Journal of Renin-Angiotensin-Aldosterone System http://jra.sagepub.com/ New drug therapies interfering with the renin−angiotensin−aldosterone system for resistant hypertension Matthieu Monge, Aurélien Lorthioir, Guillaume Bobrie and Michel Azizi Journal of Renin-Angiotensin-Aldosterone System 2013 14: 285 originally published online 12 November 2013 DOI: 10.1177/1470320313513408 The online version of this article can be found at: http://jra.sagepub.com/content/14/4/285
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JRA14410.1177/1470320313513408Journal of the Renin-Angiotensin-Aldosterone SystemMonge et al.
Renin Update
New drug therapies interfering with the renin–angiotensin–aldosterone system for resistant hypertension
Journal of the Renin-AngiotensinAldosterone System 14(4) 285–289 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320313513408 jra.sagepub.com
Matthieu Monge1,2, Aurélien Lorthioir1, Guillaume Bobrie1 and Michel Azizi1,2,3 Abstract There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension. Keywords New drug, resistant hypertension, Renin angiotensin system
Introduction Despite prescription of several appropriate antihypertensive drugs at adequate doses, including spironolactone, thus strictly following guidelines,1 the control of blood pressure (BP) is still not achievable in a significant proportion of hypertensive patients. Although non-adherence to complex therapeutic regimens remains a major issue contributing to the resistance to treatment,2,3 it is probable that (1) all the pathophysiological mechanisms implicated in resistant hypertension are not fully neutralized by the various class of antihypertensive treatments currently available, and (2) the counter-regulatory mechanisms triggered by the same treatments may also overcome their BP-lowering effect to a certain extent. Thus, there is still a need for the development of new antihypertensive drugs based on new concepts.4,5 However, the difficult conception, birth and delivery of aliskiren, a renin inhibitor, illustrates how complicated it is to bring to the market a new class of antihypertensive drug, to evaluate its safety in the long term and to define those patients who would benefit best from the therapeutic approach.6 Since the FDA/EMA
approval in 2007 of aliskiren, which remains to date the only orally active renin inhibitor available, no other new antihypertensives based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons.4,5 For example, dual neprilysin–angiotensin converting enzyme inhibition was a logical combination from a pharmacological point of view, working by mutually reinforcing the effects of vasodilatory and natriuretic peptides (ANP and bradykinin) and decreasing the effects 1Assistance
Publique – Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France 2Inserm, Clinical Investigation Centre 9201, Paris, France 3Université Paris-Descartes, Paris, France Corresponding author: Michel Azizi, Clinical Investigation Centre and Hypertension Unit, Hôpital Européen Georges Pompidou, 20-40, rue Leblanc, 75015 Paris, France. Email: [email protected]
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of vasoconstrictor and anti-natriuretic peptide (angiotensin II).7,8 Indeed, the first representative of this class, omapatrilat, had a BP-lowering effect that would have been effective to treat patients with resistant hypertension.8 However, the benefit/risk balance of this class of drugs was unfavourable.8 Indeed, their use was associated with a marked increased risk of angioedema,9 especially in black patients, in response to a synergistic inhibition of the breakdown of bradykinin and, to a lesser extent, of substance P and neurokinin.10 Blocking the endothelin 1 (ET1) pathway was also a rational approach to treating patients with resistant hypertension, taking into account the pathophysiological role of ET1 through its ETA and ETB receptors in regulating vasoconstrictor tone and inflammation.11 The dual ETA/ETB antagonist, darusentan, was indeed more effective than placebo12,13 in decreasing BP in patients with resistant hypertension, but at the cost of fluid retention, oedema, and cardiac events.12 Its development was therefore stopped. Despite these difficulties the pipeline is not dry, and different new antihypertensive strategies targeting the renin– angiotensin–aldosterone system (RAAS), the endothelin or the natriuretic peptides pathways are still are in preclinical or early clinical development stage. This review will focus on the drugs which are still in the clinical phase.
Dual angiotensin receptor– neprilysin inhibitors The pathophysiological and pharmacological rationale for the use of dual angiotensin receptor–neprilysin inhibitors (ARNIs) in hypertension is the same as that for vasopeptidase inhibitors. However, this approach theoretically conveys a much smaller risk of angioedema. Indeed, dual ARNIs do not inhibit enzymes implicated in bradykinin breakdown other than neprilysin.10 The prototype of these drugs is LCZ696, a single molecule synthesized by co-crystallisation of a well-known angiotensin II antagonist, valsartan, and the neprilysin inhibitor prodrug AHU377 (1:1 molar ratio).14 The 8-week administration of LCZ696 decreased BP dosedependently more than placebo, AHU377 given alone or valsartan given alone in patients with stage 1–2 hypertension.15 LCZ696 had a placebo-like tolerance profile and induced the expected changes in plasma hormonal profiles confirming both the blockade of AT1 receptors (increase in plasma renin concentration) and neprilysin inhibition (increase in plasma ANP and cGMP concentrations).15 LCZ696 is still in development for treatment of resistant hypertension and for heart failure.
Dual neprilysin–endothelinconverting enzyme inhibitors Daglutril is the first-in-class dual neprilysin–endothelinconverting enzyme inhibitor which has entered the clinical
phase.16 The rationale for using such a drug is to inhibit neprilysin, which is implicated in the breakdown of ANP and bradykinin – two vasodilatory and natriuretic peptides – and to inhibit endothelin-converting enzyme, which is implicated in the conversion of Big-ET1 in the active vasoconstrictor and anti-natriuretic peptide, ET1.16 A second potential advantage of this combination is that the simultaneous inhibition of the two enzymes could overcome the counter-regulatory mechanisms triggered by the inhibition of each single enzyme, including ET1 accumulation due to neprilysin inhibition alone.17 Following oral administration, daglutril is hydrolysed to its active metabolite,18 inhibits systemic conversion of Big-ET1 and increases plasma ANP in humans.16 Eight-day administration of daglutril was shown to decrease BP in patients with type 2 diabetic nephropathy but not albuminuria in a small randomized, crossover, double-blind, placebo-controlled trial.19 Of note, this trial was published in 2013, and the patients were included from 2005 to 2006, and no other data concerning this molecule are available to date.
New ways to target the aldosterone pathway: aldosterone synthase inhibitors and the third and fourth-generation nonsteroidal dihydropyridine-based mineralocorticoid receptor blockers There is now a body of evidence to suggest that blocking the mineralocorticoid receptor (MR), and hence the multiple noxious effects of aldosterone in the kidney, vessels and heart,20 is one of the most effective ways of reducing BP in patients with resistant hypertension; indeed, this approach is now recommended by international guidelines.1,21 There are multiple pathophysiological reasons for this efficacy.22-24 Blockade of the biological effects of aldosterone has mostly been achieved with two MR antagonists, spironolactone and eplerenone.20,25 Eplerenone is a short-acting MR antagonist that is less potent than spironolactone.25-27 Eplerenone has the advantage of being more selective than spironolactone for the MR. It does not interfere with progesterone or androgen receptors at the marketed doses (50–100 mg) and, therefore, does not have the sexual side effects of spironolactone, such as impotence, gynaecomastia, breast tenderness and menstrual irregularities.25 However, eplerenone has not been approved for use in the treatment of hypertension in many European countries. New potent aldosterone synthase inhibitors28 and dihydropyridine-based third- and fourth-generation MR antagonists29,30 are currently being tested as new pharmacological entities for antagonizing the effects of aldosterone. Aldosterone synthase (CYP11B2) inhibition aims at decreasing aldosterone concentrations in both plasma and tissues, and consequently at reducing MR-dependent and
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Monge et al. -independent effects at the level of the renal epithelial cells and cardiac, vascular and renal target organs. LCI699 is the first orally active aldosterone synthase inhibitor used in hypertensive patients. In a proof-of-concept study in patients with primary aldosteronism,31 LCI699 (0.5–1 mg b.i.d.) induced a dose-dependent and reversible suppression of plasma and urinary aldosterone concentration by approximately 70–80% associated with a massive dose-dependent accumulation of plasma deoxycorticosterone (>700%), the aldosterone precursor, thus confirming inhibition of the CYP11B2 gene product. This effect was associated with a rapid correction of hypokalaemia and a modest BP-lowering effect, that were both less than that obtained with eplerenone 100 mg b.i.d.32 An 8-week placebo-controlled dose– response study in patients with stage 1 and 2 essential hypertension reported an optimal decrease in BP with a dose of 1 mg LCI699 o.d., which had an antihypertensive effect similar to that of eplerenone 50 mg b.i.d.33 However, LCI699 administration was associated with biological signs of partial inhibition of the glucocorticoid axis, as shown by the dose-related increase in both plasma ACTH and in 11-deoxycortisol concentrations, the cortisol precursor, consistent with an inhibition of the CYP11B1 gene product.31 Nevertheless, the clinical and biological safety and tolerability of LCI699 were similar to those of placebo and eplerenone.33 The effects of LCI699 on the glucocorticoid axis limit the use of higher doses in hypertension because of the loss of selectivity for CYP11B2. Therefore, this aldosterone synthase inhibitor will not be able to replace MR blockade in patients with hypertension, but is now being evaluated at much higher doses in Cushing syndrome. The development of second-generation aldosterone synthase inhibitors with higher selectivity index towards CYP11B2 as compared with LCI699 will offer the possibility to test this approach at much higher doses, after the necessary toxicology and phase I studies. Non-steroidal dihydropyridine-based third- and fourthgeneration potent MR antagonists29,30 have also emerged as new drugs to selectively block the MR, displaying a similar potency as spironolactone towards the MR in vitro and thus having a greater potency than eplerenone, without interfering with the progesterone and androgen receptor, unlike spironolactone. The first-in-class of this new generation of MR blockers is BAY94-8862,29 which is currently in development for treatment of heart failure. The safety, tolerability and efficacy of 4–7-week treatment with BAY94-8862 (2.5 mg q.d., 5 mg q.d., 10 mg q.d. and 5 mg b.i.d.) has been compared with placebo or spironolactone (25–50 mg) in patients with heart failure and mild to moderate renal failure (estimated glomerular filtration rate: 30–90 ml/min/ 1.73 m2).34 BAY 94-8862 dose-dependently increased serum potassium concentration, but to a lesser extent than spironolactone, and thus was associated with a lower incidence of hyperkalaemia in this much-selected and highly monitored population of patients.34 It was as effective as spironolactone in decreasing B-type natriuretic peptide
(BNP) and amino-terminal proBNP. Adverse events were infrequent and mild.34 Such potent MR blockers could have a logical place in the armamentarium to treat patients with resistant hypertension. It should be kept in mind that the two abovementioned approaches are likely to entail the same risk of adverse events as the first generation of steroidal MR antagonists, including electrolyte disorders, hypotension, renal insufficiency and severe hypoaldosteronism, depending on residual aldosterone production, initial renal, dehydration, general anaesthesia, comorbidities (diabetes mellitus), and coprescriptions (COX inhibitors, RAS blockers, heparin, trimethoprim-sulfamethoxazole etc.).
Centrally acting aminopeptidase A inhibitors Brain renin angiotensin system (RAS) hyperactivity is implicated in the development and the maintenance of hypertension in several animal models.35 Aminopeptidase A (APA; EC3.4.11.7) and aminopeptidase N (APN; EC3.4.11.2) are both involved in the metabolism of angiotensin II and angiotensin III, respectively, in the brain.36 Angiotensin III has been shown to be one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control of BP.36 The new APA inhibitor, EC33, inhibits human, rat and mice APA in vitro with a Ki≈300 nM.37 It aims at blocking brain angiotensin III formation, and thus its biological effects. An orally active prodrug of EC33 obtained by disulfide bridge-mediated dimerization (RB150/QGC001) has been generated because EC33 does not cross the blood–brain barrier.38 In DOCA-salt rats, intravenous or oral QGC001 blocks brain angiotensin III formation, and decreases BP and plasma vasopressin levels.38 The antihypertensive effect of QGC001 was also demonstrated in spontaneously hypertensive rats.39 The first-in-class APA inhibitor QGC001 has entered the clinical development phase. When administered to healthy subjects, a single oral dose of QGC001 up to 1250 mg was safe. It did not lower BP in normotensive subjects and did not significantly change plasma renin activity, the concentrations of plasma and urine aldosterone, cortisol, and plasma copeptin levels compared with placebo. Clinical development is ongoing. In conclusion, progress is still needed to further reduce the residual burden of cardiovascular risks, within two new constraints of a quite different nature: safety and accessibility to all. In this context, new chemical entities are being developed for hypertension, type 2 diabetes and heart failure. However, it will take a long time to evaluate extensively the efficacy and safety of these new approaches. In the meantime, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension.
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Conflict of interest None declared. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References 1. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31: 1281–1357. 2. Burnier M, Wuerzner G, Struijker-Boudier H, et al. Measuring, analyzing, and managing drug adherence in resistant hypertension. Hypertension 2013; 62: 218–225. 3. Jung O, Gechter JL, Wunder C, et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens 2013; 31: 766–774. 4. Paulis L, Steckelings UM and Unger T. Key advances in antihypertensive treatment. Nat Rev Cardiol 2012; 9: 276–285. 5. Laurent S, Schlaich M and Esler M. New drugs, procedures, and devices for hypertension. Lancet 2012; 380: 591–600. 6. Azizi M and Menard J. Renin inhibitors and cardiovascular and renal protection: An endless quest? Cardiovasc Drugs Ther 2013; 27: 145–153. 7. Azizi M, Lamarre-Cliche M, Labatide-Alanore A, et al. Physiologic consequences of vasopeptidase inhibition in humans: Effect of sodium intake. J Am Soc Nephrol 2002; 13: 2454–2463. 8. Campbell DJ. Vasopeptidase inhibition: A double-edged sword? Hypertension 2003; 41: 383–389. 9. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004; 17: 103–111. 10. Sulpizio AC, Pullen MA, Edwards RM, et al. Mechanism of vasopeptidase inhibitor-induced plasma extravasation: Comparison of omapatrilat and the novel neutral endopeptidase 24.11/angiotensin-converting enzyme inhibitor GW796406. J Pharmacol Exp Ther 2005; 315: 1306–1313. 11. Dhaun N, Goddard J, Kohan DE, et al. Role of endothelin-1 in clinical hypertension: 20 years on. Hypertension 2008; 52: 452–459. 12. Weber MA, Black H, Bakris G, et al. A selective endothelinreceptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: A randomised, doubleblind, placebo-controlled trial. Lancet 2009; 374: 1423–1431. 13. Bakris GL, Lindholm LH, Black HR, et al. Divergent results using clinic and ambulatory blood pressures: Report of a darusentan-resistant hypertension trial. Hypertension 2010; 56: 824–830. 14. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010; 50: 401–414.
15. Ruilope LM, Dukat A, Bohm M, et al. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: A randomised, double-blind, placebo-controlled, active comparator study. Lancet 2010; 375: 1255–1266. 16. Seed A, Kuc RE, Maguire JJ, et al. The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans. Life Sci 2012; 91: 743–748. 17. Ferro CJ, Spratt JC, Haynes WG, et al. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Circulation 1998; 97: 2323–2330. 18. Dickstein K, De Voogd HJ, Miric MP, et al. Effect of single doses of SLV306, an inhibitor of both neutral endopeptidase and endothelin-converting enzyme, on pulmonary pressures in congestive heart failure. Am J Cardiol 2004; 94: 237–239. 19. Parvanova A, van der Meer IM, Iliev I, et al. Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: A randomised, crossover, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2013;Early Online Publication, 13 June 2013 doi: 10.1016/S2213–8587(13)70029–9. 20. Jansen PM, Danser AH, Imholz BP, et al. Aldosterone receptor antagonism in hypertension. J Hypertens 2009; 27: 680–691. 21. Calhoun DA and White WB. Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension. J Am Soc Hypertens 2008; 2: 462–468. 22. Brown NJ. Aldosterone and end-organ damage. Curr Opin Nephrol Hypertens 2005; 14: 235–241. 23. Connell JM, MacKenzie SM, Freel EM, et al. A lifetime of aldosterone excess: Long-term consequences of altered regulation of aldosterone production for cardiovascular function. Endocr Rev 2008; 29: 133–154. 24. Funder JW and Mihailidou AS. Aldosterone and mineralocorticoid receptors: Clinical studies and basic biology. Mol Cell Endocrinol 2009; 301: 2–6. 25. Menard J. The 45-year story of the development of an antialdosterone more specific than spironolactone. Mol Cell Endocrinol 2004; 217: 45–52. 26. Weinberger MH, Roniker B, Krause SL, et al. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 2002; 15: 709–716. 27. Parthasarathy HK, Menard J, White WB, et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens 2011; 29: 980–990. 28. Azizi M, Amar L and Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant 2013; 28: 36–43. 29. Barfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94–8862: A nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem 2012; 7: 1385–1403. 30. Fagart J, Hillisch A, Huyet J, et al. A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule. J Biol Chem 2010; 285: 29932–29940.
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Monge et al. 31. Amar L, Azizi M, Menard J, et al. Aldosterone synthase inhibition with LCI699: A proof-of-concept study in patients with primary aldosteronism. Hypertension 2010; 56: 831–838. 32. Amar L, Azizi M, Menard J, et al. Sequential comparison of aldosterone synthase inhibition and mineralocorticoid blockade in patients with primary aldosteronism. J Hypertens 2013; 31: 624–629; discussion 9. 33. Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and activecontrolled phase 2 trial. Circulation 2011; 124: 1945–1955. 34. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94–8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: A randomized, doubleblind trial. Eur Heart J 2013; 34: 2453–2463.
35. Zini S, Masdehors P, Lenkei Z, et al. Aminopeptidase A: Distribution in rat brain nuclei and increased activity in spontaneously hypertensive rats. Neuroscience 1997; 78: 1187–1193. 36. Reaux A, Fournie-Zaluski MC, David C, et al. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci U S A 1999; 96: 13415–13420. 37. de Mota N, Iturrioz X, Claperon C, et al. Human brain aminopeptidase A: Biochemical properties and distribution in brain nuclei. J Neurochem 2008; 106: 416–428. 38. Bodineau L, Frugiere A, Marc Y, et al. Orally active aminopeptidase A inhibitors reduce blood pressure: A new strategy for treating hypertension. Hypertension 2008; 51: 1318–1325. 39. Bodineau L, Frugiere A, Marc Y, et al. Aminopeptidase A inhibitors as centrally acting antihypertensive agents. Heart Fail Rev 2008; 13: 311–319.
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513408 2013
JRA14410.1177/1470320313513408Journal of the Renin-Angiotensin-Aldosterone SystemMonge et al.
Renin Update
New drug therapies interfering with the renin–angiotensin–aldosterone system for resistant hypertension
Journal of the Renin-AngiotensinAldosterone System 14(4) 285–289 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320313513408 jra.sagepub.com
Matthieu Monge1,2, Aurélien Lorthioir1, Guillaume Bobrie1 and Michel Azizi1,2,3 Abstract There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension. Keywords New drug, resistant hypertension, Renin angiotensin system
Introduction Despite prescription of several appropriate antihypertensive drugs at adequate doses, including spironolactone, thus strictly following guidelines,1 the control of blood pressure (BP) is still not achievable in a significant proportion of hypertensive patients. Although non-adherence to complex therapeutic regimens remains a major issue contributing to the resistance to treatment,2,3 it is probable that (1) all the pathophysiological mechanisms implicated in resistant hypertension are not fully neutralized by the various class of antihypertensive treatments currently available, and (2) the counter-regulatory mechanisms triggered by the same treatments may also overcome their BP-lowering effect to a certain extent. Thus, there is still a need for the development of new antihypertensive drugs based on new concepts.4,5 However, the difficult conception, birth and delivery of aliskiren, a renin inhibitor, illustrates how complicated it is to bring to the market a new class of antihypertensive drug, to evaluate its safety in the long term and to define those patients who would benefit best from the therapeutic approach.6 Since the FDA/EMA
approval in 2007 of aliskiren, which remains to date the only orally active renin inhibitor available, no other new antihypertensives based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons.4,5 For example, dual neprilysin–angiotensin converting enzyme inhibition was a logical combination from a pharmacological point of view, working by mutually reinforcing the effects of vasodilatory and natriuretic peptides (ANP and bradykinin) and decreasing the effects 1Assistance
Publique – Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France 2Inserm, Clinical Investigation Centre 9201, Paris, France 3Université Paris-Descartes, Paris, France Corresponding author: Michel Azizi, Clinical Investigation Centre and Hypertension Unit, Hôpital Européen Georges Pompidou, 20-40, rue Leblanc, 75015 Paris, France. Email: [email protected]
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of vasoconstrictor and anti-natriuretic peptide (angiotensin II).7,8 Indeed, the first representative of this class, omapatrilat, had a BP-lowering effect that would have been effective to treat patients with resistant hypertension.8 However, the benefit/risk balance of this class of drugs was unfavourable.8 Indeed, their use was associated with a marked increased risk of angioedema,9 especially in black patients, in response to a synergistic inhibition of the breakdown of bradykinin and, to a lesser extent, of substance P and neurokinin.10 Blocking the endothelin 1 (ET1) pathway was also a rational approach to treating patients with resistant hypertension, taking into account the pathophysiological role of ET1 through its ETA and ETB receptors in regulating vasoconstrictor tone and inflammation.11 The dual ETA/ETB antagonist, darusentan, was indeed more effective than placebo12,13 in decreasing BP in patients with resistant hypertension, but at the cost of fluid retention, oedema, and cardiac events.12 Its development was therefore stopped. Despite these difficulties the pipeline is not dry, and different new antihypertensive strategies targeting the renin– angiotensin–aldosterone system (RAAS), the endothelin or the natriuretic peptides pathways are still are in preclinical or early clinical development stage. This review will focus on the drugs which are still in the clinical phase.
Dual angiotensin receptor– neprilysin inhibitors The pathophysiological and pharmacological rationale for the use of dual angiotensin receptor–neprilysin inhibitors (ARNIs) in hypertension is the same as that for vasopeptidase inhibitors. However, this approach theoretically conveys a much smaller risk of angioedema. Indeed, dual ARNIs do not inhibit enzymes implicated in bradykinin breakdown other than neprilysin.10 The prototype of these drugs is LCZ696, a single molecule synthesized by co-crystallisation of a well-known angiotensin II antagonist, valsartan, and the neprilysin inhibitor prodrug AHU377 (1:1 molar ratio).14 The 8-week administration of LCZ696 decreased BP dosedependently more than placebo, AHU377 given alone or valsartan given alone in patients with stage 1–2 hypertension.15 LCZ696 had a placebo-like tolerance profile and induced the expected changes in plasma hormonal profiles confirming both the blockade of AT1 receptors (increase in plasma renin concentration) and neprilysin inhibition (increase in plasma ANP and cGMP concentrations).15 LCZ696 is still in development for treatment of resistant hypertension and for heart failure.
Dual neprilysin–endothelinconverting enzyme inhibitors Daglutril is the first-in-class dual neprilysin–endothelinconverting enzyme inhibitor which has entered the clinical
phase.16 The rationale for using such a drug is to inhibit neprilysin, which is implicated in the breakdown of ANP and bradykinin – two vasodilatory and natriuretic peptides – and to inhibit endothelin-converting enzyme, which is implicated in the conversion of Big-ET1 in the active vasoconstrictor and anti-natriuretic peptide, ET1.16 A second potential advantage of this combination is that the simultaneous inhibition of the two enzymes could overcome the counter-regulatory mechanisms triggered by the inhibition of each single enzyme, including ET1 accumulation due to neprilysin inhibition alone.17 Following oral administration, daglutril is hydrolysed to its active metabolite,18 inhibits systemic conversion of Big-ET1 and increases plasma ANP in humans.16 Eight-day administration of daglutril was shown to decrease BP in patients with type 2 diabetic nephropathy but not albuminuria in a small randomized, crossover, double-blind, placebo-controlled trial.19 Of note, this trial was published in 2013, and the patients were included from 2005 to 2006, and no other data concerning this molecule are available to date.
New ways to target the aldosterone pathway: aldosterone synthase inhibitors and the third and fourth-generation nonsteroidal dihydropyridine-based mineralocorticoid receptor blockers There is now a body of evidence to suggest that blocking the mineralocorticoid receptor (MR), and hence the multiple noxious effects of aldosterone in the kidney, vessels and heart,20 is one of the most effective ways of reducing BP in patients with resistant hypertension; indeed, this approach is now recommended by international guidelines.1,21 There are multiple pathophysiological reasons for this efficacy.22-24 Blockade of the biological effects of aldosterone has mostly been achieved with two MR antagonists, spironolactone and eplerenone.20,25 Eplerenone is a short-acting MR antagonist that is less potent than spironolactone.25-27 Eplerenone has the advantage of being more selective than spironolactone for the MR. It does not interfere with progesterone or androgen receptors at the marketed doses (50–100 mg) and, therefore, does not have the sexual side effects of spironolactone, such as impotence, gynaecomastia, breast tenderness and menstrual irregularities.25 However, eplerenone has not been approved for use in the treatment of hypertension in many European countries. New potent aldosterone synthase inhibitors28 and dihydropyridine-based third- and fourth-generation MR antagonists29,30 are currently being tested as new pharmacological entities for antagonizing the effects of aldosterone. Aldosterone synthase (CYP11B2) inhibition aims at decreasing aldosterone concentrations in both plasma and tissues, and consequently at reducing MR-dependent and
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Monge et al. -independent effects at the level of the renal epithelial cells and cardiac, vascular and renal target organs. LCI699 is the first orally active aldosterone synthase inhibitor used in hypertensive patients. In a proof-of-concept study in patients with primary aldosteronism,31 LCI699 (0.5–1 mg b.i.d.) induced a dose-dependent and reversible suppression of plasma and urinary aldosterone concentration by approximately 70–80% associated with a massive dose-dependent accumulation of plasma deoxycorticosterone (>700%), the aldosterone precursor, thus confirming inhibition of the CYP11B2 gene product. This effect was associated with a rapid correction of hypokalaemia and a modest BP-lowering effect, that were both less than that obtained with eplerenone 100 mg b.i.d.32 An 8-week placebo-controlled dose– response study in patients with stage 1 and 2 essential hypertension reported an optimal decrease in BP with a dose of 1 mg LCI699 o.d., which had an antihypertensive effect similar to that of eplerenone 50 mg b.i.d.33 However, LCI699 administration was associated with biological signs of partial inhibition of the glucocorticoid axis, as shown by the dose-related increase in both plasma ACTH and in 11-deoxycortisol concentrations, the cortisol precursor, consistent with an inhibition of the CYP11B1 gene product.31 Nevertheless, the clinical and biological safety and tolerability of LCI699 were similar to those of placebo and eplerenone.33 The effects of LCI699 on the glucocorticoid axis limit the use of higher doses in hypertension because of the loss of selectivity for CYP11B2. Therefore, this aldosterone synthase inhibitor will not be able to replace MR blockade in patients with hypertension, but is now being evaluated at much higher doses in Cushing syndrome. The development of second-generation aldosterone synthase inhibitors with higher selectivity index towards CYP11B2 as compared with LCI699 will offer the possibility to test this approach at much higher doses, after the necessary toxicology and phase I studies. Non-steroidal dihydropyridine-based third- and fourthgeneration potent MR antagonists29,30 have also emerged as new drugs to selectively block the MR, displaying a similar potency as spironolactone towards the MR in vitro and thus having a greater potency than eplerenone, without interfering with the progesterone and androgen receptor, unlike spironolactone. The first-in-class of this new generation of MR blockers is BAY94-8862,29 which is currently in development for treatment of heart failure. The safety, tolerability and efficacy of 4–7-week treatment with BAY94-8862 (2.5 mg q.d., 5 mg q.d., 10 mg q.d. and 5 mg b.i.d.) has been compared with placebo or spironolactone (25–50 mg) in patients with heart failure and mild to moderate renal failure (estimated glomerular filtration rate: 30–90 ml/min/ 1.73 m2).34 BAY 94-8862 dose-dependently increased serum potassium concentration, but to a lesser extent than spironolactone, and thus was associated with a lower incidence of hyperkalaemia in this much-selected and highly monitored population of patients.34 It was as effective as spironolactone in decreasing B-type natriuretic peptide
(BNP) and amino-terminal proBNP. Adverse events were infrequent and mild.34 Such potent MR blockers could have a logical place in the armamentarium to treat patients with resistant hypertension. It should be kept in mind that the two abovementioned approaches are likely to entail the same risk of adverse events as the first generation of steroidal MR antagonists, including electrolyte disorders, hypotension, renal insufficiency and severe hypoaldosteronism, depending on residual aldosterone production, initial renal, dehydration, general anaesthesia, comorbidities (diabetes mellitus), and coprescriptions (COX inhibitors, RAS blockers, heparin, trimethoprim-sulfamethoxazole etc.).
Centrally acting aminopeptidase A inhibitors Brain renin angiotensin system (RAS) hyperactivity is implicated in the development and the maintenance of hypertension in several animal models.35 Aminopeptidase A (APA; EC3.4.11.7) and aminopeptidase N (APN; EC3.4.11.2) are both involved in the metabolism of angiotensin II and angiotensin III, respectively, in the brain.36 Angiotensin III has been shown to be one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control of BP.36 The new APA inhibitor, EC33, inhibits human, rat and mice APA in vitro with a Ki≈300 nM.37 It aims at blocking brain angiotensin III formation, and thus its biological effects. An orally active prodrug of EC33 obtained by disulfide bridge-mediated dimerization (RB150/QGC001) has been generated because EC33 does not cross the blood–brain barrier.38 In DOCA-salt rats, intravenous or oral QGC001 blocks brain angiotensin III formation, and decreases BP and plasma vasopressin levels.38 The antihypertensive effect of QGC001 was also demonstrated in spontaneously hypertensive rats.39 The first-in-class APA inhibitor QGC001 has entered the clinical development phase. When administered to healthy subjects, a single oral dose of QGC001 up to 1250 mg was safe. It did not lower BP in normotensive subjects and did not significantly change plasma renin activity, the concentrations of plasma and urine aldosterone, cortisol, and plasma copeptin levels compared with placebo. Clinical development is ongoing. In conclusion, progress is still needed to further reduce the residual burden of cardiovascular risks, within two new constraints of a quite different nature: safety and accessibility to all. In this context, new chemical entities are being developed for hypertension, type 2 diabetes and heart failure. However, it will take a long time to evaluate extensively the efficacy and safety of these new approaches. In the meantime, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension.
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Journal of the Renin-Angiotensin-Aldosterone System 14(4)
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