MODULAZIONE FARMACOLOGICA DEL RAS: ATTUALITA’ E FUTURO PROSSIMO

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1 MODULAZIONE FARMACOLOGICA DEL RAS: ATTUALITA’ E FUTURO PROSSIMO

2 RAS: complessità funzionale
La complessità funzionale del RAS deriva dalla combinazione di: Azioni emodinamiche sistemiche (endocrine) Aumento della volemia Aumento delle resistenze vascolari periferiche Aumento della PA Azioni tessutali (paracrine e autocrine) La complessità biochimico-molecolare e funzionale del RAS fa si che una modulazione farmacologica completa possa avvenire solo attraverso una interazione diretta con l’attivatore fisiologico. Interventi diretti ad attività enzimatiche più basse nella cascata di attivazione del sistema o su singole popolazioni recettoriali determinano necessariamente una modulazione parziale, non modificando la generazione di effettori e la loro interazione recettoriale le cui conseguenze biologiche sono complesse e solo parzialmente conosciute. Accrescimento cellulare Differenziazione cellulare Apoptosi

3 Il Ras: visione “classica” e conoscenze attuali
Renin-angiotensin system revisited J Intern Med 2008; 264: 224–236.

4 Modulazione farmacologica del RAS

5 Evoluzione dei farmaci agenti sul RAS: dall’inibizione parziale alla prevenzione dell’attivazione
J Clin Hypertens. 2007;9:615–621

6 Vie non–ACE mediate nella generazione dei peptidi dell’ Angiotensina
Chimasi Ang I  Ang II ACE 2 Ang I and II  Ang 1-7 Catepsina Angiotensinogeno  Ang I Tonina Angiotensinogeno  Ang I Le chimasi sono i principali enzimi di generazione dell’ Ang II nel cuore umano Il ruolo delle chimasi nel bypassare il blocco ACE può essere ancora più significativo nel tessuto vascolare lesionato e/ a alterato da patologie come l’ATS. Anche altri enzimi possono svolgere questa azione Questi enzimi sono up-regolati a livello coronarico e renale nel diabetico Biochemistry (Mosc.) 65, 1337–1345 (2000). Circ. Res. 80, 219–227 (1997). Kidney Int. 59, 1374–1381 (2001).

7 Escape dell’ACE in trattamento a lungo termine con ACEI
25 50 75 100 [1/Biollaz/p 970/ Fig 3] Plasma ACE (nmol/mL/min) * * * * * * * * 10 20 30 SLIDE SUMMARY: ACEI MECHANISM OF ACTION LEAVES OTHER PATHWAYS FOR ANGIOTENSIN II PRODUCTION UNALTERED—MAY LEAD TO RECOVERY OF ANGIOTENSIN II LEVELS DESPITE CONTINUING ACEI THERAPY In an early trial (1982) of the angiotensin-converting enzyme inhibitor (ACEI) MK 421, 19 hypertensive patients were treated with a range of doses (2.5, 5, 10, 20 mg). Long-term results in 9 patients receiving MK 421, 20 mg twice daily for 4 to 10 months, are shown in the slide1 Although the ACEI reduced blood pressure, 24-hour control was far from satisfactory in all patients; in 5 of the 9 patients treated with the highest dose, hydrochlorothiazide was used to achieve adequate blood pressure control1 The slide shows that while plasma ACE activity was markedly reduced within 4 hours of administration of MK 421 (remaining at these low levels throughout the duration of the study), plasma angiotensin (Ang) II concentrations began to return to baseline levels after an initial fall at 4 hours post-dose. At 6 months, Ang II levels were no different from control when measured 12 to 16 hours following administration of MK 4211 ACEI therapy is known to increase plasma renin activity and Ang I levels. These increases may overwhelm the capacity of ACEI therapy to prevent Ang II formation, contributing to ACE escape2 Plasma Ang II (pg/mL) * [1/Biollaz/p 966/ Summary/ln 1-3, 5-8] [1/Biollaz/p 966/ Summary/ln 5-8] [1/Biollaz//p 970/Fig 3] [1/Biollaz/p 971/C 2/ P 1/ln 3-21] [2/Fisher/p 593/C 2/ P 4/ln 1-11] Placebo 4 h 24 h 1 2 3 4 5 6 Time (months) *p<0.001 vs placebo Biollaz J, et al. J Cardiovasc Pharmacol 1982 Biollaz J, Brunner HR, Gavras I, et al. Antihypertensive therapy with MK 421; angiotensin II–renin relationships to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol. 1982;4: Fisher NDL, Hollenberg NK. Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol. 2005;16:

8 La renina induce l’attivazione cronica del sistema che contribuisce allo sviluppo del danno d’organo
↓ Tasso di filtrazione glomerulare Proteinuria ↑ Rilascio di aldosterone Sclerosi glomerulare Aterosclerosi Vasocostrizione Ipertrofia vasale Disfunzione endoteliale Ipertrofia Fibrosi Rimodellamento Morte cellulare Ipertensione Ictus Insuff. cardiaca IM Insuff. renale Morte Renina Increased Ang II levels also have long-term effects on the cardiovascular system, including cardiac hypertrophy and vascular remodelling. Long-term elevation of Ang II levels also plays a pivotal role in the development and progression of renal and cerebrovascular diseases. Ang II constricts blood vessels, increases sympathetic nervous system activity, stimulates platelet aggregation, increases oxidative stress, and causes trophic changes in the heart and blood vessels (e.g. sensitizing vessels to other constrictors, hypertrophy of myocardial and vascular cells, and fibrosis). Ang II plays a critical role in the development of local inflammation and atherosclerosis in blood vessels, left ventricular hypertrophy and cardiac fibrosis, and nephrosclerosis and renal failure. Abbreviations Ang, angiotensin References Anderson. In: Izzo Jr and Black. Eds. Hypertension Primer: The Essentials of High Blood Pressure. 2003: Goodfriend. In: Izzo Jr and Black. Eds. Hypertension Primer: The Essentials of High Blood Pressure. 2003:8-11. Phillips. In: Izzo Jr and Black. Eds. Hypertension Primer: The Essentials of High Blood Pressure. 2003:21-23. Adattato da: Anderson, Goodfriend & Phillips In: Hypertension Primer, 2003.

9 Tissue Sites With Local Ang II-Generating Systems and Increased Production in Disease
Phillips/Hypertens Prim/p 21/C 1/P 1/ln 1-10, p 23/C 2/P 1/ln 12-16 Brain Aorta and Pulmonary Artery* ↑ in diabetes Pituitary Gland Heart ↑ in diabetes, post-myocardial infarction, failing ventricle Eye ↑ in diabetes Adrenal Glands SLIDE SUMMARY: GENERATION AND ACTIVITY OF ANGIOTENSIN II OCCURS AT LOCAL TISSUE SITES AS WELL AS SYSTEMICALLY, PARTICULARLY AS A BY-PRODUCT OF DISEASE PROCESSES The classic renin-angiotensin system (RAS), which begins with renin biosynthesis in renal cells, is a circulating endocrine system whose principal effector hormone is angiotensin II (Ang II). However, it is now known that renin, angiotensinogen, and angiotensin-converting enzyme (ACE) are produced and released at a number of tissue sites, especially the heart, vasculature, kidney, and adipose. Consequently, the generation and activity of Ang II occur at local tissue sites as well as systemically. Ang II levels are actually much higher in tissue than in plasma.l.,2 De novo tissue generation of Ang II and its interaction with AT-receptors on the same (autocrine) or adjacent (paracrine) cells define tissue RAS. However, it is also the case that some RAS components—renin, perhaps, whose levels tend to be low in some tissues (eg, vascular tissue)—may be taken up into the tissue system from the circulation.2 Tissue-based RAS appears to have a number of pathophysiologic consequences: Chymase-dependent Ang II formation has been isolated in atherosclerotic lesions of the aorta and other vascular tissue. This process appears to be up-regulated in the presence of high serum cholesterol3 Experimental and clinical data indicate that intrarenal RAS plays an important role in the development and pathophysiology of diabetic nephropathy. Since ACE inhibitor therapy only partially reduces local Ang II production in the kidney, renally based chymase-dependent pathways may contribute to the generation of Ang II4 A study of local RAS expression in the adipose tissue of hypertensive and nonhypertensive obese subjects and controls found a significantly higher AT1 receptor expression in hypertensive obese subjects than in normotensive obese subjects or controls (P=.04, P=.006, respectively).5 Kidney ↑ in diabetes Blood Vessels ↑ in hypertension, atherosclerosis Adipose Tissue ↑ in hypertension Pancreas ↑ in nephropathy Phillips/Hypertens Prim/p 21/C 1/P 1/ln 1-10; Carey/Endocrin Rev/p 261/Abst/ln 1-6 Ang II levels are much higher in tissue than in plasma angiotensin (Ang). *Animal study. Phillips MI. Tissue renin-angiotensin systems. In: Izzo JL, Black HR, eds. Hypertension Primer: the Essentials of High Blood Pressure. 3rd ed. Philadelphia, Pa; Lippincott Williams & Wilkins; 2003:21-23; Strain WD et al. J Renin Angiotensin Aldosterone Syst. 2002; 3: ; Kida T et al. Jpn J Ophthalmol. 2003;47:36-41; Arakawa K et al. Hypertension. 2000;36: ; Faloia E et al. J Endocrinol Invest. 2002;25: ; Guo C et al. J Clin Invest. 2001;107: ; Frustaci A et al. Circ Res. 2000;87: ; Danser AH et al. Circulation. 1997;96: ; Hokimoto S et al. Circulation. 1996;94: ; Hollenberg NK et al. Kidney Int. 2003;63: ; Huang XR. J Am Soc Nephrol. 2003;14: ; Leung PS. J Pancreas. 2003;4:89-91. Carey/p 262/C 2/P 1/ln 3-13, p 264/C 1/P 1/ln 4-10 Arakawa/Hypertens/p 640/C 1/P 1/ln 4-15 Huang/J Nephrol/p 1738/C 1/P 1/ln 1-5, C 2/P 1/ln 2-5. P1739/C 1/P 1/ln 2-5 Faloia/J Endocinrol/p 312/C 2/P 3/ln 1-9, p 313/C 1/P 1/ln 1-4 Phillips MI. Tissue renin-angiotensin systems. In: Izzo JL, Black HR, eds. Hypertension Primer: The Essentials of High Blood Pressure. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:21-23. Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocrine Rev. 2003;24:26-71. Arakawa K, Urata H. Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis. Hypertension. 2000;36: Huang XR, Chen WY, Truong LD, et al. Chymase is up-regulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease. J Am Soc Nephrol. 2003;14: Faloia E, Gatti C, Camilloni MA, et al. Comparison of circulating and local adipose tissue renin-angiotensin system in normotensive and hypertensive obese subjects. J Endocrinol Invest. 2002;25:

10 RAS: caratteristiche degli effetti tessutali
Gli effetti tessutali paracrini e autocrini, che stanno alla base della comparsa e della progressione del danno d’organo, si esplicano a seguito della generazione locale degli effettori del RAS. 1. 2. Tale generazione è possibile solo dopo la fissazione alle cellule degli organi effettori della renina circolante, prodotta a livello renale. 3. Infatti la renina, attivatore fisiologico del sistema, è l’unico componente del RAS che non può essere generato a livello tessutale*. Gli ormoni endocrini rappresentano una fase evolutiva piu’ recente rispetto ai primi ormoni sviluppati dagli organismi viventi, quelli che sono detti autocrini. Gli ormoni autocrini sono rilasciati direttamente dalle cellule sulle quali agiscono (al massimo influenzano quelle adiacenti) e non hanno bisogno del sistema circolatorio per andare alla ricerca del loro bersaglio Nel lungo cammino dell’evoluzione dopo quelli autocrini, e prima dei più complessi endocrini, sono apparsi gli ormoni paracrini, hanno un raggio di azione limitato e seguono brevi percorsi controllati e generalmente confinati a precise strutture organiche. Tipici ormoni paracrini sono i fattori di rilascio, neuro ormoni che si spostano dall’ipotalamo all’ipofisi attraverso il peduncolo ipofisario, o anche i neurotrasmettitori (come la serotonina)che, rilasciati dalle cellule nervose, attraversano i ponti che le uniscono per trasmettere il segnale ad altri neuroni. 4. La renina svolge quindi un ruolo chiave nell’attivazione del RAS tessutale, rappresentando il fattore limitante, in assenza del quale l’attivazione stessa non può avvenire**. *van Lutterotti N et al. Circulation 1994; 89: **Catanzaro DF Hypertension Res 2005; 28:

11 Non attivazione RAS tissutale
L’inibizione diretta della renina può ridurre l’attivazione del RAS tissutale CIRCOLO ORGANI BERSAGLIO Non attivazione RAS tissutale Renina Renina inattiva Increased Ang II levels also have long-term effects on the cardiovascular system, including cardiac hypertrophy and vascular remodelling. Long-term elevation of Ang II levels also plays a pivotal role in the development and progression of renal and cerebrovascular diseases. Ang II constricts blood vessels, increases sympathetic nervous system activity, stimulates platelet aggregation, increases oxidative stress, and causes trophic changes in the heart and blood vessels (e.g. sensitizing vessels to other constrictors, hypertrophy of myocardial and vascular cells, and fibrosis). Ang II plays a critical role in the development of local inflammation and atherosclerosis in blood vessels, left ventricular hypertrophy and cardiac fibrosis, and nephrosclerosis and renal failure. Abbreviations Ang, angiotensin References Anderson. In: Izzo Jr and Black. Eds. Hypertension Primer: The Essentials of High Blood Pressure. 2003: Goodfriend. In: Izzo Jr and Black. Eds. Hypertension Primer: The Essentials of High Blood Pressure. 2003:8-11. Phillips. In: Izzo Jr and Black. Eds. Hypertension Primer: The Essentials of High Blood Pressure. 2003:21-23. aliskiren PROTEZIONE D’ORGANO

12 Un nuovo possibile livello di intervento: Il RAS autocrino (intracellulare)
“In questo studio osserviamo una drammatica attivazione del RAS intracellulare, un aspetto nuovo del RAS tissutale, nel cuore di ratti diabetici”. “Dimostriamo inoltre che la Ang II correla con lo sviluppo delle condizioni patologiche associate a diabete”. La Ang II è prodotta da vie chimasi dipendenti. “Il blocco del RAS con un DRI (Aliskiren) nei ratti diabetici fornisce maggiore protezione dallo stress ossidativo e dalla fibrosi cardiaca in confronto ad ACE inibitore o sartano”. Hyperglycemia selectively upregulates the intracellular system in cardiac myocytes, vascular smooth muscle cells (VSMC), and renal mesangial cells, where Ang II synthesis is largely catalyzed by chymase, not ACE One group of diabetic animals was treated with insulin to confirm that the observed effects in the experimental groups were secondary to hyperglycemia. Rajesh Kumar, Ph.D. Diabetes published online October 1, 2008

13 Perché un ulteriore farmaco agente sul RAS
Perché un ulteriore farmaco agente sul RAS? E’ utile un’ulteriore e più completa modulazione del sistema?

14 In Europa circa il 70% dei pazienti non raggiunge i target pressori (<140/90 mmHg)
Target pressorio raggiunto Target pressorio non raggiunto 100 60 79 70 81 72 80 60 40 This slide shows the age-adjusted control rates in treated hypertensive patients aged 3564 years. As shown, the majority of patients treated for hypertension in Europe do not attain target BP goals of <140/90 mmHg (ranging from 60% to 81%). Given the detrimental effects of high BP and the burden of cardiovascular disease, it is clear that efforts need to be intensified to improve BP control rates. Reference Wolf-Maier K, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension 2004;43:1017. 20 Inghilterra Svezia Germania Spagna Italia Wolf-Maier et al. Hypertension 2004;43:10–17

15 Dalla renina alla sua modulazione farmacologica: un cammino lungo oltre un secolo
1977: captopril 1993: losartan 2007: aliskiren

16 Evolution and Development of Renin Inhibitors–A Decades Long Search
ALISKIREN Patented in 1995 First viable renin inhibitor Good oral bioavailability Dose dependent suppression of RAS in human volunteers PEPSTATIN ANALOGS Inhibit pepsin Less potent with renin With the initial substrate analogues the use of the amino acid sequence of equine angiotensinogen was used for development which led to the development of various octapeptides with micromolar potencies then with subsequent modifications researchers developed the decapeptide renin inhibitory peptide (RIP). Although this compound exhibited hypotensive activity in primates and humans parenteral administration was still necessary. It was then discovered that the amino acids around the scissile bond, point of hydrolysis, in human angiotensinogen were Leucine-Valine not Leucine-Leucine. This lead to the development of a number of 1st generation transition state mimic substrate analogues and include H-142, ditekiren, CGP 29287, BW-175, CGP 38560, YM-21095, ES-8891, remikiren and enalkiren. These compounds however had poor oral bioavailability (<10%) and still required parenteral administration. The development of the 2nd generation renin inhibitors had emerged. These compounds possessed enhanced oral bioavailability without sacrificing potency. Development continued to improve oral bioavailability and the product A was synthesized which showed appreciable oral bioavailability and efficacy in animals. This was the first compound to evaluate the clinical usefulness of an orally administered renin inhibitor. 1950s 1970s 1980s 1990s RENIN ANTIBODIES Orally inactive Induce antigenic reactions SUBSTRATE ANALOGS Equine angotensinogen Hydrolysis of Leu-Leu bond Renin inhibitory peptide TRANSITION STATE ANALOGS Mimic human angiotensinogen Hydrolysis of Leu-Val bond Good inhibitor potency Poor oral bioavailability Kleinert HD and Stein HH. Specific Renin Inhibitors: Concepts and Prospects. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. New York, NY; Raven Press Ltd;1995: ; Lin C and Frishman WH. Am Heart J 1996;131:1024–1034.

17 Presupposti teorici alla modulazione diretta della Renina
Già nel 1957 Skeggs et al. postularono tre possibili approcci all’inibizione farmacologica del RAS: 1) Inibizione dell’enzima di conversione (ACE) 2) Interferenza diretta con l’azione dell’ angiotensina II 3) Inibizione della renina “Poichè la renina è la sostanza iniziale e limitante il RAS”, osservarono, “quest’ultimo approccio potrebbe essere il migliore“ Lo sviluppo di DRI efficaci, però, si scontrava con la difficoltà di ottenere molecole con alta affinità per la renina e sufficiente biodisponibilità ed emivita, tali da permettere una somministrazione orale cronica. A coronamento di decenni di sforzi, Aliskiren rappresenta il capostipite dei DRI, dopo 15 anni dall’introduzione di losartan.

18 Aliskiren si lega con altissima affinità al sito attivo della renina
Aliskiren ha un’elevata specificità per la renina umana ed il suo studio nei modelli animali è stato problematico. Si è reso necessario sviluppare dei ratti doppi transgenici (dTGR, double TransGenic Rat) che: esprimono i geni per la renina e per l’angiotensinogeno umani sviluppano ipertensione grave e danno d’organo finale Renina Aliskiren aliskiren® reversibly binds to the S1/S3 pocket in the renin molecule, blocking catalytic activity of the Asp32 and Asp215 aspartate residues. aliskiren® thus competitively prevents binding of angiotensinogen and its cleavage to form angiotensin I. Reference 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. Angiotensinogeno Adattato da: Wood JM et al, 2003

19 Inibitore diretto della renina
A differenza degli ACEI e degli ARB, aliskiren riduce l’Ang I, l’Ang II e la PRA Inibitore diretto della renina Angiotensinogeno Renina Ang I Vie non ACE-dipendenti ACE Ciclo di feedback ACEI Ang II ARB Blockade of the Renin System (RS) at any point leads to a compensatory increase in renin release. Angiotensin converting enzyme (ACE) inhibitors or ACEIs and aliskiren cause angiotensin II (Ang II) levels to drop and angiotensin receptor blockers (ARBs) block the action of Ang II on type 1 Ang II (AT1) receptors – both these effects reduce the level of stimulation of AT1 receptors on juxtaglomerular cells in the kidney, leading to increased renin release. Aliskiren is unique in counteracting the resultant increase in circulating renin concentration by inhibiting its action as an enzyme, i.e. reducing plasma renin activity (PRA). Other classes of drugs acting on the RS, ACEIs and ARBs, are associated with elevation of PRA in parallel with increased renin release. As PRA reflects the capacity of circulating renin to cleave angiotensinogen and form angiotensin I (Ang I), levels of Ang I also increase in the presence of these agents. ACEIs reduce subsequent conversion of Ang I to Ang II, leading to an overall reduction in Ang II levels, although some Ang II generation continues, mediated by non-ACE pathways, for which substrate (Ang I) is increased. With ARBs, elevated Ang I leads to increased Ang II production. The whole RS is therefore upregulated, although AT1 receptor-mediated effects of the effector molecule Ang II are blocked. As aliskiren reduces PRA, generation of Ang I decreases. Less substrate is therefore available for conversion to Ang II by ACE or other enzymes. Direct renin inhibition therefore produces effective overall RS suppression. Abbreviations Ang I = angiotensin I Ang II = angiotensin II 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 Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 2006;24(2): Recettore AT1 Ang I Ang II Renina PRA ↑ ↓ ↑ ↑ ACEI ↑ ↑ ↑ ↑ ARB Aliskiren ↓ ↓ ↑ ↓ Azizi M et al 2006

20 Profilo farmacocinetico di aliskiren
Farmacocinetica proporzionale alla dose Emivita prolungata (>24 ore) Rapporto valle picco fino al 98% tmax di circa 1-3 ore Lo steady state viene raggiunto entro 5-7 giorni La biodisponibilità orale di aliskiren è del 2,6% aliskiren has dose proportional pharmacokinetics. The half-life of aliskiren was approximately 40 hours in both healthy volunteers and patients with type 2 diabetes, demonstrating that the pharmacokinetics of aliskiren are unaltered by the presence of diabetes.1,2 After an oral dose of aliskiren, the maximum plasma concentration occurs at approximately 1–3 hours post-dose (tmax).1,2 Steady state plasma concentrations of aliskiren® are reached within 5–7 days following once daily administration. References Vaidyanathan S, Limoges D, Yeh C-M, et al. Aliskiren, an orally effective renin inhibitor, shows dose linear pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2006a;79:64(PIII-23) . Vaidyanathan S, Zhao C, Yeh C-M, et al. Pharmacokinetics and safety of the novel oral renin inhibitor aliskiren in patients with type 2 diabetes. Clin Pharmacol Ther 2006b;79:64(PI-21). Vaidyanathan et al, 2006a; Vaidyanathan et al, 2006b

21 Profilo farmacocinetico di aliskiren (II)
Legame alle proteine plasmatiche moderato (47-51%) e indipendente dalla concentrazione L’1,4% circa della dose orale totale viene metabolizzato (via CYP 3A4) Eliminato principalmente nelle feci come farmaco immodificato (90%) Lo 0,6% della dose si ritrova nelle urine (quota di escrezione renale di circa l’11%) Interazioni farmacocinetiche clinicamente non rilevanti (esclusa Ciclosporina) aliskiren® is eliminated primarily unchanged in the faeces. Approximately 1.4% of the total oral dose is metabolized and 0.6% of the dose is recovered in the urine.1 The hepatic extraction ratio is approximately 10% (indicating minor involvement of first-pass metabolism in the elimination).2 References Data on file, Novartis 2005; study ref:SPP100A2223. Azizi M, Webb R, Nussberger J, et al. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 2006;24:243–256. Azizi et al, 2006; Novartis, dati disponibili in archivio, 2001 (Studio 2223)

22 Utilizzo in popolazioni speciali
Farmacocinetica non influenzata ad un livello da comportare variazioni di dosaggio in: Insufficienza renale da lieve a moderatamente grave* Insufficienza epatica anche severa Non aggiustamenti necessari per sesso,anziani, gruppi etnici diversi Profilo farmacocinetico non diverso nei diabetici, obesi o con Sindrome Metabolica * I pazienti con creatinina > 1.7 mg/dL (donne) e > 2.0 mg/dL (uomini) e/o estimated GFR <30 mL/min, una storia di dialisi, sindrome nefrosica o ipertensione nefrovascolare sono stati esclusi dai primi trials su Aliskiren

23 Dopo 8 settimane di trattamento la riduzione della PAD ambulatoria media si prolunga oltre le 24 ore
Placebo (n=53) Aliskiren 150 mg (n=52) Aliskiren 300 mg (n=56) Variazione rispetto al basale della PAD ambulatoria media (mm Hg) 10 5 −5 ABPM was performed in a subset of patients in Study BP reductions with aliskiren® were sustained over the 24-hour period between doses and there was no evidence of a loss of effect at the time of the lowest plasma concentrations of aliskiren®. Reference Mitchell J, Oh B, Herron J, et al. Once-daily aliskiren provides effective, smooth 24-hour blood pressure control in patients with hypertension. J Clin Hypertens 2006;8(5 Suppl. A):A93(P-209). −10 −15 2 4 6 8 10 12 14 16 18 20 22 24 Tempo dalla dose (ore) Mitchell et al, 2006 (Studio 2308)

24 Aliskiren determina marcata riduzione della PA del mattino
PAS ambulatoria media (mm Hg) 155 150 145 140 Settimana 0 135 Settimana 8 130 ABPM was performed in a subset of patients in Study After 8 weeks’ treatment, aliskiren® substantially reduced BP during the early morning BP rise compared with baseline. Reference Mitchell J, Oh B, Herron J, et al. Once-daily aliskiren provides effective, smooth 24-hour blood pressure control in patients with hypertension. J Clin Hypertens 2006;8(5 Suppl. A):A93(P-209). 125 120 115 2 4 6 8 10 12 14 16 18 20 22 24 Ora Mitchell et al, 2006 (Studio 2308)

25 Pooled analyses in >3,500 patients demonstrate that aliskiren provides dose-dependent reductions in BP Aliskiren Placebo 150 mg 300 mg Aliskiren Placebo 150 mg 300 mg n=776 n=1180 n=1603 n=776 n=1180 n=1603 −5 3.9 5.6 6.6 9.3 −6.2 −5.9 −10 −10.1 *** −11.8 −15 −12.5 *** *** −15.2 In this analysis, data from eight randomized, double-blind, multicentre trials with aliskiren monotherapy were pooled. The pooled studies included 8,481 patients with mild-to-moderate hypertension who received treatment with aliskiren monotherapy or placebo for 8–12 weeks. The effects of aliskiren 150 and 300 mg on mean sitting diastolic blood pressure (DBP) and mean sitting systolic BP (SBP) were compared with placebo for the overall pooled population and by subgroups for age and gender. Once-daily treatment with aliskiren 150 and 300 mg provided dose-dependent reductions from baseline in DBP and SBP, which were significantly greater than the reductions provided by placebo (p<0.0001). Abbreviations DBP = diastolic blood pressure SBP = diastolic blood pressure Reference Dahlöf B, Anderson DR, Arora V, et al. Aliskiren, a direct renin inhibitor, provides antihypertensive efficacy and excellent tolerability independent of age or gender in patients with hypertension. J Clin Hypertens 2007;9(Suppl A):A157 P-376. −20 *** DBP SBP −25 Mean change from baseline in mean sitting BP after 8–12 weeks (mmHg) ***p< vs placebo Values under bars represent least square mean reductions ± standard error of the mean; values in arrows represent placebo-subtracted reductions Dahlöf B, et al (Pooled analysis)

26 DBP returns to baseline levels more rapidly after discontinuation of ramipril compared with aliskiren Mean change in mean sitting DBP during the 4-week withdrawal period (mmHg) 8 6 4 2 –2 This study was a medium-term randomized, double-blind, dose-titration study, in 842 patients with mild-to-moderate essential hypertension (mean sitting diastolic blood pressure [MSDBP] ≥95 mmHg and <110 mmHg at randomization). Patients were randomized to received aliskiren 150 mg once daily (od) or ramipril 5 mg od for 6 weeks after a 2–4-week placebo run-in period. Optional dose titration to aliskiren 300 mg or ramipril 10 mg was available at Week 6 if required for patients not achieving the goal blood pressure (BP) of <140/90 mmHg. For those patients not achieving BP goal at Week 12, hydrochlorothiazide (HCTZ) was added for the remainder of the study at a starting dose 12.5 mg, with optional increase to 25 mg from Week 19 if required. At the end of Week 26, patients who completed the active-controlled treatment period were re-randomized to continue with their current treatment regimen, or to receive placebo, in a 4-week double-blind withdrawal period. During the withdrawal period, sitting BP was measured at weekly intervals (24 ± 3 hours post-dosing). The BP-lowering effect was more prolonged after discontinuation of aliskiren-based therapy compared with discontinuation of ramipril-based therapy. Increases in MSDBP occurred more rapidly after discontinuation of ramipril-based therapy than after discontinuation of aliskiren-based therapy – at the end of the first week, MSDBP increased by 4.6 mmHg in patients who had discontinued ramipril-based therapy, compared with an increase of 2.4 mmHg in patients who had discontinued aliskiren-based therapy (statistical significance not tested). In conclusion, reductions in BP and PRA with aliskiren are sustained 24 weeks after treatment is stopped in patients with hypertension. The basis for this prolonged effect may relate to the sequestration of aliskiren in deep tissue compartments such as the kidney with an ensuing slow release following cessation of therapy. These findings demonstrate the renal localization, partition and retention of aliskiren, which may have implications for its mechanism of action and could lead to effective inhibition of local generation of angiotensin II. Based on its vascular location, aliskiren is likely to be localized in juxtaglomerular cells, where it may provide the potential for inhibition of renin prior to or during its release from the kidney. In addition, if there is an intracrine renin-angiotensin system in glomerular/arterial cells, this localized distribution could operate to inhibit that system. The presence of aliskiren 3 weeks after stopping treatment suggests that long-term renal protective benefits could be derived at the tissue level. This finding may also help to explain clinical findings of sustained blood pressure lowering effects following withdrawal of aliskiren. Abbreviations BP = blood pressure HCTZ = hydrochlorothiazide MSDBP = mean sitting diastolic blood pressure Reference Andersen K, Weinberger MH, Egan B, et al. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens 2008;26:589–599. Baseline Week 1 Week 2 Week 3 Week 4 Aliskiren regimen discontinued (n=163)* Aliskiren regimen continued (n=170)† Ramipril regimen discontinued (n=177)* Ramipril regimen continued (n=165)† *Following 26-weeks’ treatment, patients randomized to discontinuation received placebo for 4 weeks; †Patients continuing active treatment could be receiving aliskiren 150 or 300 mg, or ramipril 5 or 10 mg, with or without optional HCTZ (12.5 mg or 25 mg). Andersen K, et al (Study 2306)

27 Aliskiren in monoterapia verso diuretico, ACEI e sartano: sintesi dei risultati
Figure notes: Study 2323: Hypertensive patients were randomized to HCTZ or aliskiren for 12 weeks. Comparison of aliskiren (3 weeks at 150 mg, then 9 weeks at 300 mg) vs HCTZ (3 weeks at 12.5 mg, then 9 weeks at 25 mg). Data shown at 12 weeks. DBP reduction was greater with aliskiren (12.2 vs 10.3 mmHg, p<0.01). Study 2307: In this double-blind trial, hypertensive patients (DBP >95 mmHg and <110 mmHg) with diabetes were randomized to ramipril 5 mg od, aliskiren 150 mg od, or ramipril 5 mg od + aliskiren 150 mg od. After 4 weeks, doses were doubled. Patients were treated for an additional 4 weeks. DBP reduction was similar between aliskiren and ramipril. Study 2327: In this double-blind trial, hypertensive patients with DBP >95 mmHg and <110 mmHg were randomized to valsartan 160 mg od, aliskiren 150 mg od, valsartan 160 mg od + aliskiren 150 mg od, or placebo. After 4 weeks, doses were doubled. Patients were treated for an additional 4 weeks. DBP reductions were similar between aliskiren and valsartan monotherapies (9.0 vs 9.7 mmHg). Abbreviations ACEI = angiotensin-converting enzyme inhibitor AE = adverse event BP = blood pressure CCB = calcium channel blocker CV = cardiovascular DBP = diastolic blood pressure Od = once daily HCTZ = hydrochlorothiazide *P<0.001; †P<0.05 See footnotes 1Study 2323; 2Study 2307; 3Study 2327

28 Aliskiren in terapia di combinazione: sintesi dei risultati
Aliskiren provides up to 50% more BP reduction when combined with HCTZ1, ramipril2, amlodipine3, or valsartan4 compared with the component monotherapy Figure notes: Study 2204: In this double-blind factorial trial, hypertensive patients with DBP>95 mmHg and <110 mmHg were randomized to HCTZ mg od or aliskiren mg od, alone or in combination, for 8 weeks. The mean reduction in SBP with aliskiren 300 mg was mmHg, and with placebo was -7.5 mmHg (Villamil 2006). Study 2307: In this double-blind trial, hypertensive patients (DBP>95 mmHg and <110 mmHg) with diabetes were randomized to ramipril 5 mg od, aliskiren 150 mg od, or ramipril 5 mg od + aliskiren 150 mg od. After 4 weeks, doses were doubled. Patients were treated for an additional 4 weeks. The mean reduction in SBP with aliskiren 300 mg was mmHg (Uresin 2006). Study 2305: This was a non-responder, 6-week comparison of aliskiren 150 mg + amlodipine 5 mg vs amlodipine 10 mg in patients not controlled by amlodipine 5 mg (Munger 2006). Study 2327: In this double-blind trial, hypertensive patients were randomized to placebo, aliskiren 150 mg od, valsartan 160 mg, or aliskiren/valsartan 150/160 mg for 4 weeks and then force-titrated to 300 mg, 320 mg, and 300/320 mg, respectively. Abbreviations ACEI = angiotensin-converting enzyme inhibitor BP = blood pressure CCB = calcium channel blocker CV = cardiovascular DBP = diastolic blood pressure HCTZ = hydrochlorothiazide Od = once daily SBP = systolic blood pressure *P<0.05; †P<0.01 1Study 2204; 2Study 2307; 3Study 2305 (note, this was a non-responder comparison of aliskiren 150 mg + amlodipine 5 mg vs amlodipine 10 mg in patients not controlled by amlodipine 5 mg; 4Study 2327

29 Effetti avversi di Aliskiren vs. placebo
Dosaggi approvati Pazienti con eventi avversi (%) Placebo Aliskiren 75 mg Aliskiren 150 mg Aliskiren 300 mg Aliskiren 600 mg Aliskiren globale n=781 n=478 n=774 n=768 n=296 n=2316 Qualsiasi EA 40,2 40,4 37,5 43,9 39,8 EA più frequenti Cefalea 8,7 6,5 5,4 5,7 5,1 Rinofaringite 5,8 7,1 4,3 3,8 1,7 4,4 Diarrea 1,2 1,3 2,3 9,5 2,6 Capogiri 2,2 2,5 2,7 1,8 Affaticamento 1,5 0,6 2,4 1,6 Infezioni del tratto respiratorio superiore 0,8 0,9 Rachialgia 1,4 1,0 Edemi periferici 2,0 Tosse 0,0 Pooled safety data are available for placebo-controlled trials with aliskiren®. The pooling included studies 1201, 2201, 2308, 2203 and The mean duration of exposure for the pooled studies was 54 days (maximum of 73 days) for aliskiren® monotherapy and 52 days (maximum of 83 days) for placebo. Overall, aliskiren® demonstrated placebo-like tolerability at dosages up to 300 mg/day in a broad range of patients. Discontinuations due to AEs occurred in 1.9% of patients taking aliskiren® monotherapy compared with 3.5% of those taking placebo. There was no evidence of dose-related increases in the incidence of AEs with aliskiren® in the 75–300 mg dose range. Overall, >95% of AEs with aliskiren® were mild or moderate in severity and the majority of AEs were considered not to be related to treatment. The most frequent AEs, headache and nasopharyngitis, are common conditions and occurred at a similar incidence to placebo. The overall incidence of diarrhoea with aliskiren® was higher than placebo due to a significantly higher rate with aliskiren® 600 mg (p< vs placebo); at 150 and 300 mg dosages the rate of diarrhoea was similar to placebo. References Weir, M. R., C. Bush, J. Zhang, D. L. Keefe and A. Satlin (2006). "Antihypertensive efficacy and safety of the oral renin inhibitor aliskiren in patients with hypertension: a pooled analysis." Eur Heart J 27 (Suppl): Data on file, Novartis 2006; SPP100A [summary of clinical safety in hypertension]. Weir et al, 2006 e Novartis, dati disponibili in archivio (pooled analysis)

30 Efficacia di aliskiren nell’ipertensione: riassunto
Aliskiren modula il sistema della renina al suo punto di attivazione e riduce la PRA, sia in monoterapia che in associazione. Efficacia antiipertensiva in monoterapia Efficacia antiipertensiva in associazione Efficacia costante in tutti i tipi di pazienti Efficace anche in caso di aderenza discontinua al trattamento Controllo ottimale della PA nelle 24 ore Tollerabilità e sicurezza simili a placebo

31 Il programma di studi ASPIRE HIGHER
Il programma ASPIRE HIGHER studia gli effetti della modulazione diretta della renina con Aliskiren in diverse patologie di rilevante impatto clinico, fra cui la nefropatia diabetica,lo Scompenso Cardiaco, la SCA ed il post IMA.

32 Lo Studio AVOID Aliskiren in the Evaluation of Proteinuria in Diabetes
Obiettivo: verificare se aliskiren on top ad una terapia ottimizzata avesse un effetto nefroprotettivo superiore rispetto al braccio controllo con placebo on top.

33 Studio AVOID: disegno sperimentale
Studio in doppio cieco, randomizzato, placebo-controllato in ipertesi con DM2 e nefropatia 12–14 settimane terapia antipertensiva ottimizzata, comprendente un sartano a dosaggio pieno Placebo Aliskiren 150 mg + 12 24 (endpoint) Aliskiren 300 mg Randomizzazione Fase in aperto Doppio cieco Settimane Patients enrolled in the AVOID study will initially receive 12–14 weeks of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving BP <130/80 mmHg. After the 12–14 week period, those patients with BP <150/95 mmHg will be randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 12 weeks, the dosage of aliskiren will be force-titrated from 150 to 300 mg for a further 12 weeks. References 1. Clinicaltrials.gov. Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria. ClinicalTrials.gov Identifier: NCT Accessed at: 2. Data on file, Novartis Study SPP100C2201. Titolazione forzata a 12 setimane Tutte le dosi sono somministrate una volta al giorno

34 Effetto di aliskiren e del placebo sulla pressione arteriosa nel corso dello studio
Mean sitting BP (mmHg) 140 Systolic 130 120 110 100 90 Patients enrolled in the AVOID study will initially receive 12–14 weeks of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving BP <130/80 mmHg. After the 12–14 week period, those patients with BP <150/95 mmHg will be randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 12 weeks, the dosage of aliskiren will be force-titrated from 150 to 300 mg for a further 12 weeks. References 1. Clinicaltrials.gov. Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria. ClinicalTrials.gov Identifier: NCT Accessed at: 2. Data on file, Novartis Study SPP100C2201. 80 Diastolic 70 60 –2 2 4 6 8 10 12 14 16 18 20 22 24 Week Date are shown as mean ± SEM Baseline was the week 0 (Day 1) value BP, blood pressure

35 Variazione media dal basale dell‘UACR (%)
Aliskiren riduce significativamente l’UACR verso terapia ottimizzata dal basale all’endpoint finale Variazione media dal basale dell‘UACR (%) 5 2% –5 20% di riduzione UACR vs placebo –10 Patients enrolled in the AVOID study will initially receive 12–14 weeks of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving BP <130/80 mmHg. After the 12–14 week period, those patients with BP <150/95 mmHg will be randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 12 weeks, the dosage of aliskiren will be force-titrated from 150 to 300 mg for a further 12 weeks. References 1. Clinicaltrials.gov. Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria. ClinicalTrials.gov Identifier: NCT Accessed at: 2. Data on file, Novartis Study SPP100C2201. –15 –20 –18% * Aliskiren (n = 287) Placebo (n = 289) *p = Data are shown as percentage change in geometric mean Baseline was week −2 value UACR, urinary albumin:creatinine ratio

36 Riduzioni ≥ 50% nell’ UACR dal basale tra gruppi (%)
30 * 24.7% Aliskiren (n = 287) 25 Placebo (n = 289) 20 15 12.5% 10 Patients enrolled in the AVOID study will initially receive 12–14 weeks of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving BP <130/80 mmHg. After the 12–14 week period, those patients with BP <150/95 mmHg will be randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 12 weeks, the dosage of aliskiren will be force-titrated from 150 to 300 mg for a further 12 weeks. References 1. Clinicaltrials.gov. Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria. ClinicalTrials.gov Identifier: NCT Accessed at: 2. Data on file, Novartis Study SPP100C2201. 5 *p = vs placebo Baseline was week –2 value UACR, urinary albumin:creatinine ratio

37 Variazione dal basale dell’UACR (%)
Aliskiren è efficace nel ridurre l’UACR sin dalle prime settimane di trattamento Variazione dal basale dell’UACR (%) 10 –10 Patients enrolled in the AVOID study will initially receive 12–14 weeks of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving BP <130/80 mmHg. After the 12–14 week period, those patients with BP <150/95 mmHg will be randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 12 weeks, the dosage of aliskiren will be force-titrated from 150 to 300 mg for a further 12 weeks. References 1. Clinicaltrials.gov. Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria. ClinicalTrials.gov Identifier: NCT Accessed at: 2. Data on file, Novartis Study SPP100C2201. –20 –30 –2 2 4 6 8 10 12 14 16 18 20 22 24 Week Aliskiren Data are shown as change from baseline in geometric mean (95% CI) Baseline was the week –2 value UACR, urinary albumin:creatinine ratio Placebo

38 Age-adjusted annual incidence per 1000
Cardiovascular Events According to Proteinuria The Framingham Study Women Men 5 10 15 20 25 30 Proteinuria absent Proteinuria present Cardiac Failure Stroke Total CV Events Coronary Heart Disease 22.7 16.5 15.2 Age-adjusted annual incidence per 1000 12.0 11.1 10.8 9.1 7.3 6.9 4.6 4.2 3.2 2.2 1.8 2.3 1.4 Kannel WB et al., Am Heart J 1984; 108:

39 Tollerabilità di aliskiren sovrapponibile a placebo
Aliskiren (n = 301) Placebo (n = 298) Any adverse event, n (%) 201 (66.8) 200 (67.1) Any serious adverse event, n (%) 27 (9.0) 28 (9.4) Discontinuations due to adverse events, n (%) 17 (5.6) 19 (6.4) Deaths, n (%) 2 (0.7) Adverse events reported by ≥ 5% of patients in either treatment group, n (%) Headache 18 (6.0) 11 (3.7) Nasopharyngitis 15 (5.0) Dizziness 10 (3.4) Hyperkalemia 17 (5.7) Peripheral edema 13 (4.3) 23 (7.7) Patients enrolled in the AVOID study will initially receive 12–14 weeks of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving BP <130/80 mmHg. After the 12–14 week period, those patients with BP <150/95 mmHg will be randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 12 weeks, the dosage of aliskiren will be force-titrated from 150 to 300 mg for a further 12 weeks. References 1. Clinicaltrials.gov. Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria. ClinicalTrials.gov Identifier: NCT Accessed at: 2. Data on file, Novartis Study SPP100C2201. Data are shown for the double-blind period

40 Effetto dei trattamenti su parametri di laboratorio rilevanti
Aliskiren (n = 299) Placebo (n = 297) Serum potassium, n (%) < 3.5 mEq/L 15 (5.0) 11 (3.7) > 5.5 mEq/L 41 (13.7) 32 (10.8) ≥ 6.0 mEq/L 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) Patients enrolled in the AVOID study will initially receive 12–14 weeks of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving BP <130/80 mmHg. After the 12–14 week period, those patients with BP <150/95 mmHg will be randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 12 weeks, the dosage of aliskiren will be force-titrated from 150 to 300 mg for a further 12 weeks. References 1. Clinicaltrials.gov. Safety and Efficacy of Aliskiren in Patients With Hypertension, Type 2 Diabetes and Proteinuria. ClinicalTrials.gov Identifier: NCT Accessed at: 2. Data on file, Novartis Study SPP100C2201. La proporzione di pazienti con livelli di creatinina serica > 2.0 mg/dL è stata significativamente superiore con placebo vs aliskiren (p = 0.049). L’incidenza di potassio sierico > 6.0 mEq/L è stata maggiore con aliskiren rispetto a placebo, ma non in modo statisticamente significativo (p = 0.059). *p = based on Chi-squared test Data are presented as number (%) of patients with pre-specified abnormal laboratory values at any time during the double-blind period BUN, blood urea nitrogen

41 Lo studio Aloft Mc Murray, Latini, Maggioni et al, May 20, 2008

42 Aliskiren in pazienti ipertesi con insufficienza cardiaca
Placebo Placebo Aliskiren 150 mg + Terapia standard per lo scompenso per tutta la durata dello studio run-in di 2 sett. In the ALOFT study, 280 patients with stable heart failure (HF) and hypertension will receive placebo during a 2-week run-in period, followed by 12-weeks of double-blind treatment with aliskiren® 150 mg or placebo. All patients will receive standard therapy for HF throughout the study. The primary endpoints include safety and tolerability, decrease in B-type natriuretic peptide and symptomatic relief of HF. Additional endpoints include biomarkers, 24-hour urine sampling for aldosterone and protein, cardiac ultrasound, Holter monitoring and markers of glucose metabolism. ALOFT – aliskiren® in patients with hypertension and heart failure Study design: double-blind, randomized, placebo-controlled study Patients: 280 patients aged with hypertension and stable heart failure Inclusion criteria: history or current diagnosis of hypertension; stable heart failure; stable dosage of heart failure medications; BNP >150 pg/mL Primary objective: evaluate the safety and tolerability of aliskiren® when given in addition to standard therapy in hypertensive patients with stable heart failure Secondary objectives: effect of aliskiren® on BNP, NT-proBNP and aldosterone levels; effect of aliskiren® on improvement in signs and symptoms of heart failure; effect of aliskiren® on BP B-type natriuretic peptide (BNP) B-type natriuretic peptide (BNP) is generated by cleavage from proBNP in response to myocardial stretch (stretch of the heart muscle), and is commonly used to diagnose heart failure and to follow the progress of treatment. An inactive peptide called N-terminal proBNP (NT-proBNP) is also formed by the cleavage process.2 Plasma BNP concentrations are elevated in patients with heart failure and have been shown to correlate with the severity of heart failure symptoms.2 Furthermore, concentrations of BNP at baseline are strongly associated with morbidity and mortality in patients with heart failure.3,4 Reductions in BNP concentration have been linked with decreases in morbidity and mortality – antihypertensive treatment was shown to decrease BNP, mortality and morbidity in patients with heart failure in the Val-HeFT trial.5 These results indicate that BNP can be used as a reliable surrogate marker to assess the effects of treatment on the risk of morbidity and mortality. References McMurray, J., B. Pitt, R. Latini, A. Maggioni, S. D. Solomon, J. Chung, J. Ford and B. Smith (2007). "Haemodynamic, neurohumoral, renal and ambulatory electrocardiographic effects of a new oral renin inhibitor in stable heart failure." ESC 2007 Oral Presentation. Cowie MR, Jourdain P, Maisel A, et al. Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J 2003;24:1710–1718. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107:1278–1283. Vuolteenaho O, Ala-Kopsala M, Ruskoaho H. BNP as a biomarker in heart disease. Adv Clin Chem 2005;40:1–36. Latini R, Masson S, Anand I, et al. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2002;106:2454–2458. 12 settimane di trattamento in doppio cieco n = 280 pazienti con scompenso stabile, ipertensione, BNP >100 pg/ml Stratificazione in base alla presenza o meno di disfunzione sistolica Endpoint primario: sicurezza e tollerabilità di aliskiren aggiunto alla terapia standard per lo scompenso cardiaco Valutazioni aggiuntive: NT-proBNP, BNP, aldosterone, NE, hsCRP, hsIL-6, TNFα, MMP-9, PIIINP, renina, PRA, dosaggio di aldosterone e proteine nelle urine delle 24 ore, ecocardiografia, Holter delle 24 ore per la variabilità della frequenza cardiaca, valutazione del metabolismo glucidico (glicemia a digiuno, insulina, HbA1c e HOMA IR) e QoL (KCCQ) McMurray et al, 2007 (Studio 2313)

43 Aliskiren: tollerabilità simile a placebo in add on alla terapia standard per SCC
Proportion of patients (%) 6.4 7 n=156 6 4.8 5 n=146 4 3.2 3 n=156 n=156 1.9 2 The ALiskiren Observation of heart Failure Treatment (ALOFT) study was a randomized, double-blind, placebo-controlled 12-week study in 302 patients with hypertension, stable heart failure (HF) and B-type natriuretic peptide (BNP) levels >100 pg/mL. The primary assessment for safety was the proportion of patients in each treatment group who reported at least one pre-defined adverse event (AE). These were ranked in a hierarchical order: renal dysfunction (defined as elevation of serum creatinine with discontinuation of medication and/or renal failure with discontinuation of medication), symptomatic hypotension and hyperkalaemia during the active treatment period. The proportions of patients who experienced renal dysfunction, symptomatic hypotension and hyperkalaemia in the aliskiren and placebo groups were similar. These results demonstrate that aliskiren has placebo-like tolerability when administered in addition to standard therapy in patients with stable HF. Abbreviations AE = adverse event ALOFT = ALiskiren Observation of heart Failure Treatment BNP = B-type natriuretic peptide HF = heart failure Reference McMurray JJV. Haemodynamic, neurohumoral, renal and ambulatory electrocardiographic effects of a new oral renin inhibitor in stable heart failure. Oral presentation at ESC, Vienna, Austria. 1–5 September 2007. n=146 1.4 1.4 1 n=146 Renal dysfunction Symptomatic hypotension Hyperkalaemia Standard HF therapy + aliskiren 150 mg Standard HF therapy + placebo McMurray JJV. ESC 2007 (ALOFT)

44 ALOFT Baseline characteristics and concomitant HF therapy
Aliskiren n=156 Placebo n=146 Clinical characteristics at baseline LVEF, n (%) ≤40% 125 (80) 113 (77) >40% 31 (20) 33 (23) NYHA Class II, n (%) 98 (63) 87 (60) NHYA Class III, n (%) 56 (36) 58 (40) Concomitant therapy for stable HF ARB, % 16 14 ACEI, % 83 84 β-blocker, % 94 95 Aldosterone antagonist, % 33 34 The ALiskiren Observation of heart Failure Treatment (ALOFT) study was a randomized, double-blind, placebo-controlled 12-week study in 302 patients with hypertension, stable heart failure (HF) and B-type natriuretic peptide (BNP) levels >100 pg/mL. There were no significant differences in baseline clinical characteristics between the aliskiren and placebo groups. Left ventricular function (assessed by patients’ LVEF) and severity of HF (assessed by New York Heart Association criteria) were similar between treatment groups. Patients enrolled in the ALOFT study were required to be receiving a stable dosage regimen of HF medications. These medications consisted of the following: either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB), and a β-blocker, in addition to aldosterone antagonists, diuretics and digoxin. In the aliskiren treatment group, 25 (16%), 130 (83%), 147 (94%) and 52 (33%) patients were receiving treatment with an ARB, ACEI, b-blocker or aldosterone antagonist, respectively. The use of ACEIs, ARBs, β-blockers and aldosterone antagonists was similar in the aliskiren and placebo groups. Abbreviations ACEI = angiotensin-converting enzyme inhibitor ALOFT = ALiskiren Observation of heart Failure Treatment ARB = angiotensin receptor blocker BNP = B-type natriuretic peptide HF = heart failure LVEF = left ventricular ejection fraction NHYA = New York Heart Association Reference McMurray JJV. Haemodynamic, neurohumoral, renal and ambulatory electrocardiographic effects of a new oral renin inhibitor in stable heart failure. Oral presentation at ESC, Vienna, Austria. 1–5 September 2007. McMurray JJV. ESC 2007 (ALOFT)

45 Aliskiren riduce significativamente il BNP e il NT-proBNP rispetto a placebo in pazienti con scompenso Variazione media dal basale† del BNP plasmatico alla settimana 12 (pg/mL) Variazione media dal basale‡ del NT-proBNP plasmatico alla settimana 12 pg/mL) 1000 n=148 n=137 761.7 750 n=127 −12.2 −20 500 −40 250 Dopo un trattamento di sole 12 settimane, l'aggiunta di aliskiren 150 mg alla terapia standard ha indotto riduzioni significative rispetto al valore basale nel BNP e del NT-proBNP plasmatico rispetto al placebo (p<0.05), a dimostrazione di un miglioramento della sindrome neuroendocrina che sta alla base della progressione dello scompenso cardiaco. n=137 −60 −61 −250 −243.6 * * −500 −80 Terapia standard per HF + aliskiren 150 mg + placebo †Valori basali di BNP – aliskiren 301 pg/mL, placebo 273 pg/mL ‡Valori basali di NT-proBNP – aliskiren 2158 pg/mL, placebo 2123 pg/mL *p<0.05 vs placebo McMurray et al (ALOFT) 45