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1464 Mo

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, 9-10 2010. 1464 Mo.

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1464 Mo

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  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, 9-10 2010 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. Placebo Candesartan Placebo Ramipril 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 0 0.20 0.15 0.10 0.5 0 12% relative risk reduction Population of patients Proportion died (%) Residual Risk Residual Risk 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0 500 1,000 1,500 Time (years) Days of follow-up 14.6% relative risk reduction Val-HeFT4: freedom from combined endpoint LIFE3: CV death, stroke and MI 16 14 12 10 8 6 4 2 0 100 90 80 70 0 Valsartan Placebo Atenolol Losartan Residual Risk Proportion of patients with first event (%) Event-free probability (%) Residual Risk 13.2% relative risk reduction • 0 6 12 18 24 30 36 42 48 54 60 66 0 3 6 9 12 15 18 21 24 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 Med2001;345:1667–75

  5. ACEIs and ARBs cause compensatory rises in PRA Kidney • Glomerularvasoconstriction • Inflammation • Fibrosis Angiotensinogen Renin Heart Ang I • Hypertrophy • Fibrosis • Vasoconstriction PRA Non ACE pathways ACE ACEIs Feedback Loop Vessels • Hyperplasia hypertrophy • Inflammation • Oxidation • Fibrosis Ang II ARBs AT1 Receptor Brain • Vasoconstriction Biological effects Adapted from: Müller DN & Luft FC. 2006

  6. 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% MI/CAD HYPERTENSION SAVE3: 100% Bair ACC 20092: 40% Bair ACC 20092: 106%* 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: 129-133 1741 Mo

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

  9. 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 CH3O OH H N H2N CONH2 O O CH3O 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 altreaspartil proteasi. Adattato da: Wood JM et al, 2003

  11. Direct renin inhibition acts at the point of activation of the Renin System and neutralizes the PRA rise Direct renin inhibitor Kidney • Glomerularvasoconstriction • Inflammation • Fibrosis Angiotensinogen Renin Heart Ang I • Hypertrophy • Fibrosis • Vasoconstriction Non ACE pathways PRA ACE Feedback Loop Vessels • Hyperplasia hypertrophy • Inflammation • Oxidation • Fibrosis Ang II AT1 Receptor Brain • Vasoconstriction Biological effects 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): 0 120 300 24 h 0 120 300 0 120 300 24 h 0 120 300 24 h 0 120 300 24 h 48 h Dose: Placebo 75 mg 150 mg 300 mg 600 mg Fisher NDL et al., Circulation 2008; 117: 3199-3205 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 (thousands) (ng/l) (%) 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 HCTZ ARB Irbesartan ARB/ HCTZ Valsartan/ HCTZ ACEI/ ARB Benazepril/ valsartan DRI Aliskiren DRI/ ACEI Aliskiren/ ramipril Epstein BS et al., Expert Rev Cardiovasc Ther 2009; 7: 1373-1384 2100 Mo

  16. Renal Partitioning and Localization Pattern of Aliskiren Glomeruli Aliskiren (M) Aliskiren: 10 mg/kg 3 mg/kg 10 mg/kg Renal cortical artery Non-diabetic Diabetic Feldman DL et al., Hypertension 2008; 52: 130-136 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: 1076-1083 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: 129-133 1742 Mo

  19. Aliskiren 150 mg Aliskiren 150 mg Aliskiren 300 mg Aliskiren 300 mg Aliskiren 150 mg Aliskiren 150 mg Aliskiren 300 mg Aliskiren 300 mg BMI < 30 n=512 BMI < 30 n=512 BMI ≥ 30 n=250 BMI ≥ 30 n=250 BMI < 30 n=491 BMI < 30 n=491 BMI ≥ 30 n=269 BMI ≥ 30 n=269 Men n=468 Men n=468 Women n=298 Women n=298 Men n=438 Men n=438 Women n=326 Women n=326 Changes in Systolic and Diastolic BP with Aliskiren according to Gender and Body Mass Index Mean change in SBP Mean change in DBP (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) -10.6 -10.7 -10.8 -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. Week 12 Week 12 Week 22 Week 22 Week 36 Week 36 Ali Ali Rami Rami Ali- skiren Ali- skiren Rami- pril Rami- pril Ali Ali Rami Rami ± HCTZ ± Amlo ± HCTZ ± Amlo ± HCTZ ± HCTZ Effect of Aliskiren Monotherapy and in Combination with Other Antihypertensive Agents in AGELESS Study Mean change in msSBP Mean change in msDBP -3.6 -5.1 -7.0 -7.3 -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: 157-167 2103 Mo

  23. Optimal HF therapy + Aliskiren 150 mg n=137 n=145 −0.97 −5.71 * Aliskiren provides significant reductions inPRA compared with placebo Optimal HF therapy +Placebo 0 −2 −4 −6 −8 Mean change from baseline in PRA at Week 12 (ng/mL/h) *p<0.0001 vs placebo McMurray JJV. ESC 2007 (ALOFT)

  24. Optimal HF therapy + Aliskiren 150 mg Aliskiren provides significant reductions in urinary aldosterone levels compared with placebo Optimal HF therapy +Placebo 0 n=141 n=128 –2 –4 –6 –7.0 –8 –9.2 –10 * Mean change from baseline in urinary aldosterone at Week 12 (nmol/day) McMurray JJV. ESC 2007 (ALOFT) *p=0.015 vs placebo

  25. Aliskiren provides significant reductions inBNP levels compared with placebo Optimal HF therapy + Aliskiren 150 mg Optimal HF therapy +Placebo 0 n=148 n=137 −10 −12.2 −20 −30 −40 −50 −60 −61.0 p=0.0160 −70 Mean change from baseline in BNP at Week 12 (pg/mL) McMurray JJV. ESC 2007 (ALOFT) Baseline BNP concentration = 291 pg/mL

  26. 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: 2433-2446 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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