1 Nature Reviews Drug Discovery 2008 Vol: 7(5):399-410. DOI: 10.1038/nrd2550

Aliskiren: the first renin inhibitor for clinical treatment

The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin–angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research. Here, we describe the discovery and development of aliskiren, an orally active renin inhibitor, which became the first drug in its class to receive regulatory approval. In 2007, it was approved for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency.

Mentions
Figures
Figure 1: Aliskiren: from bench to marketplace.The discovery and optimization of aliskiren using X-ray crystallography techniques, biochemical and animal pharmacological characterization was performed at Ciba–Geigy32, 33. A single-dose safety and tolerability study was performed in healthy subjects that showed the potential of the compound. However, the synthesis of aliskiren remained a central problem — it was simply too expensive for the marketplace. Novartis out-licensed the compound to Speedel in 1999 for Phase I and Phase II development and to invent a new synthesis process. Speedel successfully overcame this major technical hurdle, which was critical for advancing the development of aliskiren. During the period 1999–2002, Speedel also established the clinical efficacy of aliskiren in over 500 subjects with mild-to-moderate hypertension in 18 Phase I and II trials and selected the doses to be used later in the Phase III studies. Novartis licensed back the compound in June 2002. The subsequent clinical programme carried out by Novartis, which included over 8,000 patients, provided the evidence for the safety and efficacy of aliskiren in treating hypertension, leading to its regulatory approval in the United States and Europe in 2007. Figure 2: Schematic of the renin–angiotensin system (RAS).Cleavage of angiotensinogen by the protease renin produces the decapeptide angiotensin I (Ang I). Ang I is then further transformed by the angiotensin-converting enzyme (ACE), producing the octapeptide angiotensin II (Ang II). Ang I can also be converted by other non-ACE pathways. Ang II is the end product of the cascade and binds to Ang II subtype 1 receptors (AT1), thereby narrowing blood vessels and increasing blood pressure (BP). Direct perturbation of the RAS by ACE inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors, or indirect changes due to a fall in BP brought about by calcium-channel blockers or diuretics such as hydrochlorothiazide (not shown), lead to feedback stimulation of renin secretion and an increase in plasma renin activity. Figure 3: Renin inhibitors.a | Chemical structures of three generations of renin inhibitors: the peptide analogue H-142, the peptidomimetic remikiren and the non-peptidic aliskiren. b | Graphic depiction of the binding of aliskiren to the active site of renin. S1, S1', S2', S3 and S3sp all represent binding pockets in the active site of renin. In this model of renin, the flap is in the closed position. c | Tables showing the potency, enzyme specificity and species specificity of aliskiren40. Figure 4: The synthon approach to produce aliskiren at an acceptable cost-of-goods.Retrosynthetic analysis resulted in a novel convergent synthesis concept for aliskiren based on the synthon approach. The key elements of this approach are the three different building blocks — synthons A, B and C — which can be synthesized independently. Reactions involved include a rhodium-catalysed enantioselective hydrogenation (synthon A), a pig liver esterase-catalysed enzymatic resolution of a racemic ester (synthon B) and a one-pot nitrile reduction/ester aminolysis (synthon C) as the key steps. Further steps in the final linear and straightforward synthetic sequence for aliskiren involve three parts: first, a nickel-catalysed cross-coupling reaction of synthon A with synthon B. Second, build-up of the remaining two chiral centres with the help of the two already existing chiral centres (synthon A and B) by a highly diastereoselective halolactonisation. And third, integration of synthon C by lactone aminolysis. The synthon approach is convergent, flexible, more elegant (from a synthetic point of view) and most importantly, in the case of aliskiren, it turned out to be very efficient, resolving the long-standing problem of over-expensive manufacturing costs. Each chemical step and each of the different chemical reactions underwent feasibility studies, optimization steps and stepwise scale-up experiments from milligram to multigram to kilogram scale95, 96, 97, 98, 99, 100. Figure 5: Clinical pharmacology of aliskiren.Relationship between aliskiren plasma concentrations and plasma renin concentration (PRC), plasma renin activity (PRA) and angiotensin II plasma concentrations (Ang II). Healthy subjects were given 160 mg of aliskiren once-daily for 8 days. Ingestion of aliskiren at time 0 h leads to a reactive rise in PRC. However, owing to the potent inhibition of renin by aliskiren, the PRA and Ang II levels in plasma decrease. Samples were taken over 24 hours on day 8 (n = 9). Modified, with permission, from Ref. 12 © (2002) American Heart Association. Figure 6: Aliskiren as a monotherapy.a | Mean change in daytime ambulatory systolic and diastolic blood pressure (BP) (aSBP and aDBP, respectively) after 4 weeks of treatment with 37.5, 75, 150 and 300 mg of aliskiren. b | Mean (and standard error) of placebo-corrected changes in sitting diastolic blood pressure (sSBP) from baseline. *p < 0.05 compared with irbesartan. Panel a was adapted from Ref. 50. Panel b was adapted from Ref. 51. Figure 7: Combination of aliskiren with other antihypertensives.a | Effects of ramipril alone and in combination with aliskiren on daytime and night-time ambulatory systolic and diastolic blood pressure (SBP and DBP). *p < 0.05 **p < 0.001. b | Change from baseline in mean 24-hour ambulatory systolic blood pressure (aSBP) after 8 weeks of treatment alone and in combination with valsartan. Panel a was adapted from Ref. 55. Panel b was adapted from Ref. 21. Figure 8: Aliskiren and end-organ protection.Percentage change in urinary albumin creatinine ratio (UACR) in diabetic patients treated with aliskiren or placebo on top of optimized blood-pressure control. Adapted from Ref. 91.
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References
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    • . . . The discovery of renin1 by Tigerstedt and Bergman had itself remained unnoticed for more than 40 years, partly because the authors never published any further work in this area2 . . .
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    • . . . The discovery of renin1 by Tigerstedt and Bergman had itself remained unnoticed for more than 40 years, partly because the authors never published any further work in this area2 . . .
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    • . . . In the past 30 years, during which drugs to block the RAS were successfully developed6, 7, 8, the importance of the RAS in the control of fluid balance, hypertension and cardiovascular disease has become clear. . . .
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    • . . . In the past 30 years, during which drugs to block the RAS were successfully developed6, 7, 8, the importance of the RAS in the control of fluid balance, hypertension and cardiovascular disease has become clear. . . .
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    • . . . Clinical intervention in the RAS was first achieved with the introduction of ACE inhibitors6, 9, developed in the 1970s and 1980s . . .
  10. Brunner, H. R. et al. Clinical experience with angiotensin II receptor antagonists. Am. J. Hypertens. 5, 243S-246S , (1992) .
    • . . . Then, in the 1990s, the angiotensin II receptor blockers (ARBs), which are specific for the AT1 receptor, were introduced10, 11 . . .
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    • . . . In the case of the ACE inhibitors, large increases in PRA and angiotensin I can be observed12, 13 . . .
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    • . . . Enzymes such as cathepsin G and elastase are thought to directly convert angiotensinogen to angiotensin II, and chymases and cathepsin G are thought to provide an alternative pathway for the conversion of angiotensin I to angiotensin II14, 15, 16 . . .
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    • . . . Enzymes such as cathepsin G and elastase are thought to directly convert angiotensinogen to angiotensin II, and chymases and cathepsin G are thought to provide an alternative pathway for the conversion of angiotensin I to angiotensin II14, 15, 16 . . .
  16. Yamada, M. et al. Mast cell chymase expression and mast cell phenotypes in human rejected kidneys. Kidney Int. 59, 1374-1381 , (2001) .
    • . . . Enzymes such as cathepsin G and elastase are thought to directly convert angiotensinogen to angiotensin II, and chymases and cathepsin G are thought to provide an alternative pathway for the conversion of angiotensin I to angiotensin II14, 15, 16 . . .
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    • . . . It has been suggested that owing to the existence of collateral or 'escape' pathways that are not mediated by ACE, angiotensin II can be produced and the effect of ACE inhibitors on BP decreases over time17, 18 . . .
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    • . . . It has been suggested that owing to the existence of collateral or 'escape' pathways that are not mediated by ACE, angiotensin II can be produced and the effect of ACE inhibitors on BP decreases over time17, 18 . . .
  19. Reinhardt, L. A., Wilkin, J. K. & Kirkendall, W. M. Lichenoid eruption produced by captopril. Cutis 31, 98-99 , (1983) .
    • . . . In addition, through inhibition of other pathways, administration of ACE inhibitors can cause dry cough or Angioedema, which can lead to a life-threatening constriction of the airways19, 20 . . .
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    • . . . In addition, through inhibition of other pathways, administration of ACE inhibitors can cause dry cough or Angioedema, which can lead to a life-threatening constriction of the airways19, 20 . . .
  21. Oparil, S. et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 370, 221-229.This study showed that even at the highest recommended doses of both aliskiren and valsartan there is an additive effect on BP control , (2007) .
  22. Di, P. P. et al. Does the addition of losartan improve the beneficial effects of ACE inhibitors in patients with anterior myocardial infarction? A pilot study. Heart 81, 606-611 , (1999) .
    • . . . With the ARBs, increases in PRA and in angiotensin II are observed21, 22 . . .
  23. Villamil, A. et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J. Hypertens. 25, 217-226 , (2007) .
    • . . . Diuretics, another effective class of antihypertensive agents, also enhance PRA23 . . .
    • . . . A large Phase III trial tested all combinations of 6.25, 12.5 or 25 mg of HCTZ with 75, 150 and 300 mg of aliskiren (with the exception of 300 mg of aliskiren with 6.25 mg of HCTZ) in 2,776 patients with mild-to-moderate hypertension23 . . .
  24. Alderman, M. H. et al. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N. Engl. J. Med. 324, 1098-1104 , (1991) .
    • . . . Increases in PRA have been associated with four- to six-times higher mortality rates due to heart attacks and accelerated renal failure24, 25. . . .
  25. Alderman, M. H. et al. Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am. J. Hypertens. 10, 1-8 , (1997) .
    • . . . Increases in PRA have been associated with four- to six-times higher mortality rates due to heart attacks and accelerated renal failure24, 25. . . .
  26. Sielecki, A. R. et al. Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 Å resolution. Science 243, 1346-1351 , (1989) .
    • . . . Renin is an aspartic protease that consists of two homologous lobes, with a cleft in between that contains the two active-site catalytic aspartic residues26 . . .
  27. Hobart, P. M., Fogliano, M., O'Conner, B. A., Schaefer, I. M. & Chirgwin, J. M. Human renin gene: structure and sequence analysis. Proc. Natl Acad. Sci. USA 81, 5026-5030 , (1984) .
    • . . . Renin is often described as 'active' renin to distinguish it from its inactive precursor, prorenin27 . . .
  28. Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417-1427 , (2002) .
    • . . . Prorenin can be activated at a low temperature and pH, as well as being activated by binding to the prorenin/renin receptor28, 29 . . .
    • . . . In human cultured mesangial cells, binding of renin to the receptor increases angiotensin I and induces intracellular signalling28 . . .
  29. Danser, A. H., Batenberg, W. W. & van Esch, J. H. Prorenin and the (pro)renin receptor - an update. Nephrol. Dial. Transplant. 22, 1288-1292 , (2007) .
    • . . . Prorenin can be activated at a low temperature and pH, as well as being activated by binding to the prorenin/renin receptor28, 29 . . .
    • . . . The role of the receptor is not yet clear, although it has been suggested that the receptor helps to localize the action of renin and prorenin to the cell surface29 . . .
    • . . . The role of prorenin and renin receptors in hypertension and organ damage29 remains speculative, and we anticipate that it will be one of the most active areas in RAS research in years to come . . .
  30. Ichihara, A. et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. J. Clin. Invest. 114, 1128-1135 , (2004) .
    • . . . Peptidic antagonists of the receptor 'handle region' or decoy peptides prevent receptor-mediated prorenin activation30, but in human renin animal models, the decoy peptides had no effect31. . . .
  31. Luft, F. C. Renin and its putative receptor remain enigmas. J. Am. Soc. Nephrol. 18, 1989-1992 , (2007) .
    • . . . Peptidic antagonists of the receptor 'handle region' or decoy peptides prevent receptor-mediated prorenin activation30, but in human renin animal models, the decoy peptides had no effect31. . . .
  32. Goschke, R. et al. Novel 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamide transition state peptidomimetics are potent and orally active inhibitors of human renin. J. Med. Chem. 50, 4818-4831 , (2007) .
  33. Maibaum, J. et al. Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent non-peptide human renin inhibitor active after once daily dosing in marmosets. J. Med. Chem. 50, 4832-4844.Description of extended structure-activity relationship exploration of topologically P3-P1-tethered transition-state mimetic renin inhibitors resulting in increased in vivo potency and improved oral bioavailability , (2007) .
  34. Szelke, M. et al. Potent new inhibitors of human renin. Nature 299, 555-557 , (1982) .
    • . . . The chemical development of renin inhibitors, leading to the discovery of aliskiren32, 33, can be divided into three generations of compounds (Fig. 3a): first, peptide analogues of angiotensinogen to block the enzymatic action of renin34; second, peptidomimetic compounds that were dipeptide transition-state analogue inhibitors of the active site35, 36, 37, 38; and third, non-peptide-like compounds, of which aliskiren is the most successful example39, 40 . . .
  35. Delabays, A. et al. Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans. Hypertension 13, 941-947 , (1989) .
    • . . . The chemical development of renin inhibitors, leading to the discovery of aliskiren32, 33, can be divided into three generations of compounds (Fig. 3a): first, peptide analogues of angiotensinogen to block the enzymatic action of renin34; second, peptidomimetic compounds that were dipeptide transition-state analogue inhibitors of the active site35, 36, 37, 38; and third, non-peptide-like compounds, of which aliskiren is the most successful example39, 40 . . .
    • . . . The second-generation compounds were potent (with activity in the nanomolar range) and, when administered by a parenteral route, lowered BP both in animals and humans35, 36, 37, 38 . . .
  36. Boger, R. S. et al. Prolonged duration of blood pressure response to enalkiren, the novel dipeptide renin inhibitor, in essential hypertension. Hypertension 15, 835-840 , (1990) .
    • . . . The chemical development of renin inhibitors, leading to the discovery of aliskiren32, 33, can be divided into three generations of compounds (Fig. 3a): first, peptide analogues of angiotensinogen to block the enzymatic action of renin34; second, peptidomimetic compounds that were dipeptide transition-state analogue inhibitors of the active site35, 36, 37, 38; and third, non-peptide-like compounds, of which aliskiren is the most successful example39, 40 . . .
  37. Clozel, J. P. & Fischli, W. Discovery of remikiren as the first orally active renin inhibitor. Arzneimittelforschung 43, 260-262 , (1993) .
    • . . . The chemical development of renin inhibitors, leading to the discovery of aliskiren32, 33, can be divided into three generations of compounds (Fig. 3a): first, peptide analogues of angiotensinogen to block the enzymatic action of renin34; second, peptidomimetic compounds that were dipeptide transition-state analogue inhibitors of the active site35, 36, 37, 38; and third, non-peptide-like compounds, of which aliskiren is the most successful example39, 40 . . .
  38. Himmelmann, A., Bergbrant, A., Svensson, A., Hansson, L. & Aurell, M. Remikiren (Ro 42-5892) - an orally active renin inhibitor in essential hypertension. Effects on blood pressure and the renin-angiotensin-aldosterone system. Am. J. Hypertens. 9, 517-522 , (1996) .
    • . . . The chemical development of renin inhibitors, leading to the discovery of aliskiren32, 33, can be divided into three generations of compounds (Fig. 3a): first, peptide analogues of angiotensinogen to block the enzymatic action of renin34; second, peptidomimetic compounds that were dipeptide transition-state analogue inhibitors of the active site35, 36, 37, 38; and third, non-peptide-like compounds, of which aliskiren is the most successful example39, 40 . . .
    • . . . Structural changes in the molecules to improve metabolic stability were successful, but oral bioavailability and the associated lowering of BP remained low38, 41 . . .
  39. Rahuel, J. et al. Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem. Biol. 7, 493-504.Description of crystal structure analysis of renin-inhibitor complexes and the interaction with the hitherto unrecognized large, distinct, sub-pocket S3sp of the enzyme, which is essential for high binding affinity , (2000) .
    • . . . The chemical development of renin inhibitors, leading to the discovery of aliskiren32, 33, can be divided into three generations of compounds (Fig. 3a): first, peptide analogues of angiotensinogen to block the enzymatic action of renin34; second, peptidomimetic compounds that were dipeptide transition-state analogue inhibitors of the active site35, 36, 37, 38; and third, non-peptide-like compounds, of which aliskiren is the most successful example39, 40 . . .
    • . . . Binding to this sub-pocket is essential for strong renin inhibition by aliskiren39, 40 . . .
  40. Wood, J. M. et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem. Biophys. Res. Commun. 308, 698-705.Description of the discovery of aliskiren using a combination of molecular modelling and crystallographic structure analysis , (2003) .
  41. Weber, C. et al. Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients. Br. J. Clin. Pharmacol. 36, 547-554 , (1993) .
    • . . . Structural changes in the molecules to improve metabolic stability were successful, but oral bioavailability and the associated lowering of BP remained low38, 41 . . .
    • . . . Their clinical use was limited not only by their lack of oral activity but also by their short duration of action41. . . .
  42. Davio, S. R., McShane, M. M., Kakuk, T. J., Zaya, R. M. & Cole, S. L. Precipitation of the renin inhibitor ditekiren upon i.v. infusion; in vitro studies and their relationship to in vivo precipitation in the cynomolgus monkey. Pharm. Res. 8, 80-83 , (1991) .
    • . . . Indeed, many of the early animal studies with aliskiren used primates, such as marmosets42, 43, 44, 45, which are much closer to man in their IC50 of aliskiren . . .
  43. Shibasaki, M., Usui, T., Inagaki, O., Asano, M. & Takenaka, T. Pharmacokinetics and cardiovascular effects of YM-21095, a novel renin inhibitor, in dogs and monkeys. J. Pharm. Pharmacol. 46, 68-72 , (1994) .
    • . . . Indeed, many of the early animal studies with aliskiren used primates, such as marmosets42, 43, 44, 45, which are much closer to man in their IC50 of aliskiren . . .
  44. Wood, J. M., Schnell, C. R., Cumin, F., Menard, J. & Webb, R. L. Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats. J. Hypertens. 23, 417-426.A thorough review of the preclinical research on aliskiren , (2005) .
    • . . . Indeed, many of the early animal studies with aliskiren used primates, such as marmosets42, 43, 44, 45, which are much closer to man in their IC50 of aliskiren . . .
    • . . . Aliskiren was first studied in sodium-depleted marmosets and in SHRs44 . . .
    • . . . In the sodium-depleted marmoset, oral administration of aliskiren led to a sustained decrease in BP, an increase in plasma renin concentration and a decrease in renin activity40, 44 . . .
    • . . . The decrease in BP was dose-dependent over a range of 1–30 mg per kg following oral administration44 . . .
    • . . . A single oral dose of 3 mg per kg of aliskiren was more powerful than equivalent doses of the renin inhibitors remikiren or zankiren, and 10 mg per kg doses of aliskiren were more potent than the ACE inhibitor benazepril or the ARB valsartan in lowering BP44. . . .
    • . . . Aliskiren was also shown to effectively lower BP in SHRs, although the doses needed were up to 10-times higher than those used in marmosets44, which reflects the differences in the in vitro inhibitory activity of human renin inhibitors between species (Fig. 3c) . . .
    • . . . Aliskiren lowered BP in a dose-dependent, long-acting and persistent manner during 14 days of once-a-day dosing, and combination of suboptimal doses of aliskiren with valsartan or benazepril potentiated the antihypertensive effects of both agents44. . . .
  45. Wood, J. M. et al. Evaluation of a potent inhibitor of subprimate and primate renins. J. Pharmacol. Exp. Ther. 253, 513-517 , (1990) .
    • . . . Indeed, many of the early animal studies with aliskiren used primates, such as marmosets42, 43, 44, 45, which are much closer to man in their IC50 of aliskiren . . .
  46. Ganten, D. et al. Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. Proc. Natl Acad. Sci. USA 89, 7806-7810 , (1992) .
    • . . . Recently, double transgenic rat models (dTGRs)46, which incorporate the human genes for angiotensinogen and renin, have been very useful in screening newer generations of renin inhibitors . . .
    • . . . Not only do these animals exhibit hypertension, but they also develop severe kidney and heart dysfunction when not treated with drugs that affect the RAS, and so they can be used to study end-organ protection46, 47. . . .
  47. Pilz, B. et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 46, 569-576 , (2005) .
    • . . . Not only do these animals exhibit hypertension, but they also develop severe kidney and heart dysfunction when not treated with drugs that affect the RAS, and so they can be used to study end-organ protection46, 47. . . .
    • . . . Subcutaneous administration of aliskiren for 14 days using an osmotic minipump decreased BP in a dose-dependent manner as well as proteinuria (a marker for kidney damage) and cardiac hypertrophy47 . . .
    • . . . However, whereas 100% of animals in the placebo-treated group died by the ninth week of the experiment and 26% survived in the valsartan-treated group, 100% of the rats survived in the aliskiren-treated group47 . . .
  48. Azizi, M. et al. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J. Am. Soc. Nephrol. 15, 3126-3133 , (2004) .
    • . . . A subsequent study confirmed these results at doses of 150 and 300 mg of aliskiren48 . . .
    • . . . However, these effects were measured at suboptimal doses of both valsartan (80 mg) and aliskiren (150 mg)48. . . .
  49. Stanton, A., Jensen, C., Mann, J., and O'Brien, E. Blood pressure lowering with SPP100, a novel orally active renin inhibitor. A pilot study. Hypertension 38, 526 , (2001) .
    • . . . The first proof of concept was obtained in patients with mild-to-moderate hypertension treated with 75 and 150 mg of aliskiren each (forced titration) for 14 days49 . . .
  50. Stanton, A., Jensen, C., Nussberger, J., and O'Brien, E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 42, 1137-1143.The first dose-finding study with aliskiren in patients using 24-hour ambulatory BP measurements , (2003) .
  51. Gradman, A. H. et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 111, 1012-1018 , (2005) .
  52. Chobanian, A. V. et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 289, 2560-2572 , (2003) .
    • . . . The treatment of hypertensive patients currently involves the use of several therapeutic approaches52, 53, 54 . . .
    • . . . Although the rate of hypertension-related morbidity has slowed in the past decade, the incidence of chronic heart failure and end-stage renal disease (ESRD) is now increasing52 . . .
  53. Williams, B. et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ 328, 634-640 , (2004) .
    • . . . The treatment of hypertensive patients currently involves the use of several therapeutic approaches52, 53, 54 . . .
  54. Erdine, S. et al. ESH-ESC guidelines for the management of hypertension. Herz 31, 331-338 , (2006) .
    • . . . The treatment of hypertensive patients currently involves the use of several therapeutic approaches52, 53, 54 . . .
  55. O'Brien, E. et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 49, 276-284 , (2007) .
  56. Uresin, Y. et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J. Renin Angiotensin Aldosterone Syst. 8, 190-198 , (2007) .
    • . . . A Phase III trial using ramipril confirmed these results and added some important observations on efficacy and adverse events in diabetic patients with mild-to-moderate hypertension56 . . .
    • . . . However, with combination therapy, the incidence of cough was also lower than with ramipril alone, suggesting an attenuation of ACE inhibitor-induced cough56. . . .
    • . . . Aliskiren monotherapy (300 mg) or aliskiren plus ramipril (300 mg and 10 mg, respectively) has been shown to be more effective than ramipril alone in controlling BP in hypertensive diabetic patients, particularly during the early morning BP surge 21 to 24 hours after the last dose56. . . .
  57. Drummond, W. et al. Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy. J. Clin. Hypertens. 9, 742-750 , (2007) .
    • . . . In a 6-week randomized, parallel group study, patients with mild-to-moderate hypertension treated with 5 mg of amlodipine for 4 weeks who still had 90 mm Hg or higher diastolic BP were randomized to either continue on 5 mg amlodipine, to receive double the dose of amlodipine (10 mg) or receive 150 mg of aliskiren together with 5 mg of amlodipine57 . . .
  58. Bramlage, P. et al. Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am. J. Hypertens. 17, 904-910 , (2004) .
    • . . . It has been estimated that nearly 75% of obese patients are hypertensive but that less than 20% of those are well controlled58 . . .
  59. Jordan, J., Engeli, S., Boye, S. W., Le, B. S. & Keefe, D. L. Direct renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension 49, 1047-1055 , (2007) .
    • . . . In a large multi-centred trial, 489 patients who were non-responders to a 4-week treatment with HCTZ were randomly assigned to double-blind, once-daily aliskiren (150 mg), irbesartan (150 mg), amlodipine (5 mg) or placebo in addition to continuing HCTZ (25 mg) once daily59 . . .
  60. Sekikawa, A. & Hayakawa, T. Prevalence of hypertension, its awareness and control in adult population in Japan. J. Hum. Hypertens. 18, 911-912 , (2004) .
    • . . . Hypertension affects almost 50% of the Japanese population60, 61, and in patients over 40 years old, less than half reach BP treatment targets62 . . .
  61. Hasegawa, T., Hori, Y., Sakamaki, H. & Suzuki, K. Meta-analysis on the therapeutic state of hypertensive population in Japan: focusing on the impact of new diagnostic criteria of Japanese Guideline for the Management of Hypertension 2000. J. Epidemiol. 12, 112-119 , (2002) .
    • . . . Hypertension affects almost 50% of the Japanese population60, 61, and in patients over 40 years old, less than half reach BP treatment targets62 . . .
  62. Hozawa, A. et al. Blood pressure control assessed by home, ambulatory and conventional blood pressure measurements in the Japanese general population: the Ohasama study. Hypertens. Res. 25, 57-63 , (2002) .
    • . . . Hypertension affects almost 50% of the Japanese population60, 61, and in patients over 40 years old, less than half reach BP treatment targets62 . . .
  63. Kushiro, T. et al. Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension. Hypertens. Res. 29, 997-1005 , (2006) .
    • . . . Aliskiren was shown to be as effective in the Japanese population as in the Caucasian population at doses of 75, 150 and 300 mg once-daily in 455 patients with mild-to-moderate hypertension63 . . .
  64. Vaidyanathan, S., Jermany, J., Yeh, C., Bizot, M. N. & Camisasca, R. Aliskiren, a novel orally effective renin inhibitor, exhibits similar pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects. Br. J. Clin. Pharmacol. 62, 690-698 , (2006) .
    • . . . The pharmacokinetic profile of aliskiren in Japanese subjects has also been reported to be similar to that of Caucasians when single oral doses of 300 mg were compared64. . . .
  65. Vaidyanathan, S. et al. Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects. J. Clin. Pharmacol. 47, 453-460 , (2007) .
    • . . . It has, however, been reported that plasma levels of aliskiren could be up to 30% higher in elderly patients following a single oral dose of 300 mg of aliskiren65 . . .
  66. Weir, M., Bush, C. & Zhang, J. Antihypertensive efficacy and safety of the oral renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Eur. Heart J. 27 (Suppl. 1), 299 , (2006) .
    • . . . Pooled data from seven clinical trials did not show a difference in adverse event profiles for elderly patients compared with younger patients66. . . .
  67. Waldmeier, F. et al. Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers. Drug Metab. Dispos. 35, 1418-1428 , (2007) .
    • . . . The pharmacokinetic profile of aliskiren has been examined in healthy subjects and in patients with hepatic and renal disease following single oral and intravenous doses67, 68, 69 . . .
    • . . . Aliskiren is absorbed rapidly following oral doses, with maximal plasma concentrations reached between 1 and 3 hours after dosing67 . . .
    • . . . Very little metabolism of aliskiren occurs; the parent compound represents more than 80% of the radioactivity in plasma67. . . .
  68. Vaidyanathan, S. et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment. Clin. Pharmacokinet. 46, 661-675 , (2007) .
    • . . . The pharmacokinetic profile of aliskiren has been examined in healthy subjects and in patients with hepatic and renal disease following single oral and intravenous doses67, 68, 69 . . .
    • . . . The steady-state pharmacokinetics of aliskiren have also been studied in patients with various degrees of renal insufficiency68 . . .
  69. Vaidyanathan, S. et al. Pharmacokinetics, safety, and tolerability of the oral renin inhibitor aliskiren in patients with hepatic impairment. J. Clin. Pharmacol. 47, 192-200 , (2007) .
    • . . . The pharmacokinetic profile of aliskiren has been examined in healthy subjects and in patients with hepatic and renal disease following single oral and intravenous doses67, 68, 69 . . .
    • . . . Following a single oral 300 mg dose of aliskiren, the elimination pharmacokinetics were similar in patients with hepatic disease compared with matched healthy subjects, as measured by the area under the measured concentration curve (AUC)69 . . .
  70. Zhao, C., Vaidyanathan, S., Yeh, C. M., Maboudian, M. & Armin, D. H. Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with type 2 diabetes mellitus. Clin. Pharmacokinet. 45, 1125-1134 , (2006) .
    • . . . Aliskiren exhibited similar pharmacokinetics in patients with type 2 diabetes and in healthy volunteers70 . . .
  71. European Medicines Agency (EMEA). Rasilez: European Public Assessment Report. EMEA web site [online], , (2007) .
    • . . . Preclinical safety pharmacology studies with aliskiren revealed no significant effects on the central nervous system, cardiovascular, respiratory or renal systems in animal models71 . . .
    • . . . For the European Medicines Agency (EMEA) submission71, clinical safety assessment was based on observations obtained in a total of 11,566 treated patients . . .
    • . . . As aliskiren does not interact with the cytochrome P450 system71, 78, it is unlikely that aliskiren would have significant interactions with agents that are metabolized by this system. . . .
    • . . . Aliskiren has no known clinically relevant interactions with commonly used medicinal products for the treatment of hypertension or diabetes71 . . .
    • . . . The EMEA has concluded that no dose adjustments for aliskiren or these co-administered medicinal products are necessary71. . . .
  72. Textor, S. C., Bravo, E. L., Fouad, F. M. & Tarazi, R. C. Hyperkalemia in azotemic patients during angiotensin-converting enzyme inhibition and aldosterone reduction with captopril. Am. J. Med. 73, 719-725 , (1982) .
    • . . . Mild increases in potassium are expected with agents that block the RAS (including ACE inhibitors and ARBs) by multiple mechanisms, including sudden changes in both glomerular filtration rate and aldosterone secretion72, 73. . . .
  73. Kostis, J. B. et al. Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators. Am. Heart J. 131, 350-355 , (1996) .
    • . . . Mild increases in potassium are expected with agents that block the RAS (including ACE inhibitors and ARBs) by multiple mechanisms, including sudden changes in both glomerular filtration rate and aldosterone secretion72, 73. . . .
  74. Sealey, J. E. & Laragh, J. H. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am. J. Hypertens. 20, 587-597 , (2007) .
    • . . . It has been speculated that increases in renin could result in hypertensive episodes or limit the efficacy of aliskiren74 . . .
  75. Pool, J. L. et al. Aliskiren, a novel renin inhibitor, provides long-term suppression of the renin system, when used alone or in combination with hydrochlorothiazide in the treatment of hypertension. Eur. Heart J. 27 (Suppl. 1), 119 , (2006) .
    • . . . However, long-term studies have shown that the BP-lowering effects are constant over a 12-month period75 . . .
  76. Weinberger, M. H. et al. Aliskiren-based therapy provides long-term suppression of plasma renin activity that persists after treatment withdrawal in patients with hypertension. J. Am. Coll. Cardiol. 49, 390A , (2007) .
    • . . . In addition, the initial increase in plasma renin concentration due to RAS inhibition was also steady over the same period of treatment76 . . .
  77. Keefe, D. L. et al. Blood pressure lowering effects persist following the last dose of long-term therapy with aliskiren: an oral direct renin inhibitor. J. Am. Coll. Cardiol. 49, 372A , (2007) .
    • . . . Indeed, upon cessation of treatment with aliskiren, the BP-lowering effect persists for at least 2 weeks and there is no rebound effect due to increased plasma renin concentrations77. . . .
  78. Vaidyanathan, S. Aliskiren, a novel oral renin inhibitor, has no interaction with cytochrome P450 isoenzymes in vitro. Basic Res. Pharmacol. Toxicol. 97, 239-239 , (2005) .
    • . . . As aliskiren does not interact with the cytochrome P450 system71, 78, it is unlikely that aliskiren would have significant interactions with agents that are metabolized by this system. . . .
  79. Zhao, C. et al. Assessment of the pharmacokinetic interaction between the oral direct inhibitor aliskiren and furosemide: a study in healthy volunteers. Clin. Pharmacol. Ther. 81 (Suppl. 1) S110 , (2007) .
    • . . . Co-administration with furosemide led to a 30% decrease in furosemide AUC and a 50% decrease in Cmax in healthy subjects following single doses79; however, in clinical trials there was no adjustment of furosemide dose when the two drugs were administered together . . .
  80. Vaidyanathan, S. et al. Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers. Int. J. Clin. Pract. 60, 1343-1356 , (2006) .
    • . . . Co-administration of aliskiren with either valsartan, metformin, amlodipine or cimetidine resulted in a 20–30% change in Cmax or AUC of aliskiren80 . . .
    • . . . Co-administration of aliskiren had no significant effect on atorvastatin, valsartan, metformin or amlodipine pharmacokinetics80 . . .
  81. Azizi, M. & Menard, J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 109, 2492-2499 , (2004) .
    • . . . Although some improvements in clinical outcome have been reported with dual blockade, there is still room for further improvement81, 82. . . .
  82. Muller, D. N. & Luft, F. C. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin. J. Am. Soc. Nephrol. 1, 221-228 , (2006) .
    • . . . Although some improvements in clinical outcome have been reported with dual blockade, there is still room for further improvement81, 82. . . .
  83. Mervaala, E. et al. Angiotensin-converting enzyme inhibition and AT1 receptor blockade modify the pressure-natriuresis relationship by additive mechanisms in rats with human renin and angiotensinogen genes. J. Am. Soc. Nephrol. 10, 1669-1680 , (1999) .
    • . . . Experiments in dTGRs, which develop kidney and heart damage due to an overactivated and non-responsive human renin system, have demonstrated that treatment with ACE inhibitors or ARBs can provide considerable organ protection83 . . .
  84. Mervaala, E. et al. Blood pressure-independent effects in rats with human renin and angiotensinogen genes. Hypertension 35, 587-594 , (2000) .
    • . . . This protective effect is independent of BP changes84 . . .
  85. Shagdarsuren, E. et al. Complement activation in angiotensin II-induced organ damage. Circ. Res. 97, 716-724 , (2005) .
    • . . . Another experiment showed that aliskiren ameliorates complement activation of C3c and C5b–9, with improvements in target-organ damage85. . . .
  86. Fisher, N. D. & Hollenberg, N. K. Unprecedented renal response to direct bloackade of the renin-angiotensin system with aliskiren, a novel renin inhibitor. Circulation 116 (Suppl. 2) 556 , (2007) .
    • . . . In healthy human subjects, dose-dependent increases in renal plasma flow following single-dose treatment with 75, 150 and 300 mg of aliskiren have been reported86 . . .
  87. Kjeldsen, S. E. Direct renin inhibition with focus on aliskiren and cardiovascular outcome studies. Eur. Cardiovasc. Dis. 2, 17-19 , (2006) .
    • . . . Clinical trials with aliskiren have been initiated to study primary and secondary prevention in more than 20,000 subjects with both cardiovascular and renal risk87 . . .
  88. Recio-Mayoral, A. et al. Clinical trials update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY. Cardiovasc. Drugs Ther. 21, 1573-7241 , (2007) .
    • . . . ALOFT was designed to assess the safety of adding 150 mg aliskiren to standard therapy in hypertensive patients with stable heart failure88, 89, 90 . . .
  89. Recion-Mayoral, A. et al. Clinical trials update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY. Cardiovasc. Drugs Ther. 21, 459-465 , (2007) .
    • . . . ALOFT was designed to assess the safety of adding 150 mg aliskiren to standard therapy in hypertensive patients with stable heart failure88, 89, 90 . . .
  90. Pitt, B. et al. Neurohormonal effects of a new oral direct renin inhibitor in stable heart failure: the alisikiren observation of heart failure treatment study (ALOFT). Circulation 116 (Suppl. 2), 549 , (2007) .
    • . . . ALOFT was designed to assess the safety of adding 150 mg aliskiren to standard therapy in hypertensive patients with stable heart failure88, 89, 90 . . .
  91. Parving, H. H., Lewis, J. B., Lewis, E. J. & Hollenberg, N. K. Aliskiren in the evaluation of proteinuria in diabetes (AVOID). Renal Week October 31-November 5; Abstract SA-PO1051. American Society of Nephrology web site [online], , (2007) .
  92. Persson, F., Rossing, P., Schjoedt, K. J., Stehouwer, C. D. & Parving, H. H. Time course of the antiproteinuric and antihypertensive effect of direct renin inhibition with aliskiren in patients with type 2 diabetes and albuminuria. Circulation 116 (Suppl.), PS112 , (2007) .
    • . . . The effect of aliskiren on decreasing albuminuria was observed within 3 days and reached a maximal effect within 28 days of treatment with doses of 300 mg once-daily92. . . .
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