New drug therapies interfering with the renin–angiotensin–aldosterone system for resistant hypertension

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.

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 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 placebo^12,13 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 dose-dependently 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–endothelin-converting enzyme inhibitors

Daglutril is the first-in-class dual neprilysin–endothelin-converting 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 non-steroidal 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 inhibitors ²⁸ and dihydropyridine-based third- and fourth-generation MR antagonists^29,30 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 -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 fourth-generation potent MR antagonists^29,30 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 K_i≈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.