensive therapy

Parving H-H, et al. 2008 (AVOID)

17

Optimal antihypertensive therapy +

VariableAliskiren(n=301)

Placebo (n=298)

Mean sitting blood pressure, mmHg

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)

Mean eGFR, mL/min/1.73 m2 68.5 ± 25.7 66.8 ± 24.5

Baseline laboratory variables were Baseline laboratory variables were similar in the aliskiren and placebo similar in the aliskiren and placebo

groupsgroups

UAER – urinary albumin excretion rateeGFR – estimated glomerular filtration rateData 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 BP remained similar in the aliskiren and placebo groups throughout the course of placebo groups throughout the course of

the studythe study

60

140

Mean sitting BP (mmHg)

130

120

110

20161284–2Week

24

Systolic

Diastolic

100

90

80

70

22181410620

Aliskiren PlaceboOptimal antihypertensive therapy +

Parving H-H, et al. 2008 (AVOID)

19

Optimal treatment + aliskiren 300 mg

Mean change from baseline§ in UACR at Month 6 (%)

0

−15

−20

−10

−5

n=289n=287

−18

52

*Optimal treatment

+ placebo

Aliskiren provides significantly greater Aliskiren provides significantly greater reductions in UACR compared with reductions in UACR compared with

placeboplacebo

§Baseline UACR values – aliskiren 513 pg/mL, placebo 553 pg/mL; baselinewas Week −2 value; data are shown as percentage change in geometric mean*p<0.001 vs placebo

Parving H-H, et al. 2007 (AVOID)Parving H-H, et al. 2008 (AVOID)

20% reductionin UACRVs. placebo

20% reductionin UACRVs. placebo

20

Patients with ≥50% reduction in UACR from baseline at Month 6 (%)

25

10

0

15

20

30

12.5

5

n=298n=301

24.7*

Optimal treatment + aliskiren 300 mg

Optimal treatment+ placebo

Significantly more patients achieve Significantly more patients achieve ≥50% reduction in UACR from ≥50% reduction in UACR from

baseline with aliskiren than with baseline with aliskiren than with placeboplacebo

*p<0.001 vs placeboBaseline was Week –2 valuen values represent number of patients randomized to each group Parving H-H, et al. 2008 (AVOID)

21

Aliskiren provides greater reductions in Aliskiren provides greater reductions in UACR than placebo across different patient UACR than placebo across different patient

subgroupssubgroups

Data are shown as geometric mean with 95% CI for the ratio of the treatment effect for aliskiren:placebo

MalesFemales

Gender

Non-CaucasianCaucasian

Race

< median≥ median

Age, years

Interaction p-value

0.63

0.77

0.28

Favoursaliskiren

Favoursplacebo

0.1 1 10

eGFR, mL/min/1.73 m2

≥ median< median

UACR, mg/g

< median≥ median

< median≥ median

SBP, mmHg

0.89

0.29

1.00

Interaction p-value

0.1 1 10

Favoursaliskiren

Favoursplacebo

Parving H-H, et al. 2008 (AVOID)

22Aliskiren provides effective BP-Aliskiren provides effective BP-lowering lowering

in patients with impaired renal in patients with impaired renal function: pooled analysisfunction: pooled analysis

Mean change from baseline in mean sitting BP after 8 weeks (mmHg)

Weir MR, et al. 2007 (Pooled analysis)

Aliskiren 300 mgAliskiren 150 mg

eGFR <60

–14.9

0

5

10

15 –14.7

–10.4–9.4

–11.2–10.1

–11.5

n=25 n=740 n=736n=26 n=25 n=740 n=736 n=26

–11.4

eGFR <60 eGFR ≥60 eGFR ≥60

DBP SBP

eGFR: estimated glomerular filtration rate (assessed in mL/min/1.73 m2)

23Addition of Rasilez® to losartan Addition of Rasilez® to losartan and optimal antihypertensive and optimal antihypertensive

therapy was generally well tolerated therapy was generally well tolerated during the studyduring the studyOptimal antihypertensive

therapy +

Rasilez® (n=301)

Placebo(n=298)

Any adverse event (AE), n (%) 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)

Deaths, n (%) 0 2 (0.7)

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

24

Effect of study treatments Effect of study treatments on laboratory valueson laboratory values

Optimal antihypertensive therapy +

Aliskiren (n=299)

Placebo(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)

BUN – blood urea nitrogenData are presented as number of patients with pre-specified abnormallaboratory values at any time during the double-blind period

• The incidence of serum potassium >6.0 mEq/L was numerically, but not significantly greater with aliskiren compared with placebo (p=0.06)

Parving H-H, et al. 2008 (AVOID)

25

AVOIDAVOIDSummarySummary

In patients with hypertension, type 2 diabetes and In patients with hypertension, type 2 diabetes and nephropathy, receiving losartan 100 mg once-daily and nephropathy, receiving losartan 100 mg once-daily and optimal antihypertensive therapy aliskiren 300 mg optimal antihypertensive therapy aliskiren 300 mg provided a significant additional mean reduction in UACR provided a significant additional mean reduction in UACR from baseline of 20% compared with placebofrom baseline of 20% compared with placebo

As differences in BP between the aliskiren and placebo As differences in BP between the aliskiren and placebo groups were small and not considered clinically groups were small and not considered clinically meaningfulmeaningful, the effect of aliskiren on UACR appears to be , the effect of aliskiren on UACR appears to be independent of the level of BP control, suggesting a independent of the level of BP control, suggesting a potential renoprotective effect for aliskirenpotential renoprotective effect for aliskiren

Aliskiren has Aliskiren has tolerabilitytolerability comparable to placebo when comparable to placebo when administered to patients with hypertension, type 2 administered to patients with hypertension, type 2 diabetes and nephropathy, receiving losartan 100 mg and diabetes and nephropathy, receiving losartan 100 mg and optimal antihypertensive therapyoptimal antihypertensive therapy

26

27

Anti-proteinuric effect of aliskiren in Anti-proteinuric effect of aliskiren in patients with hypertension and Type patients with hypertension and Type

2 diabetes – 2 diabetes – Study designStudy design

Day 1 Day 28 Day 56

*slow-release furosemide; UACR: urinary albumin-to-creatinine ratio

28 day washout 28 day treatment 28 day washout

Furosemide* Aliskiren 300 mg odFurosemide 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

Persson F, et al. 2008

28

Aliskiren significantly reduces Aliskiren significantly reduces UACR from baseline in patients UACR from baseline in patients with diabetes and albuminuriawith diabetes and albuminuriaGeometric mean UACR (mg/g)

200

50

100

150

01

2–45–7

8–1011–13

14–1617–19

20–2223–25

26–2829–31 53–54

32–3435–37

38–4041–43

44–4647–49

50–52

Washout phaseTreatment phase

Day*p=0.04; **p<0.001; †p=0.02 vs baseline; NS: not statistically significant (p=0.14)

*

**†**

NS

Persson F et al. Kidney Int 2008

44% reduction in UACR from baseline at Day 28

Effect persisted 11 days

44% reduction in UACR from baseline at Day 28

Effect persisted 11 days

29

Aliskiren significantly reduces UACR Aliskiren significantly reduces UACR from baseline in patients with Type 2 from baseline in patients with Type 2

diabetes and albuminuriadiabetes and albuminuria

*p<0.05; **p<0.001 vs baseline

Aliskiren 300 mg + furosemide

Days 2–4 Days 8–10 Days 26–28

n=15 n=15 n=15

−17

−31

−44

Mean change from baseline in UACR (%)

−50

0

−40

−30

−20

−10

*

**

**

Persson F, et al. 2008

30

Values are mean±SEM* p≤0.05 vs baseline

Aliskiren significantly reduces Aliskiren significantly reduces 24-h SBP from baseline in 24-h SBP from baseline in patients with diabetes and patients with diabetes and

albuminuriaalbuminuria

**

* *

Mea

n (

SE

)S

BP

(m

mH

g)

130

135

140

145

150

Day

-1 7 14 21 28 35 42 49 56 Treatment phase Washout phase

Persson F, et al. Kidney Int 2008

Max. ↓ in av. 24-h SBP on day 14

Reduction persisted for 3 days after

treatment disc.

Max. ↓ in av. 24-h SBP on day 14

Reduction persisted for 3 days after

treatment disc.

31

comprised of three studiescomprised of three studies• The AVOID2 programme consists of three studies in diabetic The AVOID2 programme consists of three studies in diabetic

and non-and non-diabeticdiabetic patients, with and without patients, with and without nephropathynephropathy• Study #1 (SPP100A2243)Study #1 (SPP100A2243)

• Evaluating the effect of Evaluating the effect of aliskiren monotherapy and aliskiren monotherapy and aliskiren/ARB aliskiren/ARB combination therapy on albuminuriacombination therapy on albuminuria

• Study #2 (SPP100A2329)Study #2 (SPP100A2329)• Evaluating the effect of aliskiren compared with ACEI Evaluating the effect of aliskiren compared with ACEI

or ARB therapy or ARB therapy on renal blood flow and glomerular on renal blood flow and glomerular filtration ratefiltration rate

• Study #3 (SPP100A2260)Study #3 (SPP100A2260) • Evaluating the Evaluating the anti-proteinuric effect of aliskiren, anti-proteinuric effect of aliskiren,

on top of ACEI therapy and hydrochlorothiazide 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

33Antiproteinuric effect of aliskiren compared, and Antiproteinuric effect of aliskiren compared, and in combination, with irbesartan in patients with in combination, with irbesartan in patients with Type 2 diabetes, hypertension and albuminuria – Type 2 diabetes, hypertension and albuminuria –

Study designStudy design

Randomization*4 weeks

Placebo

8 weeks

Irb 300

Alis 300

Run-in

8 weeks 8 weeks8 weeks

Ali/Irb 300/300

Placebo

Irb 300

Alis 300

Ali/Irb 300/300

Irb 300 Ali/Irb 300/300

Placebo Irb 300

Ali/Irb 300/300 Alis 300

Alis 300 Placebo

Furosemide# 40–60 mg

Double-blind

*Patients randomized to one of the treatment sequences#Furosemide administered to control fluid retention and BP Persson F, et al. 2008

34

−75

−100

−50

−25

0n=26n=26

*

n=26

–48%–58%

*–71%

* ‡

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

Aliskiren300 mg

Irbesartan300 mg

Aliskiren/irbesartan300/300mg

Aliskiren/irbesartan combination Aliskiren/irbesartan combination provides significantly greater provides significantly greater

reductions in UAER than either reductions in UAER than either component monotherapycomponent monotherapy

Persson F, et al. 2008

35

Change in mean sitting BP relative to placebo at Week 8 (mmHg)

DBP SBP

Aliskiren 300 mg Irbesartan 300 mg Aliskiren/irbesartan300/300 mg

−14

–2

–8

−12

–6

–4

0

–10

n=26 n=26n=26

–3.9

n=26

–7.2

n=26

–3.6

n=26

–6.4

–7.6

–11.8

Placebo BP at endpoint: 135/78 mmHg*p<0.05 vs placebo

Aliskiren/irbesartan combination provides Aliskiren/irbesartan combination provides numerically greater reductions in BP than numerically greater reductions in BP than

either component monotherapyeither component monotherapy

*

**

*

*

Persson F, et al. 2008

36

Aliskiren neutralises the rise in PRA Aliskiren neutralises the rise in PRA induced by irbesartan in patients with Type induced by irbesartan in patients with Type 2 diabetes, hypertension and albuminuria 2 diabetes, hypertension and albuminuria

Mean change in PRA relative to placebo at Week 8 (%)

Aliskiren300 mg

Aliskiren/irbesartan300/300 mg

Irbesartan300 mg

Persson F, et al. 2008

n=26

**

−200

0

200

400

n=26

–87

**

n=26

321

–47

*

*p<0.01; **p<0.001 vs placebo

37

AVOID2 – Study #2AVOID2 – Study #2Effect on renal blood flow and GFR: Effect on renal blood flow and GFR: Design overviewDesign overview

GFR = glomerular filtration rateClinicaltrials.gov http://clinicaltrials.gov/ct2/show/NCT00660309 (Study 2329)

2 weeks2 weeks

Randomization

1 daysingle dose

High sodium diet (3 days)

Wash-out Captopril25 mg n=36

Aliskiren 300 mg n=18

Irbesartan 300 mg n=18

High sodium Diet (3 days)

Open-label treatment period

38

39

Effect of aliskiren on renal plasma Effect of aliskiren on renal plasma flow in healthy volunteers – flow in healthy volunteers – Study Study

designdesign

Fisher ND, et al. 2008

Single-blind study in 20 healthy volunteersSingle-blind study in 20 healthy volunteers Subjects tested on 3 separate days, separated Subjects tested on 3 separate days, separated

by 48 hour intervalsby 48 hour intervals On each day of testing, subjects were assigned to On each day of testing, subjects were assigned to

receive a single dose of aliskiren (75, 150, 300, or receive a single dose of aliskiren (75, 150, 300, or 600 mg) or placebo600 mg) or placebo

RPF* assessed using clearance of PAH**RPF* assessed using clearance of PAH** On each study day, basal RPF determined after On each study day, basal RPF determined after

which aliskiren administered as a single dosewhich aliskiren administered as a single dose

*RPF – renal plasma flow**PAH – para-aminohippurate

40

Aliskiren provides dose-Aliskiren provides dose-dependentdependent

increases in peak RPFincreases in peak RPF

0

50

100

150

200

250

n=7 n=7 n=15 n=19 n=7

Peak change† from baseline in RPF after a single dose (mL/min/1.73 m2)

Placebo 75 mg 150 mg 300 mg

Aliskiren

600 mg

†Peak change determined from hourly assessmentsof RPF made over 6 hours post-doseBaseline RPF – 575 mL/min/1.73 m2; *p<0.05 vs baseline

197

124

93

33

169

Fisher ND, et al. 2008

*

*

**

41

RPF remains above baseline 48 RPF remains above baseline 48 hours after aliskiren hours after aliskiren

administrationadministration

Placebo 75 mg 150 mg 300 mg

Aliskiren

Change in RPF from baseline 48-hours post-dose (mL/min/1.73 m2)

*p<0.05 vs baseline

100

0n=8n=15

n=6n=3

*

**

50

-50

Fisher ND, et al. 2008

42

Change in renal plasma flow in response to Change in renal plasma flow in response to ACE inhibition, angiotensin receptor ACE inhibition, angiotensin receptor blockade and Direct Renin Inhibitionblockade and Direct Renin Inhibition

0 50 100 150 200Change in RPF (ml/min/1.73 m2)

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

Enalapril 5–20 mg1

Captopril 25 mg2

Candesartan 16 mg3

Zankiren 250 mg4

Enalkiren 0.5 mg/kg2

Enalkiren* 36 mg5

Aliskiren 300 mg6

ACEI

ARB

DRI

*mean dosage based on patient weight

43Rasilez®/ramipril combination Rasilez®/ramipril combination therapy demonstrates a lower therapy demonstrates a lower

incidence of cough compared with incidence of cough compared with ramipril monotherapyramipril monotherapyRamipril

monotherapy*

(n=278)

Rasilez®monotherapy*

(n=282)

Rasilez®/ramipril

combination therapy* (n=277)

Any AE, (%) 33.8 32.3 30.0

Serious AEs, (%) 2.2 2.8 1.4

Discontinuation due to AEs, (%) 4.0 3.9 2.2

Treatment-related AEs, (%) 11.9 7.4 6.1

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

Uresin Y, et al. JRAAS 2007

*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

44

RasilezRasilez®® (Aliskiren) 150-300 mg daily (Aliskiren) 150-300 mg daily –– new generation in antihypertensive treatment new generation in antihypertensive treatment

First direct renin inhibitor for hypertensionFirst direct renin inhibitor for hypertension

Uniquely lowers PRA in monotherapy and combinationUniquely lowers PRA in monotherapy and combination

Effective and sustained monotherapyEffective and sustained monotherapy

Additional BP lowering when combined with other Additional BP lowering when combined with other antihypertensivesantihypertensives

Sustained 24-hour BP control with prolonged effectSustained 24-hour BP control with prolonged effect after after withdrawalwithdrawal

Placebo-like safety and tolerability profilePlacebo-like safety and tolerability profile

Potential for improved end-organ protection viaPotential for improved end-organ protection via optimal optimal suppression of the renin systemsuppression of the renin system BNP reduction in heart failureBNP reduction in heart failure LVH regression in hypertensive obesity LVH regression in hypertensive obesity Proteinuria reduction in DM nephropathyProteinuria reduction in DM nephropathy