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Renin inhibitors: the last challenge in the RAAS blockade

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Presentation on theme: "Renin inhibitors: the last challenge in the RAAS blockade"— Presentation transcript:

1 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, 1464 Mo

2 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 Prorenin ACE2 Angiotensin(1,9) Angiotensin I Asp-Arg-Val-Tyr-Lle-His-Pro-Phe-His-Leu Bradykinin ACE ACE ACE ACE2 Angiotensin(1,7) Angiotensin II Asp-Arg-Val-Tyr-Lle-His-Pro-Phe Inactive peptides Mas AT2 AT1 (Pro)renin receptors - + - ?? + Kidney: Na retention, fibrosis Heart: Hypertrophy (?), fibrosis Adrenals: Aldosterone release Vessels: Constriction, hypertrophy Brain: SNS activation, ADH release, thirst, salt appetite 1948 Mo

3 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

4 Residual risk: morbidity and mortality remains high, despite treatment with ACEIs and ARBs
CHARM-Overall1: CV death HOPE2: CV death, stroke and MI 22% relative risk reduction 30 25 20 15 10 5 Placebo Candesartan 0.20 0.15 0.10 0.5 12% relative risk reduction Placebo Ramipril Proportion died (%) Population of patients Residual Risk Residual Risk ,000 1,500 Time (years) Days of follow-up References 1. Pfeffer et al. Lancet 2003;362:759–66 2. Yusuf et al. N Engl J Med 2000;342:145–53 3. Dahlöf et al. Lancet 2002;359:995–1003 4. Cohn et al. N Engl J Med 2001;345:1667–75 14.6% relative risk reduction LIFE3: CV death, stroke and MI Val-HeFT4: freedom from combined endpoint 16 14 12 10 8 6 4 2 100 90 80 70 Atenolol Losartan Valsartan Placebo Residual Risk Proportion of patients with first event (%) Event-free probability (%) Residual Risk 13.2% relative risk reduction Time (months) Time post-randomization (months) 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

5 ACEIs and ARBs cause compensatory rises in PRA
Kidney Glomerular vasoconstriction Inflammation Fibrosis Angiotensinogen Renin Heart Ang I Hypertrophy Fibrosis Vasoconstriction PRA Non ACE pathways ACE Plasma renin activity (PRA) is a measure of the level of activity in the Renin System (RS) and is an indicator for hypertension. The RS is targeted at different places by existing antihypertensive therapies. Angiotensin converting enzyme (ACE) inhibitors or ACEIs reduce the production of angiotensin II (Ang II), by inhibiting the conversion of angiotensin I (Ang I) to Ang II by these enzymes. Angiotensin receptor blockers (ARBs) antagonize type 1 Ang II (AT1) receptors and prevent Ang II from binding. However, ACEIs and ARBs are associated with a feedback loop which increases PRA, as loss of stimulation of AT1 receptors on juxtaglomerular cells in the kidney (i.e. removal of negative feedback) leads to a compensatory increase in renin release. Diuretics also stimulate renin release, to activate the RS in response to a drop in fluid volume. The resulting increase in PRA may limit the organ protection offered by these drugs. Abbreviations Ang I = angiotensin ACE = angiotensin converting enzyme ACEI = angiotensin converting enzyme inhibitor ARB = angiotensin receptor blocker AT1 = type 1 angiotensin II receptor PRA = plasma renin activity RS = Renin System Reference Müller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006;1:221–8. ACEIs Feedback Loop Vessels Ang II Hyperplasia hypertrophy Inflammation Oxidation Fibrosis ARBs AT1 Receptor Brain Biological effects Vasoconstriction Adapted from: Müller DN & Luft FC. 2006

6 % = increased risk of event for high versus low PRA
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% HYPERTENSION MI/CAD SAVE3: 100% Bair ACC 20092: 40% Bair ACC 20092: 106%* References Alderman MH, Ooi WL, Cohen H, et al. Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am J Hypertens 1997;10:1–8 Bair TL, May HT, Prescott MF, et al. Association between baseline levels of plasma renin activity and risk of cardiovascular events. J Am Coll Cardiol 2009;53:A383 [Abstract]. Rouleau JL, Packer M, Moyé L, et al. Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril. J Am Coll Cardiol 1994;24:583–91 4. Latini R, Masson S, Anand I, et al; For the Val-HeFT Investigators. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J 2004;25:292–9 5. Vergaro G, Fontana M, Poletti R, et al. Plasma renin activity is an independent prognostic factor in chronic heart failure. Eur Heart J 2008;29(Suppl.):393 [Abstract]. 6. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;435:1667–75. DEATH or CV EVENTS DEATH CHF Time points: Alderman: 3.6 years (mean) SAVE: 38 months (mean) Bair ACC: >5 years Val-HeFT6: 23 months (mean) Vergaro: 23 months (mean) Val-HeFT4: 30% Vergaro5: 50% 1Alderman et al. Am J Hypertens 1997;10:1–8 2Bair 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 Cardiology SAVE: Survival and Ventricular Enlargement study; Val-HeFT: Valsartan Heart Failure Trial

7 Nonproteolytic Activation of Prorenin Bound to the (Pro)renin Receptor
AOG Ang I Prorenin Ang II Renin PRR ACEI PRR ERK1/2 ERK1/2 Nucleus  Fibronectin  Collagen I Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 1741 Mo

8 Ricerca farmacologica e sviluppo dei DRIs
Glaxo Wellcome BMS Searle Harvard SKB Astra Merck Dainippon BI/Bio-Mega Sankyo Wyeth-Ayerst Zeneca Speedel Serie SPP800 Serie SPP1148 SPP635 Kissei Parke Davis Pfizer Aliskiren P&U Sanofi Vitae/GSK Abbott Plexxikon/Servier Fujisawa HMR Actelion/Merck Merck KGaA Roche Yamanouchi 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 2007 8

9 Aliskiren: the first orally available direct renin inhibitor
CH3O OH H N H2N CONH2 O O CH3O Molecular weight = 609.8 High solubility in water and biological fluids Non-peptide drug suitable for oral administration Aliskiren is a small (molecular weight g/moL), non-peptide molecule, developed using molecular modelling techniques and crystallographic structure analysis, with the molecular formula C30H53N3O6. It is a hydrophilic molecule, with aqueous solubility >350 mg/mL at pH 7.4, and a partition co-efficient (log Poctanol/water) of 2.45 at pH 7.4. These properties make aliskiren suitable for oral administration. Aliskiren lacks the spanning peptide-like backbone of earlier-generation renin inhibitors, conferring improved pharmacokinetic properties. References Stanton A. Potential of renin inhibition in cardiovascular disease. JRAAS 2003;4:6–10. Wood JM, Maibaum J, Rahuel J, et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun 2003;308:698–705. Wood JM, et al. 2003

10 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. La renina contiene 2 domini, con il sito attivo posizionato in una piega tra questi 2 domini. Ciascun dominio contribuisce per un residuo di acido aspartico necessario per l’attività catalitica. Un significativo migliorameto dell’affinità di legame si è ottenuto grazie alla scoperta di composti meno lipofili e in grado di ottimizzare l’interazione sulla superficie idrofobica della tasca S3-S1. Un risultato chiave fu anche l’identificazione dell’unica sottotasca chiamata S3sp. Sebbene l’inibitore CGP non utilizzi questa cavità, la più nuova struttura disegnata per occupare questa tasca mostrava caratteristiche nettamente migliorate. Questo sottosito S3sp si trova solo nella renina, ciò consente una nuova differenziazione nella classe delle proteasi dell’aspartico. Aliskiren (in viola nella figura) si lega a questo sottosito S3sp, sistemando la catena metossialcossi dell’inibitore; ciò aumenta considerevolmente l’affinità di legame per la renina e la selettività superiore alle altre proteasi dell’aspartico. Nella sottotasca S3sp, il residuo Ser219 della renina crea un legame idrogeno attraverso il gruppo ossidrilico dell’inibitore. Adattato da: Wood JM et al, 2003 10

11 Direct renin inhibitor
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 Hypertrophy Fibrosis Vasoconstriction PRA Non ACE pathways ACE Plasma renin activity (PRA) reflects the capacity of circulating renin to cleave angiotensinogen to form angiotensin I (Ang I), and thus provides a measure of the level of activity in the Renin System (RS). Direct renin inhibitors target the RS at its point of activation, resulting in reduction of PRA. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers block the RS at different points in the cycle. Both classes of drug increase PRA, by triggering a compensatory mechanism whereby feedback inhibition on renin release is removed and PRA therefore rises. Direct renin inhibition neutralizes the reactive rise in PRA associated with other antihypertensive classes. Therefore, direct renin inhibitors not only reduce PRA when used alone, but offer the potential to optimize RS suppression and may increase end-organ protection benefits when co-administered with other antihypertensive agents. Abbreviations Ang I = angiotensin I Ang II = angiotensin II ACE = angiotensin converting enzyme AT1 = type 1 angiotensin II receptor PRA = plasma renin activity RS = Renin System Reference Müller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006;1:221–8. Feedback Loop Vessels Ang II Hyperplasia hypertrophy Inflammation Oxidation Fibrosis AT1 Receptor Brain Biological effects Vasoconstriction Adapted from: Müller DN & Luft FC. 2006

12 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

13 Concentration of Aliskiren in the Circulation Aliskiren conc. (ng/ml)
Time (min): 120 300 24 h 120 300 120 300 24 h 120 300 24 h 120 300 24 h 48 h Dose: Placebo 75 mg 150 mg 300 mg 600 mg Fisher NDL et al., Circulation 2008; 117: 1824 Mo

14 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] Renin inhibition (ng/l) (thousands) (%) PRA AII (ng AII l/ml.h) (pg/ml) Danser JAH et al., Hypertension Research 2010; 34: 4-10 2202 Mo

15 Change in PRA in Patients Treated with
Various Antihypertensives and Combination RAS Blockade PRA increase (%) CCB Amlodipine ACEI Ramipril HCTZ ARB Irbesartan ARB/ HCTZ Valsartan/ ACEI/ ARB Benazepril/ valsartan DRI Aliskiren DRI/ ACEI Aliskiren/ ramipril Epstein BS et al., Expert Rev Cardiovasc Ther 2009; 7: 2100 Mo

16 Renal Partitioning and Localization Pattern of Aliskiren
Glomeruli Aliskiren (M) Aliskiren: 10 mg/kg 3 mg/kg 10 mg/kg Non-diabetic Diabetic Renal cortical artery Feldman DL et al., Hypertension 2008; 52: 1839 Mo

17 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 % aliskiren-bound log [aliskiren] (mol/l) Krop M et al., Hypertension 2008; 52: 1934 Mo

18 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 Nguyen G. et al., Curr Opin Nephrol Hypertens 2007; 16: 1742 Mo

19 Changes in Systolic and Diastolic BP with Aliskiren
according to Gender and Body Mass Index Mean change in SBP Mean change in DBP Men n=468 Women n=298 n=438 n=326 BMI < 30 n=512 ≥ 30 n=250 n=491 n=269 Aliskiren 150 mg 300 mg Men n=468 Women n=298 n=438 n=326 BMI < 30 n=512 ≥ 30 n=250 n=491 n=269 Aliskiren 150 mg 300 mg (mmHg) Jarugula V et al., J Clin Pharm, March 2010 2213 Mo

20 Change in Sitting Systolic and Diastolic BP
with Aliskiren Monotherapy in Women, Analysed by Age Mean change in msSBP Mean change in msDBP Aliskiren 150 mg Aliskiren 300 mg Aliskiren 150 mg Aliskiren 300 mg < 50 y 148 50-55 y 100 > 55 y 244 < 50 y 170 50-55 y 147 > 55 y 388 < 50 y 148 50-55 y 100 > 55 y 244 < 50 y 170 50-55 y 147 > 55 y 388 n = n = (mmHg) -10.8 -10.7 -10.6 -11.4 -12.4 -12.9 -13.6 -13.9 -15.0 -16.0 -17.0 -17.8 Gradman AH et al., J Human Hypertens, March 2010 2206 Mo

21 Effect of Aliskiren Monotherapy and in Combination with Other Antihypertensive Agents in AGELESS Study Mean change in msSBP Mean change in msDBP Week 12 Week 22 Week 36 ± HCTZ ± Amlo Rami Ali Rami- pril Ali- skiren Week 12 Week 22 Week 36 ± HCTZ ± Amlo Rami Ali Rami- pril Ali- skiren -3.6 -5.1 -7.3 -7.0 -8.2 -8.2 (mmHg) P < 0.01 P = 0.14 P = 0.03 -11.6 -14.0 -17.1 -18.1 -19.6 -20.0 P = 0.02 P = 0.03 P = 0.07 Duprez A et al., J Human Hypertens, December 2009 2210 Mo

22 Systolic and Diastolic Blood Pressure during the
Post-active-controlled-treatment with Aliskiren and Ramipril SBP DBP mmHg mmHg Week Week Andersen K et al., J Renin Angiotensin Aldosterone Syst 2009; 10: 2103 Mo

23 Aliskiren provides significant reductions in PRA compared with placebo
Optimal HF therapy + Placebo Optimal HF therapy + Aliskiren 150 mg n=145 −5.71 * n=137 −0.97 −2 −4 After 12 weeks’ treatment, aliskiren 150 mg added to optimal heart failure (HF) therapy provided significantly greater reductions in plasma renin activity (PRA) compared with placebo (p<0.0001). The mean reduction from baseline in PRA was 5.7 ng/mL/h in aliskiren-treated patients compared with 1.0 ng/mL/h in the placebo group. Reference McMurray JJV. Haemodynamic, neurohumoral, renal and ambulatory electrocardiographic effects of a new oral renin inhibitor in stable heart failure. Oral presentation at European Society of Cardiology Congress, Vienna, Austria. 1–5 September 2007. −6 −8 Mean change from baseline in PRA at Week 12 (ng/mL/h) *p< vs placebo McMurray JJV. ESC 2007 (ALOFT)

24 Optimal HF therapy + Placebo
Aliskiren provides significant reductions in urinary aldosterone levels compared with placebo Optimal HF therapy + Placebo Optimal HF therapy + Aliskiren 150 mg n=141 n=128 –2 –4 After 12 weeks’ treatment, aliskiren 150 mg added to optimal heart failure (HF) therapy provided significantly greater reductions in urinary aldosterone levels compared with placebo (p<0.05). The mean reduction from baseline in urinary aldosterone was 9.2 nmol/day in aliskiren-treated patients compared with 7.0 nmol/day in the placebo group. Reference McMurray JJV. Haemodynamic, neurohumoral, renal and ambulatory electrocardiographic effects of a new oral renin inhibitor in stable heart failure. Oral presentation at European Society of Cardiology Congress, Vienna, Austria. 1–5 September 2007. –6 –7.0 –8 –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)

25 Aliskiren provides significant reductions in BNP levels compared with placebo
Optimal HF therapy + Aliskiren 150 mg Optimal HF therapy + Placebo n=148 n=137 −10 −12.2 −20 −30 In patients receiving optimal heart failure (HF) therapy, addition of aliskiren 150 mg provided significant reductions in plasma B-type natriuretic peptide (BNP) levels compared with placebo after 12 weeks of treatment (p<0.05). The mean change from baseline in BNP level in patients who received aliskiren 150 mg was −61.0 pg/mL compared with −12.2 pg/mL in patients who received placebo. Reference McMurray JJV. Haemodynamic, neurohumoral, renal and ambulatory electrocardiographic effects of a new oral renin inhibitor in stable heart failure. Oral presentation at European Society of Cardiology Congress, Vienna, Austria. 1–5 September 2007. −40 −50 −60 −61.0 −70 p=0.0160 Mean change from baseline in BNP at Week 12 (pg/mL) Baseline BNP concentration = 291 pg/mL McMurray JJV. ESC 2007 (ALOFT)

26 albumin-to-creatinine ratio
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 S D Week Week Week Parving HH et al., NEJM 2008; 358: 1832 Mo

27 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


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