Finerenone : third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease.

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Drug Evaluation

1.

Introduction

2.

Aldosterone and the mineralocorticoid receptor

3.

Chemistry of finerenone

4.

Pharmacodynamics

5.

Pharmacokinetics

6.

Clinical efficacy

7.

Safety and tolerability

8.

Conclusion

9.

Expert opinion

Finerenone: third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease Licette CY Liu, Elise Schutte, Ron T Gansevoort, Peter van der Meer & Adriaan A Voors† †

University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands

Introduction: The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF), and attenuate progression of diabetic kidney disease. However, their use is limited by the fear of inducing hyperkalemia, especially in patients with renal dysfunction. Finerenone is a novel nonsteroidal MRA, with higher selectivity toward the mineralocorticoid receptor (MR) compared to spironolactone and stronger MR-binding affinity than eplerenone. Areas covered: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of finerenone. Expert opinion: The selectivity and greater binding affinity of finerenone to the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with HF and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease and diabetic kidney disease, showed promising results. Phase III trials will have to show whether finerenone might become the third-generation MRA for the treatment of HF and diabetic kidney disease. Keywords: aldosterone, BAY 94-8862, chronic kidney disease, diabetic kidney disease, diabetic nephropathy, finerenone, heart failure, nonsteroidal mineralocorticoid receptor antagonist Expert Opin. Investig. Drugs [Early Online]

1.

Introduction

To date, only two steroidal compounds of mineralocorticoid receptor antagonists (MRAs) have been developed for therapeutic use. Spironolactone represents the first-generation MRA and was introduced in 1960 [1]. Spironolactone is highly potent but is structurally similar to progesterone, thereby allowing sex-steroid receptor cross-reactivity. Its administration is therefore often accompanied with associated adverse effects such as gynecomastia, impotence and menstrual irregularities [2,3]. The second-generation MRA eplerenone has improved selectivity but showed a relatively low affinity [4,5]. Despite the evidence for their benefit in two common diseases in developed countries, which are closely interrelated -- heart failure (HF) and chronic kidney disease (CKD) [6-13], MRAs are underused (Table 1) [14-18]. One would expect that these low numbers are owed to their characteristic side effects [3,19,20]. However, the aftermath of the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) 10.1517/13543784.2015.1059819 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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L. C. Y. Liu et al.

Box 1. Drug summary. Drug name Stage of development Indication

Finerenone (BAY 94-8862) Phase II Heart failure with mild/moderate chronic kidney dysfunction, diabetic kidney disease Mechanism of action Nonsteroidal mineralocorticoid receptor antagonist Route of administration Oral CH3 Chemical structure


H N

CH3

N

NH2 O

H3C H3C

O

O

N

Pivotal trials

[50,87]

demonstrated that eplerenone was at least as beneficial in high-risk patients -- including patients aged > 75 years, patients with a history of diabetes mellitus, patients with renal dysfunction and hypotensive patients -- as in the other patients, without an increase in risk of serious hyperkalemia or worsening renal function [21]. In fact, the absolute reduction in mortality by eplerenone was even higher in high-risk patients, compared to patients at low risk (4.1 vs 1.0 death per 100 patient-years) [22]. These results make it difficult to understand why MRAs remain underutilized, as the concern of developing of hyperkalemia and worsening renal function seems unjust. These limitations have stimulated further research to a more cardioselective MRA with less renal side effects, resulting in the development of finerenone (BAY 94-8862) [23]. In this review, we discuss properties of finerenone and its possible use in HF and diabetic kidney disease Box 1. 2. Aldosterone and the mineralocorticoid receptor

One of the well-known actions of aldosterone is Na+ reabsorption and K+ excretion in the distal nephron, in order to maintain electrolyte balance and volume homeostasis [24]. Besides sodium retention, aldosterone also induces a variety of pathologic processes leading to inflammation, remodeling and fibrosis [25,26]. Activation of the mineralocorticoid receptor (MR) by aldosterone may also have a direct vasoconstrictor effect of the vascular wall [27-29]. Also, aldosterone has been shown to elicit direct renal tissue damage, resulting in 2

increased proteinuria/albuminuria [30-33]. Excessive levels of aldosterone result in conditions as HF, hypertension and CKD [34-38], and inhibition of the activity of the renin-angiotensin-aldosterone system (RAAS) results in improved outcomes. However, treatment with angiotensin converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) may not block the RAAS sufficiently, as several studies demonstrated that patients treated with these agents still have high aldosterone levels [39-43]. This ‘aldosterone breakthrough’ may contribute to the progression of renal and cardiovascular dysfunction [43-46]. Patients experiencing aldosterone breakthrough during treatment with RAAS inhibiting agents may therefore benefit from treatment with MRAs. 3.

Chemistry of finerenone

Ultra-high-throughput screening revealed that 1.4-dihydropyridines (DHPs) possesses MR antagonistic activity in vitro [23] -- an interesting observation as DHP were known for their activity to antagonize L-type calcium channel (nifedipine, nimodipine, amlodipine) [23]. DHP-1 was identified as a primary candidate, since the compound demonstrated promising selectivity not only over the glucocorticoid receptor (> 20-fold) but also over the androgen and progesterone receptors. However, DHP-1 was associated with a low metabolic stability and a significant interaction with the L-type calcium channel and was therefore further explored. The first step in success of the development of finerenone was achieved by replacing the chromenone head group with a 4-cyano2-methoxyphenyl moiety in the naphthyridine series, which can be considered as conformationally frozen bioisosteres of 1.4-DHP esters, resulting in the dihydronaphthyridine series [23]. Chiral high-performance liquid chromatography resolution led to a more active enantiomer. Then a methyl group was introduced at C8, followed by replacement of the C3 cyano group by a primary amide. This final step led to a compound with greater potency and selectivity: finerenone. Finerenone is a potent nonsteroidal MRA with IC50 of 18 nM (spironolactone: 24 nM, eplerenone: 990 nM) with exceptional selectivity versus the glucocorticoid receptor, androgen receptor and progesterone receptor (> 500-fold) 2+ [23]. Finerenone demonstrated no L-type Ca channel activity (IC50 > 10 µM) [23]. The specificity was demonstrated as it showed no significant effects on 65 different enzymes and ion channels. In rats, finerenone has a low blood clearance and long half-life (0.014 L h-1kg-1 and 8.5 h) [23]. Compared with eplerenone, finerenone showed more natriuretic effects as it exhibits a threefold to tenfold greater potency and higher efficacy [23]. 4.

Pharmacodynamics

Similar to spironolactone and eplerenone, finerenone competitively antagonizes the MR. In rodents, finerenone showed cardiac and renal protection (Table 2). Compared to

Expert Opin. Investig. Drugs (2015) 24(8)

Finerenone

Table 1. Use of mineralocorticoid receptor antagonists in heart failure.


Author, Publication Date

Acronym

Period

n

Study population

Medication use at admission (AHF)/ baseline(CHF)

Medication use at discharge

Ref.

Europe Nieminen et al. (2006)

EHFS II

2004 -- 2005

3580

ESC-HF Pilot

2009 -- 2010

5118

b-blockers: 43% ACEi: 55% MRA: 28% AHF: b-blockers: 62% ACEi/ARBs: 60% MRA: 33% CHF: b-blockers: 86.7% ACEi/ARBs: 88.5% MRA: 43.7%

b-blockers:61% ACEi: 71% MRA: 48% AHF: b-blockers: 80% ACEi/ARBs:78% MRA: 55%

[14]

Maggioni et al. (2010)

Patients hospitalized for AHF Patients admitted for AHF, and patients with CHF

US Fonarow et al. (2008)

IMPROVE-HF

2005 -- 2007

15381

Patients with CHF

Albert et al. (2009)

GWTG-HF

2005 -- 2007

43625

Patients with AHF

CHF: b-blockers: 86% ACEi/ARBs: 80% MRA: 36% Unknown

Krantz et al. (2011)

GWTG-HF

2009 -- 2010

9474

Patients with AHF

b-blockers: 72.6% ACEi/ARBs: 65.3% MRA: 15.6%

[15]

[16]

b-blockers: 89.7% ACEi/ARBs: 89.0% MRA: 32.5% b-blockers: 94.6% ACEi/ARBs: 92.9% MRA: 32.2%

[17]

[18]

ACEi: Angiotensin converting enzyme inhibitor; AHF: Acute heart failure; ARB: Angiotensin receptor blocker; CHF: Chronic heart failure; HF: Heart failure; MRA: Mineralocorticoid receptor antagonist.

eplerenone, finerenone resulted in more pronounced end-organ protective activity reflected by higher dosages of eplerenone being needed to achieve similar effects [47,48]. In healthy males, finerenone reversed the diminishing effect of fludrocortisone on urinary sodium:potassium ratio and resulted in dose-dependent natriuresis compared to eplerenone 50 mg [49]. In HF patients with mild-to-moderate CKD, finerenone dose-dependently increased serum aldosterone levels, but decreased brain natriuretic peptide (BNP) and N-terminal prohormone of BNP (NT-proBNP) levels and urinary albumin: creatinine ratio (UACR) [50]. Although treatment with finerenone resulted in a rise in potassium and a decrease in estimated glomerular filtration rate (eGFR), these changes were significantly smaller than in the spironolactone group (Figure 1) [50]. 5.

Pharmacokinetics

Finerenone is administrated as oral, immediate-release tablet. In healthy humans, the plasma half-life of finerenone is ~ 2 h, which is lower than the half-lives of the active metabolites of spironolactone and eplerenone (respectively > 12 and 3 -- 5 h) [4,49-55]. Quantitative whole-body autoradiography of rodents revealed that finerenone is distributed equally into cardiac (4409 ug-eq/l) and renal tissues (3782 ug-eq/l). This is in contrast to spironolactone and eplerenone, which have

respectively, a six-fold and three-fold higher renal drug concentration in comparison to cardiac concentrations [48,52,54]. This unequal distribution may explain the pronounced pharmacologic effects of all steroidal MRAs in the kidney in relation to the effects in the heart. Indeed, the doses of a steroidal MRA needed to induce natriuresis or renal electrolyte handling in rats are actually lower than the doses needed to achieve cardiac protective effects -- in terms of relative heart weight reduction and BNP reduction [56-59]. 6.

Clinical efficacy

Heart failure In current HF guidelines, MRAs are recommended in all patients with HF with reduced ejection fraction who are still symptomatic (New York Heart Association [NYHA] II -- IV) despite treatment with diuretics, ACEis and b-blockers [60]. The Randomized Aldactone Evaluation Study (RALES) evaluated the effect of spironolactone versus placebo in severe symptomatic (NYHA III -- IV) patients with chronic HF with reduced ejection fraction. RALES was the first trial to demonstrate mortality benefit of a MRA in HF patients [8]. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that treatment with eplerenone also resulted in improved outcomes in patients with acute myocardial infarction 6.1


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L. C. Y. Liu et al.


Table 2. Preclinical finerenone studies. Author, publication date

Animal model

Treatment arms

n

Results

Ref.

Kolkhof et al. (2012)

Spontaneously hypertensive, stroke prone male rats on high salt diet

Finerenone -10 mg/kg/day Eplerenone -30 mg/kg/day Spironolactone -30 mg/kg/day Vehicle

12 per group

Delbeck et al. (abstract) Kolkhof et al. (2014)

Sprague-Dawley rat hypertensive-driven heart failure model (deoxycorticosterone acetate/salt model),

Finerenone - 0.1 mg/kg/day -1 mg/kg/day -10 mg/kg/day Eplerenone -30 mg/kg/day -100 mg/kg/day Vehicle

7 -- 12 per group

Kolkhof et al. (2014) AlbrechtKupper et al. (2012) (abstract)

Male Wistar rats with heart failure induced by left anterior descending coronary artery ligation

Finerenone -0.1 mg/kg/day -0.3 mg/kg/day -1 mg/kg/day Eplerenone -100 mg/kg/day Vehicle

10 -- 14 per group

[102] Finerenone resulted in reduction in mortality, compared to placebo. Finerenone reduced urinary:protein ratio, compared to vehicle group (0.4 ± 0.03 vs 1.99 ± 0.40), urinary OPN protein and mRNA in kidneys, reduction of vascular, glomerular and tubule interstitial damage. No mortality benefit or reduction in OPN concentration and vascular, glomerular and tubule interstitial damage was observed in eplerenone or spironolactone group [47,48] Finerenone reduced systolic blood pressure and heart weight-to-body weight ratio, proBNP levels and resulted in a dose-dependent protection from structural heart injury. Also, finerenone resulted in functional as well as structural protection from kidney injury. Relative kidney weights were decreased and proteinuria was dose-dependently reduced by treatment with finerenone. In addition, treatment with finerenone dose-dependently protected from glomerular, tubular and vascular damage and reduced expression of remodeling marker genes PAI-1, MCP-1, OPN, MMP-2. More pronounced end-organ protective activity was observed in finerenone-treated rats compared to eplerenone-treated rats [48,103] Finerenone improved left ventricular systolic dysfunction in heart failure -- terms of contractility (dp/dtmax) and relaxation (dp/dtmin). Finerenone reduced plasma pro-BNP levels. OPN levels were dose-dependently decreased by finerenone

MCP-1: Monocyte chemoattractant protein; MMP-2: Matrix metalloproteinase; OPN: Osteopontin; PAI-1: Plasminogen activator inhibitor-1; proBNP: Pro-brain natriuretic peptide.

complicated by HF due to left ventricular dysfunction [13]. This study was followed by EMPHASIS-HF [6]. During EMPHASIS-HF, patients with NYHA II HF were randomly assigned to eplerenone (up to 50 mg/day) or placebo. The trial was terminated early due to distinct benefit of treatment with eplerenone after a median follow up of 21 months. Despite recommendations of current guidelines, widespread prescription of these steroidal MRAs is limited. Several observational studies illustrate the underuse of MRA among HF patients (Table 1) [14-18]. In the largest observational study, only 32.5% of eligible patients received a MRA at hospital discharge, whereas 89.7 and 89.0% of patients received b-blockers and ACEis and ARBs, respectively. One would expect that the concern of hyperkalemia and renal dysfunction was the main reason of the modestly use of MRAs. However, inappropriate use was rare: 3.1% had at least a documented 4

contraindication, serum creatinine level of ‡ 3.0 mg/dl or a serum potassium level of ‡ 6.0 mEq/l. The safety and tolerability of finerenone was recently investigated during the Mineralocorticoid-Receptor Antagonist Tolerability Study (ARTS) in patients with chronic HF and mild/moderate CKD [50,61]. A total of 457 patients were randomized to finerenone, placebo or spironolactone and received study drug for 4 weeks. Treatment with 5 and 10 mg/day finerenone was associated with less increase in serum potassium and slower renal function decline, compared to spironolactone 25 or 50 mg/day, whereas the reduction in BNP, NT-proBNP levels and albuminuria were at least similar (Figure 2) [50]. Following these positive outcomes, the ARTS-HF was initiated (NCT01807221), investigating the effects of finerenone in patients with worsening chronic systolic HF and type 2 diabetes and/or CKD. In this Phase IIb


Finerenone


A.

B.

Figure 1. Results from the ARTS-study showing (A) mean change from baseline in serum potassium concentration in patients receiving finerenone, placebo or spironolactone and (B) mean change from baseline in the eGFR in patients receiving finerenone, placebo or spironolactone. Reprinted from [50] with permission from Oxford University Press. ARTS: Mineralocorticoid Receptor Antagonist Tolerability Study; b.i.d.: Twice daily; eGFR: Estimated glomerular filtration rate; q.d.: Once daily; SD: Standard deviation.

trial, the treatment effect of finerenone on NT-proBNP levels will be compared to eplerenone in patients with worsening chronic HF and either type 2 diabetes with or without CKD or CKD alone.

Diabetic kidney disease With the growing worldwide prevalence of diabetes mellitus, diabetic kidney disease is one of the common causes of CKD [62-64]. RAAS activation, hypertension, hyperglycemia, 6.2


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L. C. Y. Liu et al.

Figure 2. Changes from baseline in serum BNP (median change), NT-proBNP (median change), UACR (geometric mean) and serum aldosterone (mean change) in the ARTS-study are shown. Reprinted from [50] with permission from Oxford University Press. b.i.d.: Twice daily; BNP: Brain natriuretic peptide; IQR: Interquartile range; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; q.d.: Once daily; UACR: Urinary albumin:creatinine ratio.

dyslipidemia and proteinuria are established risk factors for progression of diabetic kidney disease. There is accumulating evidence that aldosterone/MR signaling is involved in the 6

development of renal injury, leading to glomerular and tubular sclerosis independent of angiotensin II [30,31]. The precise mechanism is yet unknown. Aldosterone/MR signaling may have harmful effects on non-aldosterone-sensitive kidney cells, such as mesangial cells and renal fibroblast [31-33], and may induce apoptosis or alteration of adhesive capacity of podocytes, enhancing protein leakage [65-68]. In addition, animal studies revealed that aldosterone is involved in renal inflammation, oxidative stress, fibrosis and mesangial cell proliferation [69-72]. ACEis, ARBs and more recently renin inhibitors are frequently used in these patients. However, full doses of these drugs slow down but do not stop renal function decline. MRAs have been recognized as a novel approach to slow down residual CKD progression [73-78]. Several studies have investigated the additional renal protective effects of MRA on top of ACEi and/or ARB treatment in patients with diabetic kidney disease (Table 3). In both type 1 and type 2 diabetes patients with diabetic kidney disease receiving either ACEi or an ARB, additive treatment with MRAs lowered urinary albumin/protein excretion by 30 to 60% [11,79-87]. The eGFR declined significantly in most studies shortly after starting MRA treatment [11,82,83,85,86]. Two of the longer-term studies reported that eGFR stabilized after the first months of treatment [11,83], which may indicate that the initial fall in eGFR found in short-term studies may be an acute and reversible hemodynamic effect on the kidney, similar to the effects known from ACEis and ARBs [88,89]. It should be noted that there was substantial heterogeneity among the studies not only in the type and dose of the MRA that was used but also in respect to the choice for control treatment (placebo or ACEi or ACEi and ARB combination therapy). Furthermore, the results of these studies cannot easily be extrapolated to the treatment of the general diabetic population, as most studies were small, included high doses of MRAs and included patients who had in general preserved renal function (mean eGFR in all studies was > 60 ml/min/1.73). Recently, preliminary results of the ARTS-Diabetic Nephropathy (ARTS-DN) study were presented, a large Phase IIb trial including 823 type 2 diabetes patients with diabetic kidney disease defined as albuminuria of at least 30 mg/g and treated with a RAS blocker prior to the screening visit, which investigated the safety and efficacy of different oral doses of finerenone [87]. Patients were randomized to receive either 90-day treatment with placebo or 1.25, 2.5, 5, 7.5, 10, 15 or 20 mg finerenone, on top of standard care which included a RAS blocker. Finerenone showed a dosedependent reduction in the primary end point of UACR at day 90, with significant reduction in the finerenone 7.5 -- 20 mg groups. The top of the dose--response curve was reached at the dose of 20 mg, with a UACR decrease of 38%. Safety variables in this study were change in serum potassium and incidence of hyperkalemia. Serum potassium increased by 0.11 to 0.46 mmol/l in the 7.5 -- 20 mg groups and hyperkalemia occurred in 1.8% in the patients treated


Finerenone


Table 3. Clinical trials with mineralocorticoid receptor antagonists in diabetic kidney disease. Author, publication date

n

Study Treatment arms population

Schjoedt et al. (2005)

20

Type 1 DM

Rossing et al. (2005)

20

Type 2 DM

Schjoedt et al. (2006)

20

Type 1 and type 2 DM

Epstein et al. (2006)

268 Type 2 DM

van den Meiracker et al. (2006)

59

Type 2 DM

Saklayen et al. (2008)

30

Type 2 DM

Mehdi et al. (2009)

80

Type 1 and type 2 DM

Nielsen et al. (2012)

21

Type 1 DM

Esteghamati et al. (2013)

136 Type 2 DM

Ruilope et al. (2015)

823 Type 2 DM

Crossover trial with ACEi ARB + spironolactone 25 versus placebo Crossover trial with ACEi ARB + spironolactone 25 versus placebo

Results

or mg

30% reduction in albuminuria, no significant difference in GFR, potassium and 24-h ambulatory BP or 33% reduction in albuminuria, 6 mmHg mg reduction in SBP, potassium increase of 0.3 mmol/l, no significant difference in GFR Crossover trial with ACEi -or 32% reduction in albuminuria, 6 mmHg ARB + spironolactone 25 mg reduction in SBP, no significant versus placebo difference in GFR and potassium Enalapril + placebo 42 and 50% reduction in albuminuria vs for eplerenone 50 and 100 mg, enalapril + eplerenone 50 mg respectively, vs 9% reduction in the vs placebo group. No additional BPenalapril + eplerenone 100 mg lowering effect of eplerenone; eGFR reduction in eplerenone groups (-2 to 4 ml/min/1.73m2). No difference in incidence of hyperkalemia between the three study groups. ACEi or ARB + spironolactone 41% reduction in albuminuria, 7 mmHg 50 mg vs placebo reduction in SBP, more eGFR decline in the spironolactone group compared to placebo during the first 3 months of treatment, 0.5 mmol/l increase in serum potassium. Crossover trial, ACEi or 57% reduction in proteinuria, 12 mmHg ARB + spironolactone 50 mg reduction in SBP, eGFR decreased 7 ml/ (first month 25 mg) vs placebo min/1.73m2 during the first 30 days of treatment and was stable during the remainder of the trial. Serum potassium increased by 0.4 mEq/l ACEi + losartan 100 mg vs 34% reduction in albuminuria spironolactone 25 mg vs (spironolactone compared to placebo), placebo no difference in SBP and eGFR between the treatment arms. Serum potassium higher and more hyperkalemia in the active treatment arms compared to placebo Crossover trial, ACEi or 60% reduction in albuminuria, GFR ARB + spironolactone 25 mg decreased 6 ml/min/1.73m2 during the first 2 months of treatment with vs placebo spironolactone, no significant difference in SBP or increase in serum potassium, yet 6 patients experienced hyperkalemia on spironolactone Enalapril (30 -- 40 mg) and After 1 year: 53% reduction in losartan (50 -- 100 mg) vs albuminuria vs 20% reduction in losartan (50 -- 100 mg) and ACEi + ARB group, 7 mmHg decrease in spironolactone 25 mg SBP, eGFR decline of 7 ml/min/1.73m2, serum potassium increase of 0.2 mEq/l, and 3 patients on spironolactone experienced hyperkalemia. No hyperkalemia in the ACEi + ARB group ACEi or ARB + finerenone Dose-dependent reduction in (7 doses ranging from 1.25 to albuminuria of 21 -- 38% in the dose 20 mg) vs placebo range of finerenone 7.5 -- 20 mg. 1.8% of patients in the 7.5 -- 20 mg groups developed hyperkalemia.

Study duration

Ref.

2 2 months [79] 2 2 months [80]

2 2 months [81] 3 months

[82]

1 year

[11]

7 months

[83]

1 year

[84]

4 months

[85]

1.5 years

[86]

3 months

[87]

ACEi: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; BP: Blood pressure; DM: Diabetes mellitus; eGFR: Estimated GFR; GFR: Glomerular filtration rate; SBP: Systolic blood pressure. Expert Opin. Investig. Drugs (2015) 24(8)

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L. C. Y. Liu et al.

with finerenone 7.5 -- 20 mg. In conclusion, the ARTS-DN trial showed promising results, yet it must be noted that this was a study with short duration and the long-term effects of finerenone are to be investigated in a Phase III study.


7.

Safety and tolerability

Homeostasis of potassium is regulated by potassium excretion according to dietary intake and potassium distribution between intracellular and extracellular fluid compartments [90]. Under normal conditions, excessive intake of potassium does not lead to hyperkalemia, as the kidney, the primary organ of potassium excretion, is able to excrete a large amount of potassium [91]. However, chronic kidney dysfunction can lead to impaired renal potassium secretion and patients suffering from CKD thus have a predisposition to a positive potassium balance and are susceptible to develop hyperkalemia [92,93]. Aldosterone stimulates the activity of Na,K-ATPase and H,K-ATPase, thereby promoting Na+ absorption and K+ secretion in the distal nephron [92,93]. Hyperkalemia is therefore considered as one of the most important adverse effects of MRA therapy [94]. Although the risk of serious hyperkalemia can be minimized by routine monitoring of potassium and renal function, with timely dose adjustment, physicians are not eager to prescribe these drugs in patients with renal dysfunction. Diabetic patients are considered to be even at higher risk of developing hyperkalemia due to insulin deficiency, hypertonity and hyporeninemic hypoaldosteronism [95,96]. In a proof-of-concept study and Phase I study, finerenone was safe and well tolerated [49,61]. In the ARTS study, HF patients with mild/moderate CKD treated with finerenone experienced a lower incidence of hyperkalemia (serum K+ ‡ 5.8 mmol/l measured by central laboratory or serum K+ ‡ 5.2 mmol/l measured by local laboratory) compared to spironolactone (5.3 vs 12.7%, p = 0.048) after day 29 ± 2 days of treatment [50]. Figure 1 summarizes the increases in serum potassium between finerenone and spironolactone during the ARTS trial. To date, there are no direct comparisons on the incidence of hyperkalemia between finerenone and eplerenone in HF patients. Nevertheless, the numbers of incidence of increased potassium levels reported in previous studies may be used for observational comparison. In the RALES trial, serious hyperkalemia (serum K+ ‡ 6.0 mmol/l) occurred in 3.9% of patients and hyperkalemia (serum K+ ‡ 5.5 mmol/l) occurred in 19% of patients treated with spironolactone during a mean follow-up period of 24 month (vs 1.2 and 5.6%, respectively, in the placebo group) [97]. In the EPHESUS trial, serious hyperkalemia (serum K+ ‡ 6.0 mmol/l) occurred in 5.5% of patients after 1 year of treatment with eplerenone group (vs 3.9% in the placebo group) [13]. In the EMPHASIS trial, serious hyperkalemia (serum K+ > 6.0 mmol/l) occurred in 2.5% of patients and a serum potassium level > 5.5 mmol/l occurred in 11.8% of patients treated with eplerenone after a median follow-up period of 21 months (vs 1.9 and 7.2%, respectively, in the 8

placebo group) [6]. Thus, based on the numbers of the ARTS, EPHESUS and EMPHASIS trials, the incidence numbers of hyperkalemia were 5.3% for finerenone, 12.7% for spironolactone and 11.8% for eplerenone. These numbers may indicate that the incidence of hyperkalemia is lower with finerenone. It should be noted however, that the treatment duration was different between these studies. Furthermore, the incidence of hyperkalemia (serum potassium ‡ 5.6 mmol/l) in the ARTS-DN study was only 1.5%, and only one case of serum potassium ‡ 6.0 mmol/l was observed [87]. These observations underscore the safety profile of finerenone. Previous studies describe that treatment with a MRA may induce worsening renal function [6,98]. In the ARTS trial, the incidence of renal failure was higher in the finerenone group compared with placebo (1.5 vs 0%), whereas the incidence of renal impairment was lower (3.8 vs 9.2%). Compared to spironolactone, the incidence of renal failure and renal impairment was lower in the finerenone group (1.5 vs 7.9%, and 3.8 vs 28.6%, respectively). Mean change in eGFR in finerenone- and placebo-treated patients in the ARTS-HF study are presented in Figure 1. Again, there are no direct comparisons published between finerenone and eplerenone in respect to the risk of worsening renal function. In the EPHESUS trial, eGFR declined gradually by 4.6 ± 0.9 and 2.7 ± 0.9 ml/min/1.73m2 in the eplerenone and placebo groups [98]. In the EMPHASIS trial, eGFR was reduced annually by 0.288 (95% CI: -0.395 to -0.182) ml/ min/1.73 m2 in the eplerenone group and was reduced by 0.066 (95% CI: -0.174 to -0.042) ml/min/1.73 m2 in the placebo group [99]. A > 20% reduction of eGFR occurred in 30.1% of patients treated with eplerenone and in 24.4% of patients treated with placebo [99]. A > 30% reduction of eGFR occurred in 14.0% of patients treated with eplerenone and 16.1% of patients treated with placebo [99]. At least in comparison with spironolactone, the incidence of worsening renal function is lower in patients treated with finerenone. 8.

Conclusion

Finerenone, a nonsteroidal MRA, could become the thirdgeneration MRA for the treatment of HF and diabetic kidney disease. The initial results with finerenone are encouraging. MRAs improve prognosis in HF patients and attenuate progression of renal impairment in patients with CKD, but the risk of hyperkalemia and worsening renal function may limit prescriptions. Finerenone seems to exert the same beneficial effects, with lower risks of renal dysfunction and hyperkalemia, compared with spironolactone and eplerenone. The first large Phase IIb study of finerenone in patients with diabetic kidney disease showed promising results with significant reduction in albuminuria and a low rate of hyperkalemia, and the results of a large Phase IIb study in patients with HF are pending.


Finerenone


9.

Expert opinion

The time span of development of first to third generation MRA is remarkable. Since the introduction of first MRA in 1960, it took half a century to develop a MRA with improved potency and higher selectivity for the MR receptor. Compared to spironolactone and eplerenone, finerenone has a lower IC50 for the MR, indicating that finerenone is a stronger MR antagonist. Further, the magnitude of selectivity of finerenone versus other members of the oxo-steroid receptor family is higher compared to spironolactone, suggesting that the risk of developing progestogenic and anti-androgenicrelated side effects during finerenone administration would be minimal. In addition, lower doses of finerenone were needed to achieve similar cardiorenal protective effects compared to both spironolactone and eplerenone. Although these observations illustrate improved potency, greater affinity and selectivity to the MR of finerenone, it needs to be established whether these differences will translate into meaningful improvements in clinical outcome. Only a few animal studies have investigated the effects of finerenone. Interestingly, these preclinical studies demonstrated that finerenone is equally distributed in cardiac and renal tissues in animals, in contrast to spironolactone and eplerenone, which have higher renal concentrations than in the cardiac tissue [48]. The lower concentration of finerenone in the kidney may be an explanation for the lower incidence of hyperkalemia in patients. To date, there are three clinical studies that have investigated the effects of finerenone in patients. The first two studies included patients with chronic HF and mild or moderate CKD (with/without diabetes). One of these two studies, was published in 2013, and included 457 HF patients. The other study, including ~ 1060 HF patients, was recently completed and results are now pending. The initial results with finerenone in heart failure are promising. However, it should be noted that both studies were Phase II studies, and the primary end points were ‘soft’ end points (serum potassium, eGFR, albuminuria and NT-proBNP levels). The third study was the ARTS-DN trial including 823 type 2 diabetes patients with diabetic kidney disease. The primary end point was

also a ‘soft’ end point (UACR). Although MRAs have been proven to be lifesaving, these drugs are under prescribed due to their adverse effects. The novel selective nonsteroidal MRA finerenone may be an answer to the known disadvantages of current MRAs. The results in preclinical studies and Phase I/II studies are positive, but need to be confirmed by further studies (Phase III) investigating whether the beneficial effects of finerenone translated into improved clinical outcomes (e.g., death, hospitalizations, incidence of end-stage renal disease) in these patients. Hyperkalemia appears to be a feared adverse effect of MRA therapy. In addition to the relatively low incidence of hyperkalemia during treatment with finerenone compared to other MRAs, other therapies to avoid and/or treat hyperkalemia in patient with HF are currently being developed. Until recently, treatment of hyperkalemia with MRAs was limited to stopping or decreasing the dose of the MRA, or co-prescription of potassium-losing diuretics or potassium-binding polymer resins. These resins in general have poor tolerability. Two novel potassium-binding medications (Patiromer and ZS-9) are currently being investigated and the initial results are promising, in respect to potassium lowering as well as tolerability [100,101]. It is therefore reassuring that in the near future the benefits of RAAS blockage may become available to patients with a high risk of hyperkalemia, with, on the one hand, the availability of novel MRAs with a lower risk of hyperkalemia and, on the other hand, better treatment options for incident hyperkalemia.

Declaration of interest AA Voors is a member of the steering committee of the ARTS-HF trial and has received consultancy fees from Bayer Healthcare. RT Gansevoort is a member of the steering committee of the ARTS-DN trial, for which financial reimbursement is paid to their institution. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


9

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Affiliation Licette CY Liu1 MD, Elise Schutte2 MD, Ron T Gansevoort2 MD PhD, Peter van der Meer1 MD PhD & Adriaan A Voors†3 MD PhD † Author for correspondence 1 University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands 2 University of Groningen, University Medical Center Groningen, Department of Nephrology, Groningen, The Netherlands 3 Professor of Cardiology, University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands Tel: +31 0 50 361 2355; E-mail: [email protected]

13

Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure.

or chronic kidney disease.

The novel mineralocorticoid receptor antagonist finerenone attenuates neointima formation after vascular injury.

Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure.

Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.

Temporal Trends and Hospital Variation in Mineralocorticoid Receptor Antagonist Use in Veterans Discharged With Heart Failure.

Local mineralocorticoid receptor activation and the role of Rac1 in obesity-related diabetic kidney disease.

Guideline concordance of testing for hyperkalemia and kidney dysfunction during initiation of mineralocorticoid receptor antagonist therapy in patients with heart failure.

Galectin-3 and mineralocorticoid receptor antagonist use in patients with chronic heart failure due to left ventricular systolic dysfunction.

Relationship between galectin-3 levels and mineralocorticoid receptor antagonist use in heart failure: analysis from HF-ACTION.

Myeloid mineralocorticoid receptor activation contributes to progressive kidney disease.

Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist.

Diagnosis and treatment of diabetic kidney disease.

Mineralocorticoid receptor antagonists as diuretics: Can congestive heart failure learn from liver failure?

Predictors of congestive heart failure after treatment with an endothelin receptor antagonist.

Evaluating the efficacy of mineralocorticoid receptor antagonism in patients with STEMI without heart failure.

Present and future in the treatment of diabetic kidney disease.

Barriers to Adoption of Mineralocorticoid Receptor Antagonists in Patients With Heart Failure: A Mixed-Methods Study.

Interplay of parathyroid hormone and aldosterone antagonist in prevention of heart failure hospitalizations in chronic kidney disease.

Resistant Hypertension: Mineralocorticoid Receptor Antagonist or Renal Denervation?

The kidney in heart failure.

Beta receptor antagonists in the treatment of heart failure.

JAK inhibition in the treatment of diabetic kidney disease.

The "mineralocorticoid-like" actions conferred on corticosterone by carbenoxolone are inhibited by the mineralocorticoid receptor (type I) antagonist RU28318.