Drug Evaluation

Finerenone: third-generation
mineralocorticoid receptor
antagonist for the treatment of
1. Introduction
2. Aldosterone and the
heart failure and diabetic kidney
3.
mineralocorticoid receptor
Chemistry of finerenone
disease
4. Pharmacodynamics Licette CY Liu, Elise Schutte, Ron T Gansevoort, Peter van der Meer &
5. Pharmacokinetics Adriaan A Voors†
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†
University of Groningen, University Medical Center Groningen, Department of Cardiology,
6. Clinical efficacy
Groningen, The Netherlands
7. Safety and tolerability
8. Conclusion
Introduction: The mineralocorticoid receptor antagonists (MRAs) spironolac-
tone and eplerenone reduce the risk of hospitalizations and mortality in
9. Expert opinion
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 dys-
function. 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
For personal use only.

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 irregular-
ities [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 fail-
ure (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 1

All rights reserved: reproduction in whole or in part not permitted
 L. C. Y. Liu et al.

Box 1. Drug summary.

increased proteinuria/albuminuria [30-33]. Excessive levels of
aldosterone result in conditions as HF, hypertension and
Drug name Finerenone (BAY 94-8862) CKD [34-38], and inhibition of the activity of the renin-angio-
Stage of development Phase II
Indication Heart failure with mild/moderate
tensin-aldosterone system (RAAS) results in improved out-
chronic kidney dysfunction, diabetic comes. However, treatment with angiotensin converting
kidney disease enzyme inhibitors (ACEis) or angiotensin receptor blockers
Mechanism of action Nonsteroidal mineralocorticoid (ARBs) may not block the RAAS sufficiently, as several stud-
receptor antagonist ies demonstrated that patients treated with these agents still
Route of administration Oral
Chemical structure CH3 have high aldosterone levels [39-43]. This ‘aldosterone break-
H through’ may contribute to the progression of renal and
N CH3 cardiovascular dysfunction [43-46]. Patients experiencing aldo-
sterone breakthrough during treatment with RAAS inhibiting
N NH2 agents may therefore benefit from treatment with MRAs.
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H3C O O 3. Chemistry of finerenone

H3C O

Ultra-high-throughput screening revealed that 1.4-dihydro-

pyridines (DHPs) possesses MR antagonistic activity in vitro
[23] -- an interesting observation as DHP were known for their

N activity to antagonize L-type calcium channel (nifedipine,

Pivotal trials [50,87] nimodipine, amlodipine) [23]. DHP-1 was identified as a
primary candidate, since the compound demonstrated prom-
ising selectivity not only over the glucocorticoid receptor
(> 20-fold) but also over the androgen and progesterone
For personal use only.

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 reduc-
tion 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, result-
ing in the development of finerenone (BAY 94-8862) [23]. In
this review, we discuss properties of finerenone and its possi-
ble 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+ reab-
sorption 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 recep-
tor (MR) by aldosterone may also have a direct vasoconstric-
tor effect of the vascular wall [27-29]. Also, aldosterone has
been shown to elicit direct renal tissue damage, resulting in
receptors. However, DHP-1 was associated with a low meta-
bolic stability and a significant interaction with the L-type cal-
cium 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-cyano-
2-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 compet-
itively antagonizes the MR. In rodents, finerenone showed
cardiac and renal protection (Table 2). Compared to

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

 Finerenone

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

Author, Acronym Period n Study population Medication use at Medication use Ref.
Publication Date admission (AHF)/ at discharge
baseline(CHF)

Europe
Nieminen et al. EHFS II 2004 -- 2005 3580 Patients b-blockers: 43% b-blockers:61% [14]
(2006) hospitalized ACEi: 55% ACEi: 71%
for AHF MRA: 28% MRA: 48%
Maggioni et al. ESC-HF Pilot 2009 -- 2010 5118 Patients admitted AHF: AHF: [15]
(2010) for AHF, and b-blockers: 62% b-blockers: 80%
patients with CHF ACEi/ARBs: 60% ACEi/ARBs:78%
MRA: 33% MRA: 55%
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CHF:
b-blockers: 86.7%
ACEi/ARBs: 88.5%
MRA: 43.7%
US
Fonarow et al. IMPROVE-HF 2005 -- 2007 15381 Patients with CHF CHF: [16]
(2008) b-blockers: 86%
ACEi/ARBs: 80%
MRA: 36%
Albert et al. (2009) GWTG-HF 2005 -- 2007 43625 Patients with AHF Unknown b-blockers: 89.7% [17]
ACEi/ARBs: 89.0%
MRA: 32.5%
Krantz et al. (2011) GWTG-HF 2009 -- 2010 9474 Patients with AHF b-blockers: 72.6% b-blockers: 94.6% [18]
ACEi/ARBs: 65.3% ACEi/ARBs: 92.9%
For personal use only.

MRA: 15.6% MRA: 32.2%

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 eplere-
none 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 pro-
hormone of BNP (NT-proBNP) levels and urinary albumin:
creatinine ratio (UACR) [50]. Although treatment with finere-
none resulted in a rise in potassium and a decrease in estimated
glomerular filtration rate (eGFR), these changes were signifi-
cantly 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 metab-
olites 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 car-
diac (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 con-
centration in comparison to cardiac concentrations [48,52,54].
This unequal distribution may explain the pronounced phar-
macologic effects of all steroidal MRAs in the kidney in rela-
tion 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
6.1 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 Fail-
ure Efficacy and Survival Study (EPHESUS) demonstrated
that treatment with eplerenone also resulted in improved
outcomes in patients with acute myocardial infarction

Expert Opin. Investig. Drugs (2015) 24(8) 3

 L. C. Y. Liu et al.

Table 2. Preclinical finerenone studies.

Author, Animal model Treatment arms n Results Ref.

publication
date

Kolkhof et al. Spontaneously Finerenone 12 per Finerenone resulted in reduction in mortality, [102]
(2012) hypertensive, -10 mg/kg/day group compared to placebo.
stroke prone male Eplerenone Finerenone reduced urinary:protein ratio, compared
rats on high salt -30 mg/kg/day to vehicle group (0.4 ± 0.03 vs 1.99 ± 0.40),
diet Spironolactone urinary OPN protein and mRNA in kidneys,
-30 mg/kg/day reduction of vascular, glomerular and tubule
Vehicle interstitial damage.
No mortality benefit or reduction in OPN
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concentration and vascular, glomerular and tubule

interstitial damage was observed in eplerenone or
spironolactone group
Delbeck et al. Sprague-Dawley rat Finerenone 7 -- 12 per Finerenone reduced systolic blood pressure and [47,48]
(abstract) hypertensive-driven - 0.1 mg/kg/day group heart weight-to-body weight ratio, proBNP levels
Kolkhof et al. heart failure model -1 mg/kg/day and resulted in a dose-dependent protection from
(2014) (deoxycorticoster- -10 mg/kg/day structural heart injury.
one acetate/salt Eplerenone Also, finerenone resulted in functional as well as
model), -30 mg/kg/day structural protection from kidney injury. Relative
-100 mg/kg/day kidney weights were decreased and proteinuria was
Vehicle dose-dependently reduced by treatment with
finerenone. In addition, treatment with finerenone
dose-dependently protected from glomerular,
tubular and vascular damage and reduced
For personal use only.

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
Kolkhof et al. Male Wistar rats Finerenone 10 -- 14 per Finerenone improved left ventricular systolic [48,103]
(2014) with heart failure -0.1 mg/kg/day group dysfunction in heart failure -- terms of contractility
Albrecht- induced by left -0.3 mg/kg/day (dp/dtmax) and relaxation (dp/dtmin).
Kupper et al. anterior descending -1 mg/kg/day Finerenone reduced plasma pro-BNP levels.
(2012) coronary artery Eplerenone OPN levels were dose-dependently decreased by
(abstract) ligation -100 mg/kg/day finerenone
Vehicle

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 obser-
vational 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
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 inves-
tigated 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 ran-
domized 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 simi-
lar (Figure 2) [50]. Following these positive outcomes, the
ARTS-HF was initiated (NCT01807221), investigating the
effects of finerenone in patients with worsening chronic sys-
tolic HF and type 2 diabetes and/or CKD. In this Phase IIb

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

 Finerenone

A.
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B.
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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 6.2Diabetic kidney disease
will be compared to eplerenone in patients with worsening With the growing worldwide prevalence of diabetes mellitus,
chronic HF and either type 2 diabetes with or without diabetic kidney disease is one of the common causes of
CKD or CKD alone. CKD [62-64]. RAAS activation, hypertension, hyperglycemia,

Expert Opin. Investig. Drugs (2015) 24(8) 5

 L. C. Y. Liu et al.
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For personal use only.
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 Expert Opin. Investig. Drugs (2015) 24(8)
development of renal injury, leading to glomerular and tubu-
lar 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 podo-
cytes, enhancing protein leakage [65-68]. In addition, animal
studies revealed that aldosterone is involved in renal inflam-
mation, 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 treat-
ment 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 dia-
betic 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 dose-
dependent 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, n Study Treatment arms Results Study Ref.

publication date population duration

Schjoedt et al. 20 Type 1 DM Crossover trial with ACEi or

30% reduction in albuminuria, no 2  2 months [79]
(2005) ARB + spironolactone 25 mg
significant difference in GFR, potassium
versus placebo and 24-h ambulatory BP
Rossing et al. 20 Type 2 DM Crossover trial with ACEi or 33% reduction in albuminuria, 6 mmHg 2  2 months [80]
(2005) ARB + spironolactone 25 mg reduction in SBP, potassium increase of
versus placebo 0.3 mmol/l, no significant difference in
GFR
Schjoedt et al. 20 Type 1 and Crossover trial with ACEi -or 32% reduction in albuminuria, 6 mmHg 2  2 months [81]
(2006) type 2 DM ARB + spironolactone 25 mg reduction in SBP, no significant
versus placebo difference in GFR and potassium
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Epstein et al. 268 Type 2 DM Enalapril + placebo 42 and 50% reduction in albuminuria 3 months [82]
(2006) vs for eplerenone 50 and 100 mg,
enalapril + eplerenone 50 mg respectively, vs 9% reduction in the
vs placebo group. No additional BP-
enalapril + 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.
van den 59 Type 2 DM ACEi or ARB + spironolactone 41% reduction in albuminuria, 7 mmHg 1 year [11]
Meiracker et al. 50 mg vs placebo reduction in SBP, more eGFR decline in
(2006) the spironolactone group compared to
placebo during the first 3 months of
treatment, 0.5 mmol/l increase in serum
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potassium.
Saklayen et al. 30 Type 2 DM Crossover trial, ACEi or 57% reduction in proteinuria, 12 mmHg 7 months [83]
(2008) 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
Mehdi et al. 80 Type 1 and ACEi + losartan 100 mg vs 34% reduction in albuminuria 1 year [84]
(2009) type 2 DM 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
Nielsen et al. 21 Type 1 DM Crossover trial, ACEi or 60% reduction in albuminuria, GFR 4 months [85]
(2012) ARB + spironolactone 25 mg decreased 6 ml/min/1.73m2 during the
vs placebo first 2 months of treatment with
spironolactone, no significant difference
in SBP or increase in serum potassium,
yet 6 patients experienced hyperkalemia
on spironolactone
Esteghamati et al. 136 Type 2 DM Enalapril (30 -- 40 mg) and After 1 year: 53% reduction in 1.5 years [86]
(2013) 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
Ruilope et al. 823 Type 2 DM ACEi or ARB + finerenone Dose-dependent reduction in 3 months [87]
(2015) (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.

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) 7

 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
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potassium [91]. However, chronic kidney dysfunction can
lead to impaired renal potassium secretion and patients suffer-
ing from CKD thus have a predisposition to a positive potas-
sium 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,
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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 insu-
lin deficiency, hypertonity and hyporeninemic hypoaldoster-
onism [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) com-
pared 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 compari-
sons 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 Expert Opin. Investig. Drugs (2015) 24(8)
placebo group) [6]. Thus, based on the numbers of the
ARTS, EPHESUS and EMPHASIS trials, the incidence num-
bers 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 treat-
ment duration was different between these studies. Further-
more, 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 inci-
dence of renal impairment was lower (3.8 vs 9.2%). Com-
pared 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 pla-
cebo 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 third-
generation 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 pro-
gression 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 hyperkale-
mia, 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.

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 stron-
ger 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-androgenic-
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 06/24/15
related side effects during finerenone administration would
be minimal. In addition, lower doses of finerenone were
needed to achieve similar cardiorenal protective effects com-
pared 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 dis-
tributed in cardiac and renal tissues in animals, in contrast to
spironolactone and eplerenone, which have higher renal
For personal use only.
concentrations than in the cardiac tissue [48]. The lower con-
centration 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 pub-
lished 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 finere-
none 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
Expert Opin. Investig. Drugs (2015) 24(8)
Finerenone
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 disadvan-
tages 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 out-
comes (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 hyper-
kalemia 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 stop-
ping 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 tolera-
bility [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 reim-
bursement 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
 L. C. Y. Liu et al.
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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: a.a.voors@umcg.nl
13