1464 Mo1464 Mo

Renin inhibitors:Renin inhibitors:the last challenge in the RAAS blockade the last challenge in the RAAS blockade

Alberto MorgantiAlberto Morganti

U.O. Medicna Generale e Centro Ipertensione ArteriosaU.O. Medicna Generale e Centro Ipertensione ArteriosaOspedale San Giuseppe Ospedale San Giuseppe

Unversità degli Studi di MilanoUnversità degli Studi di Milano

Tenth International Symposium Heart Failure Tenth International Symposium Heart Failure Milan April, 9-10 2010 Milan April, 9-10 2010

1948 Mo1948 Mo

Different Levels of Pharmacological Blockade of Different Levels of Pharmacological Blockade of the Renin-Angiotensin Systemthe Renin-Angiotensin System

AngiotensinogenAngiotensinogenAsp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu-Val…Asp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu-Val…

Angiotensin IAngiotensin IAsp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-LeuAsp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu

Angiotensin IIAngiotensin IIAsp-Arg-Val-Tyr-Lle-His-Pro-PheAsp-Arg-Val-Tyr-Lle-His-Pro-Phe

Angiotensin(1,9)Angiotensin(1,9)

Angiotensin(1,7)Angiotensin(1,7)

Kidney:Kidney: Na retention, fibrosis Na retention, fibrosisHeart:Heart: Hypertrophy (?), fibrosis Hypertrophy (?), fibrosisAdrenals:Adrenals: Aldosterone release Aldosterone releaseVessels:Vessels: Constriction, hypertrophy Constriction, hypertrophyBrain:Brain: SNS activation, ADH release, thirst, salt appetite SNS activation, ADH release, thirst, salt appetite

LiverLiver Kidney, Adrenals, Kidney, Adrenals, Retina, Ovaries, TestisRetina, Ovaries, Testis

ProreninProrenin

(Pro)renin receptors(Pro)renin receptors

ReninRenin

Inactive peptidesInactive peptides

BradykininBradykinin

MasMas AT2AT2 AT1AT1

ACEACE

ACE2ACE2

ACE2ACE2

ACEACE ACEACE

-- -- ++++

????

943 Mo943 Mo

Antagonism of the RAAS has been Proven Effective in:Antagonism of the RAAS has been Proven Effective in:

Essential hypertensionEssential hypertension

Renovascular hypertensionRenovascular hypertension

PheochromocytomaPheochromocytoma

Primary hyperaldosteronism?Primary hyperaldosteronism?

Acute and chronic heart failureAcute and chronic heart failure

Acute MIAcute MI

Cardiac arrhythmiasCardiac arrhythmias

Ischemic heart diseaseIschemic heart disease

Stroke and TIAStroke and TIA

Dementia?Dementia?

Diabetic and nondiabetic nephropathyDiabetic and nondiabetic nephropathy

Proteinuria and non-proteinuric renal insufficiencyProteinuria and non-proteinuric renal insufficiency

Portal hypertensionPortal hypertension

Residual risk: morbidity and mortality remains high, despite treatment with ACEIs and ARBs

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

30

25

20

15

10

5

0

Pro

po

rtio

n d

ied

(%

)

Time (years)

12% relative risk reduction

Re

sid

ua

l R

isk

CHARM-Overall1: CV death

0 500 1,000 1,500

0.20

0.15

0.10

0.5

0

Po

pu

lati

on

of

pa

tien

ts

Days of follow-up

22% relative risk reduction

Re

sid

ua

l R

isk

HOPE2: CV death, stroke and MI

0 6 12 18 24 30 36 42 48 54 60 66

16141210

86420P

rop

ort

ion

of

pat

ien

ts

wit

h f

irst

eve

nt

(%)

Time (months)

14.6% relative risk reduction

Re

sid

ua

l R

isk

LIFE3: CV death, stroke and MI

0 3 6 9 12 15 18 21 24

100

90

80

70

0Eve

nt-

free

pro

bab

ilit

y (%

)

Time post-randomization (months)

13.2% relative risk reduction

Re

sid

ua

l R

isk

Val-HeFT4: freedom from combined endpoint

PlaceboRamipril

AtenololLosartan

ValsartanPlacebo

1Pfeffer 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

PlaceboCandesartan

ACEIs and ARBs cause compensatory rises in PRA

Glomerularvasoconstriction

Inflammation Fibrosis

Kidney

Hypertrophy Fibrosis Vasoconstriction

Heart

Vasoconstriction

Brain

Hyperplasia hypertrophy Inflammation Oxidation Fibrosis

VesselsFeedback Loop

AT1 Receptor

ReninAng I

Angiotensinogen

Ang II

Biological effects

ACE

Non ACE pathways

ARBs

ACEIsPRA

Adapted from: Müller DN & Luft FC. 2006

HYPERTENSION MI/CAD

DEATH CHFDEATH or

CV EVENTSVal-HeFT4: 30%

Vergaro5: 50%

SAVE3: 100%

Alderman1:280%

1Alderman et al. Am J Hypertens 1997;10:1–82Bair 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

*Hospitalization for CHF; ACC: American College of CardiologySAVE: Survival and Ventricular Enlargement study; Val-HeFT: Valsartan Heart Failure Trial

Bair ACC 20092: 40% Bair ACC 20092: 106%*

High PRA is associated with an increase in the incidence of events across the CVD continuum

Time points:Alderman: 3.6 years (mean)SAVE: 38 months (mean)Bair ACC: >5 yearsVal-HeFT6: 23 months (mean)Vergaro: 23 months (mean)

% = increased risk of event for high versus low PRA

1741 Mo1741 Mo

Nonproteolytic Activation of Prorenin Bound to Nonproteolytic Activation of Prorenin Bound to the (Pro)renin Receptorthe (Pro)renin Receptor

Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 129-133Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 129-133

ReninRenin

ProreninProrenin

AOGAOGAng IAng I

Ang IIAng II

PRRPRR

PRRPRR

NucleusNucleus

FibronectinFibronectin Collagen ICollagen I

ACEIACEI

ERK1/2

ERK1/2ERK1/2ERK1/2

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997

Glaxo Wellcome

Astra

BMSHarvardMerck

DainipponSankyo

Kissei Zeneca

Parke DavisPfizer P&USanofi

FujisawaHMRMerck KGaARocheYamanouchi

Abbott

SearleSKB

BI/Bio-MegaWyeth-Ayerst

SpeedelSerie SPP800 Serie SPP1148SPP635

Actelion/Merck

Vitae/GSK

Plexxikon/Servier

2007

Ricerca farmacologica e sviluppo dei DRIs

Aliskiren

Wood JM, et al. 2003

Aliskiren: the first orally available direct renin inhibitor

Molecular weight = 609.8

High solubility in water and biological fluids

Non-peptide drug suitable for oral administration

O

NH

CONH2

OH

H2N

CH3O

O

CH3O

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 altreaspartil 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

Feedback Loop

AT1 Receptor

ReninAng I

Angiotensinogen

Ang II

Direct renin inhibitor

Biological effects

ACE

Non ACE pathways

PRA

Adapted from: Müller DN & Luft FC. 2006

Glomerularvasoconstriction

Inflammation Fibrosis

Kidney

Hypertrophy Fibrosis Vasoconstriction

Heart

Vasoconstriction

Brain

Hyperplasia hypertrophy Inflammation Oxidation Fibrosis

Vessels

1683 Mo1683 Mo

Inibitori Diretti della ReninaInibitori Diretti della ReninaCaratteristiche Farmacologiche di AliskirenCaratteristiche Farmacologiche di Aliskiren

Potente e specifico inibitore non peptidico della renina umana Potente e specifico inibitore non peptidico della renina umana (IC(IC5050 = 0.6 nmol/L) = 0.6 nmol/L)

Lunga emivita plasmatica (30-40 ore)Lunga emivita plasmatica (30-40 ore)

Assorbimento rapido ma scarso e variabile; migliore a digiunoAssorbimento rapido ma scarso e variabile; migliore a digiuno

Binding alle proteine plasmatiche 50%Binding alle proteine plasmatiche 50%

Bassa biodisponibilità (2.6%)Bassa biodisponibilità (2.6%)

Lunga persistenza nei tessuti (specie nel rene)Lunga persistenza nei tessuti (specie nel rene)

Escrezione prevalentemente per via fecale (90%)Escrezione prevalentemente per via fecale (90%)

120

80

40

0

1824 Mo1824 Mo

Concentration of Aliskiren in the CirculationConcentration of Aliskiren in the Circulation

Fisher NDL et al., Circulation 2008; 117: 3199-3205Fisher NDL et al., Circulation 2008; 117: 3199-3205

Alis

kir

en c

onc.

(n

g/m

l)A

lisk

iren

con

c. (

ng/

ml)

PlaceboPlacebo 75 mg75 mg 150 mg150 mg 300 mg300 mg 600 mg600 mgDose:Dose:

TimeTime(min):(min):

00 120120 300300 2424hh

00 120120 300300 00 120120 300300 2424hh

00 120120 300300 2424hh

00 120120 300300 2424hh

4848hh

0 75 150 300 600 0

50

100

0 75 150 300 600 0

10

20

0 75 150 300 600 0

5

10

15

20

0 75 150 300 600 0

1

2

3

4

0 75 150 300 600 0

200

400

600

2202 Mo2202 Mo

Plasma Renin, Aliskiren/Renin Concentration Ratio, Plasma Renin, Aliskiren/Renin Concentration Ratio, Percentage Renin Inhibition, PRA and Plasma AII Percentage Renin Inhibition, PRA and Plasma AII

Following Exposure to Escalating Doses of Aliskiren on Separate Study DaysFollowing Exposure to Escalating Doses of Aliskiren on Separate Study Days

Danser JAH et al., Hypertension Research 2010; 34: 4-10Danser JAH et al., Hypertension Research 2010; 34: 4-10

(ng/

l)(n

g/l)

ReninReninReninRenin [Aliskiren]/[renin][Aliskiren]/[renin][Aliskiren]/[renin][Aliskiren]/[renin] Renin inhibitionRenin inhibitionRenin inhibitionRenin inhibition

PRAPRAPRAPRA AIIAIIAIIAII

(th

ousa

nd

s)(t

hou

san

ds)

(%)

(%)

(pg/

ml)

(pg/

ml)

(ng

AII

l/m

l.h)

(ng

AII

l/m

l.h)

58

143178

205

380

650

-70-44.3

-100

0

100

200

300

400

500

600

700

2100 Mo2100 Mo

Change in PRA in Patients Treated with Change in PRA in Patients Treated with Various Antihypertensives and Combination RAS BlockadeVarious Antihypertensives and Combination RAS Blockade

Epstein BS et al., Expert Rev Cardiovasc Ther 2009; 7: 1373-1384Epstein BS et al., Expert Rev Cardiovasc Ther 2009; 7: 1373-1384

PR

A in

crea

se (

%)

PR

A in

crea

se (

%)

CCBCCB

AmlodipineAmlodipine

ACEIACEI

RamiprilRamipril

HCTZHCTZ

HCTZHCTZ

ARBARB

IrbesartanIrbesartan

ARB/ARB/HCTZHCTZ

Valsartan/Valsartan/HCTZHCTZ

ACEI/ACEI/ARBARB

Benazepril/Benazepril/valsartanvalsartan

DRIDRI

AliskirenAliskiren

DRI/DRI/ACEIACEI

Aliskiren/Aliskiren/ramiprilramipril

1839 Mo1839 Mo

Renal Partitioning and Localization Pattern of AliskirenRenal Partitioning and Localization Pattern of Aliskiren

Feldman DL et al., Hypertension 2008; 52: 130-136Feldman DL et al., Hypertension 2008; 52: 130-136

Ali

skir

en (

Ali

skir

en (

M)

M)

Kidney

Plasma 12

10

8

6

4

2

0

Aliskiren:Aliskiren: 10 mg/kg10 mg/kg 3 mg/kg3 mg/kg 10 mg/kg10 mg/kg

Non-diabeticNon-diabetic DiabeticDiabetic

GlomeruliGlomeruli

Renal cortical arteryRenal cortical artery

-10 -9 -8 -7 -6 0

20

40

60

80

100Renin

Prorenin

-10 -9 -8 -7 -6 0

20

40

60

80

100

-10 -9 -8 -7 -6 0

20

40

60

80

100

1934 Mo1934 Mo Krop M et al., Hypertension 2008; 52: 1076-1083Krop M et al., Hypertension 2008; 52: 1076-1083

Percentage of (pro)renin that is Aliskiren-bound in the Cell Lysates, Percentage of (pro)renin that is Aliskiren-bound in the Cell Lysates, Culture Medium, and Stimulation Medium of HMC-1 Cells Culture Medium, and Stimulation Medium of HMC-1 Cells

after Incubation of Cells in the Absence or Presence of Aliskirenafter Incubation of Cells in the Absence or Presence of Aliskiren

% a

lisk

iren

-bou

nd

% a

lisk

iren

-bou

nd

Cell lysateCell lysateCell lysateCell lysate Culture mediumCulture mediumCulture mediumCulture medium Stimulation mediumStimulation mediumStimulation mediumStimulation medium

log [aliskiren] (mol/l)log [aliskiren] (mol/l)

1742 Mo1742 Mo

Potential Inhibition of Receptor-bound Activated Prorenin and of Renin Potential Inhibition of Receptor-bound Activated Prorenin and of Renin and Receptor Interaction by Renin Inhibitor Blocking the Active Site of and Receptor Interaction by Renin Inhibitor Blocking the Active Site of

Renin and Modifying Its ConformationRenin and Modifying Its Conformation

Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 129-133Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 129-133

?? Ang IAng I

NucleusNucleus

ERK1/2ERK1/2

??

Mature reninMature renin

Renin inhibitorRenin inhibitor

ProreninProrenin

-20

-15

-10

-5

0

-20

-15

-10

-5

0

Placebo Aliskiren 150 mg Aliskiren 300 mg

2213 Mo2213 Mo

Changes in Systolic and Diastolic BP with AliskirenChanges in Systolic and Diastolic BP with Aliskirenaccording to Gender and Body Mass Indexaccording to Gender and Body Mass Index

Jarugula V et al., J Clin Pharm, March 2010Jarugula V et al., J Clin Pharm, March 2010

Mean change in SBPMean change in SBPMean change in SBPMean change in SBP Mean change in DBPMean change in DBPMean change in DBPMean change in DBP

(mm

Hg)

(mm

Hg)

MenMenn=468n=468

WomenWomenn=298n=298

MenMenn=438n=438

WomenWomenn=326n=326

BMI BMI < 30< 30

n=512n=512

BMI BMI ≥ ≥ 3030

n=250n=250

BMI BMI < 30 < 30

n=491n=491

BMI BMI ≥ ≥ 3030

n=269n=269

AliskirenAliskiren150 mg150 mg

AliskirenAliskiren300 mg300 mg

AliskirenAliskiren150 mg150 mg

AliskirenAliskiren300 mg300 mg

MenMenn=468n=468

WomenWomenn=298n=298

MenMenn=438n=438

WomenWomenn=326n=326

BMI BMI < 30< 30

n=512n=512

BMI BMI ≥ ≥ 3030

n=250n=250

BMI BMI < 30 < 30

n=491n=491

BMI BMI ≥ ≥ 3030

n=269n=269

AliskirenAliskiren150 mg150 mg

AliskirenAliskiren300 mg300 mg

AliskirenAliskiren150 mg150 mg

AliskirenAliskiren300 mg300 mg

-20

-15

-10

-5

0

-20

-15

-10

-5

0

2206 Mo2206 Mo

Change in Sitting Systolic and Diastolic BP Change in Sitting Systolic and Diastolic BP with Aliskiren Monotherapy in Women, Analysed by Agewith Aliskiren Monotherapy in Women, Analysed by Age

Gradman AH et al., J Human Hypertens, March 2010Gradman AH et al., J Human Hypertens, March 2010

Mean change in msSBPMean change in msSBPMean change in msSBPMean change in msSBP Mean change in msDBPMean change in msDBPMean change in msDBPMean change in msDBP

(mm

Hg)

(mm

Hg)

Aliskiren 150 mgAliskiren 150 mg Aliskiren 300 mgAliskiren 300 mg

< 50 y< 50 y148148

50-55 y50-55 y100100

> 55 y> 55 y244244n =n =

< 50 y< 50 y170170

50-55 y50-55 y147147

> 55 y> 55 y388388

< 50 y< 50 y148148

50-55 y50-55 y100100

> 55 y> 55 y244244n =n =

< 50 y< 50 y170170

50-55 y50-55 y147147

> 55 y> 55 y388388

Aliskiren 150 mgAliskiren 150 mg Aliskiren 300 mgAliskiren 300 mg

-13.9-13.9-15.0-15.0

-13.6-13.6

-17.8-17.8-17.0-17.0

-16.0-16.0

-10.8-10.8 -10.7-10.7-11.4-11.4

-12.4-12.4

-10.6-10.6

-12.9-12.9

2210 Mo2210 Mo

Effect of Aliskiren Monotherapy and in Combination with Effect of Aliskiren Monotherapy and in Combination with Other Antihypertensive Agents in AGELESS StudyOther Antihypertensive Agents in AGELESS Study

Duprez A et al., J Human Hypertens, December 2009Duprez A et al., J Human Hypertens, December 2009

Mean change in msSBPMean change in msSBPMean change in msSBPMean change in msSBP Mean change in msDBPMean change in msDBPMean change in msDBPMean change in msDBP

(mm

Hg)

(mm

Hg)

0

-5

-10

-15

-20

-25

0

-5

-10

-15

-20

-25

Week 12Week 12 Week 22Week 22 Week 36Week 36

± HCTZ± HCTZ± Amlo± Amlo

RamiRamiAliAli

± HCTZ± HCTZRamiRamiAliAliRami-Rami-

prilprilAli-Ali-

skirenskiren

Week 12Week 12 Week 22Week 22 Week 36Week 36

± HCTZ± HCTZ± Amlo± Amlo

RamiRamiAliAli

± HCTZ± HCTZRamiRamiAliAliRami-Rami-

prilprilAli-Ali-

skirenskiren

-14.0-14.0

-11.6-11.6

-19.6-19.6

-17.1-17.1

-20.0-20.0

-18.1-18.1

-5.1-5.1-3.6-3.6

-8.2-8.2-7.3-7.3

-8.2-8.2-7.0-7.0

P = 0.03P = 0.03P = 0.14P = 0.14P < 0.01P < 0.01

P = 0.07P = 0.07P = 0.03P = 0.03P = 0.02P = 0.02

26 27 28 29 30130

135

140

145

150

Aliskiren (n = 170) Aliskiren placebo (n = 163) Ramipril (n = 165) Ramipril placebo (n = 177)

26 27 28 29 3080

85

90

95

100

2103 Mo2103 Mo

Systolic and Diastolic Blood Pressure during the Systolic and Diastolic Blood Pressure during the Post-active-controlled-treatment with Aliskiren and RamiprilPost-active-controlled-treatment with Aliskiren and Ramipril

Andersen K et al., J Renin Angiotensin Aldosterone Syst 2009; 10: 157-167Andersen K et al., J Renin Angiotensin Aldosterone Syst 2009; 10: 157-167

SBPSBPSBPSBP DBPDBPDBPDBPmmHgmmHg mmHgmmHg

WeekWeek WeekWeek

Aliskiren provides significant reductions inPRA compared with placebo

Mean change from baseline in PRA at Week 12 (ng/mL/h)

Optimal HF therapy +Aliskiren 150 mg

Optimal HF therapy +Placebo

*p<0.0001 vs placebo

−8

−4

−2

0

−6

McMurray JJV. ESC 2007 (ALOFT)

n=137

−0.97n=145

−5.71*

Aliskiren provides significant reductions in urinary aldosterone levels compared with placebo

Mean change from baseline in urinary aldosterone at Week 12 (nmol/day)

–4

–2

0

Optimal HF therapy +Aliskiren 150 mg

–6

–8

n=128n=141

–9.2

–7.0

–10

*p=0.015 vs placebo

*

Optimal HF therapy +Placebo

McMurray JJV. ESC 2007 (ALOFT)

Aliskiren provides significant reductions inBNP levels compared with placebo

Mean change from baseline in BNP at Week 12 (pg/mL)

−10

−40

−70

−30

−20

0

−50

Optimal HF therapy + Aliskiren 150 mg

Optimal HF therapy +Placebo

−60

n=137n=148

−61.0

−12.2

p=0.0160

Baseline BNP concentration = 291 pg/mL McMurray JJV. ESC 2007 (ALOFT)

-2 0 2 4 6 8 10 12 14 16 18 20 22 24-30

-20

-10

0

10

-2 0 2 4 6 8 10 12 14 16 18 20 22 24-30

-20

-10

0

10

20

Aliskiren Placebo

-2 0 2 4 6 8 10 12 14 16 18 20 22 2460

80

100

120

140

1832 Mo1832 Mo

Changes in Albumin Excretion Rate in Patients with Diabetes and Hypertension Changes in Albumin Excretion Rate in Patients with Diabetes and Hypertension Treated with Losartan Alone or in Combination with AliskirenTreated with Losartan Alone or in Combination with Aliskiren

Parving HH et al., NEJM 2008; 358: 2433-2446Parving HH et al., NEJM 2008; 358: 2433-2446

Urinary Urinary albumin-to-creatinine ratioalbumin-to-creatinine ratio

Urinary Urinary albumin-to-creatinine ratioalbumin-to-creatinine ratio

Urinary albuminUrinary albuminexcretion rateexcretion rate

Urinary albuminUrinary albuminexcretion rateexcretion rate

Mean sittingMean sittingblood pressureblood pressureMean sittingMean sitting

blood pressureblood pressure

SS

DD

%% %% mmHgmmHg

WeekWeekWeekWeekWeekWeek

1684 Mo1684 Mo

ConclusioniConclusioni

Aliskiren è il primo di una nuova classe di farmaci che antagonizzano Aliskiren è il primo di una nuova classe di farmaci che antagonizzano l’attività del SRAA inibendo direttamente l’attività enzimatica della l’attività del SRAA inibendo direttamente l’attività enzimatica della reninarenina

Aliskiren è l’unico farmaco che inibisce i meccanismi di Aliskiren è l’unico farmaco che inibisce i meccanismi di controregolazione che possono limitare l’efficacia degli altri bloccanti controregolazione che possono limitare l’efficacia degli altri bloccanti del SRAA (ACEI/ARB)del SRAA (ACEI/ARB)

In studi controllati la riduzione della pressione arteriosa indotta da In studi controllati la riduzione della pressione arteriosa indotta da aliskiren è uguale o superiore a quella di alcuni ACEI/ARBaliskiren è uguale o superiore a quella di alcuni ACEI/ARB

Grazie alla elevata concentrazione a livello renale e alla interferenza Grazie alla elevata concentrazione a livello renale e alla interferenza del binding di renina e prorenina agli specifici recettori, aliskiren del binding di renina e prorenina agli specifici recettori, aliskiren potrebbe esercitare effetti locali di protezione d’organo indipendenti potrebbe esercitare effetti locali di protezione d’organo indipendenti dall’effetto antipertensivodall’effetto antipertensivo