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Non-s e oidal mine aloco icoid ecep o an agonism o he ea men o
ca dio ascula and enal disease
Pe e B amlage 1,2, S ephanie Swi 1, Ma in Thoenes 3, Joan Mingue 1, Ca men Fe e o 2,
Roland E. Schmiede 4
1 Ins i u e o Pha macology and P e en i e Medicine, Mahlow, Ge many
2 Depa men o Pha macy and Pha maceu ical Technology, Facul y o Pha macy, Uni e si y
o Se illa, Spain
3 Léman Resea ch Ins i u e, Obe äge i, Swi ze land
4 Depa men o Neph ology and Hype ension, Uni e si y Hospi al o he Uni e si y
E langen-Nü nbe g, E langen, Ge many
Co espondence:
Pe e B amlage, MD, PhD, FESC, FACC
Ins i u e o Pha macology and P e en i e Medicine
Menzels asse 21, 15831 Mahlow, Ge many
Tel.: +49 3379 3147890 Fax: +49 3379 3147892
Email: pe e .b [email protected]
Jou nal: Eu J Hea Fail Ve sion: 13.09.2015
Wo d coun : 4,767 Abs ac : 170 Tables: 2
Figu es: 4 Re e ences: 65
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Abs ac
Pha maceu ical an agonism o he mine aloco icoid ecep o (MR) can p o ec agains o gan
damage caused by ele a ed aldos e one le els in pa ien s expe iencing hea ailu e (HF),
ch onic kidney disease (CKD), p ima y aldos e onism and hype ension. While adi ional
s e oid-based MR an agonis s e ec i ely educe mo ali y a es and ex end pa ien su i al,
hei b oad applica ion has been limi ed by signi ican side e ec s, mos no ably
hype kalaemia. Recen ly, ine enone (BAY94-8862) has eme ged as a nex -gene a ion non-
s e oidal dihyd opy idine-based MR an agonis designed o minimise o - a ge e ec s while
main aining po en e icacy. In his e iew, he au ho s explo e he ou comes o ine enone
he apy in se e al diseases associa ed wi h MR ac i i y. The au ho s compa e he (p e-)
clinical e icacy o ine enone wi h adi ional s e oid-based MR an agonis s. Finally, he
au ho s discuss ecen and ongoing clinical ials using ine enone o ea ch onic HF, CKD,
and diabe ic neph opa hy. Taken oge he p eclinical and clinical e idence sugges s ha
ine enone may achie e equi alen o gan-p o ec i e e ec s wi h educed le els o elec oly e
dis u bance compa ed o adi ional s e oid-based MR an agonis s. This suppo s u he
clinical de elopmen o ine enone o he ea men o ca dio ascula and enal disease.
Keywo ds: mine aloco icoid; ecep o ; an agonis ; hea ; kidney; ailu e; disease;
ine enone; ARTS, BAY94-8862
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In oduc ion
The speci ic in acellula s e oidal mine aloco icoid ecep o (MR) has a majo ole in he
enin-angio ensin-aldos e one sys em (RAAS), which egula es sodium eabso p ion and
po assium leakage in neph ons, and achie es co-o dina ed con ol o luid, ex acellula
olume, and elec oly e balance o egula e blood p essu e (BP) 1. The MR binds se e al
ligands, including aldos e one and co isol. Unde no mal condi ions, aldos e one ac s as a
MR agonis , while co isol ac s as an an agonis 2, and bo h bind he MR wi h simila
a ini ies 3.
Se e al disease s a es a e associa ed wi h ele a ed ac i a ion o he MR, including hea
ailu e (HF), ch onic kidney disease (CKD), p ima y aldos e onism, and hype ension.
Enhanced MR ac i i y can be d i en by inc eased le els o ci cula ing aldos e one, swi ches
in co isol ac i i y om MR an agonis o MR agonis , o ele a ed local exp ession o he MR
4. Such changes a e obse ed ollowing dis up ions in ho monal homeos asis du ing
ca dio ascula , enal, o ad enal pa hology 5. Pa hophysiological le els o aldos e one o
co isol, especially in combina ion wi h inapp op ia e sal and edox s a us, can damage
mul iple issues ha exp ess he MR 2, 6-8. Blockade o he aldos e one/co isol signalling
pa hway h ough MR an agonism is a clinically e ec i e me hod o p e en ing o gan
pa hologies.
MR an agonis he apy o ca dio ascula and enal disease
Cu en clinically-app o ed s e oid-based MR an agonis s, including spi onolac one,
can enone and he la e de eloped eple enone, mimic he molecula s uc u e o he na u al
MR ligands, aldos e one and co isol (Figu e 1) 9. These agen s ha e demons a ed signi ican
clinical e icacy in he ea men o se e al disease condi ions, including ch onic HF 10-14,
CKD 15, 16, p ima y aldos e onism, and hype ension 17-21. Spi onolac one and eple enone a e
conside ed highly e ec i e s a egies o he managemen o ca dio enal disease, and cu en
guidelines ecommend he addi ion o MR an agonis s du ing he managemen o
symp oma ic sys olic HF in pa ien s al eady ecei ing angio ensin-con e ing enzyme (ACE)
inhibi o s and be a-blocke s 22. Ye , su p isingly, only low numbe s (9–30%) o eligible
hospi alised HF pa ien s a e p esc ibed MR an agonis s 23. Despi e hese clea clinical
bene i s, he e emains a bias ha p e en s he p esc ip ion o MR an agonis s o pa ien s
displaying HF.
Such bias is undoub edly ela ed o he side e ec s associa ed wi h spi onolac one and
eple enone he apy. While he i s -gene a ion spi onolac one displays signi ican MR
an agonis ic po ency, i also an agonises he and ogen ecep o (AR) o d i e he de elopmen
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o gynaecomas ia and impo ence in men, and ac s as an agonis o he p oges e one ecep o
o cause ameno hoea in p e-menopausal women (Table 1) 10, 23. These side e ec s ypically
limi pa ien adhe ence o he apy. While he second-gene a ion eple enone a ge s he MR
wi h a g ea e speci ici y, leading o ewe side e ec s, i lacks he po ency o spi onolac one
(Table 1) 18, 19.
Finally, and pe haps o g ea es clinical conce n, blockade o MRs in he kidney inc eases
sodium exc e ion wi h a subsequen educ ion in blood olume, and a co esponding e en ion
o po assium. This e ec may be exace ba ed by he biodis ibu ion pa e n o bo h
spi onolac one and eple enone, which build up o highe concen a ions in enal issue
compa ed o myoca dium 24. Reduced enal elimina ion o po assium esul s in
hype kalaemia, whe e po assium le els in he blood inc ease o po en ially pa hological le els
10, 11, 16, 25. Incidence o hype kalaemia in he Randomized Aldac one E alua ion S udy
(RALES) was only sligh ly g ea e in he spi onolac one a m han in he placebo a m 10. In a
subsequen assessmen o he eal wo ld si ua ion, howe e , signi ican hype kalaemia- ela ed
mo bidi y and mo ali y co ela ed wi h an inc ease in he p esc ip ion a e o he d ug 26. In a
sepa a e s udy in ol ing a popula ion o unselec ed hea ailu e pa ien s ea ed wi h
spi onolac one, 36% eached a se um po assium le el o >5 mmol/L 27. In he Eple enone
Pos -acu e Myoca dial In a c ion Hea Failu e E icacy and Su i al S udy (EPHESUS),
highe p opo ions o pa ien s being ea ed wi h eple enone we e no ed o ha e po assium
le els > 5 mEq/L in compa ison o hose ecei ing a placebo (15.6 s. 11.2%; p < 0.001) 28. A
simila end was ound in he Eple enone in Mild Pa ien s Hospi aliza ion And Su I al
S udy in Hea Failu e (EMPHASIS-HF; 11.8 s. 7.2% o eple enone and placebo,
espec i ely; p < 0.001) 25. These high a es o hype kalaemia appea o be manageable in
pa ien s wi h no mal kidney unc ion o mild- o-mode a e kidney disease. Howe e , pa ien s
wi h condi ions such as CKD o diabe es a e a inc eased isk o de eloping ele a ed
po assium le els, and display inc eased a es o hype kalaemia- ela ed hospi alisa ion and
dea h ollowing MR an agonis he apy 29-32. Ul ima ely, all pa ien s ecei ing spi onolac one
o eple enone he apy equi e ca e ul se ial moni o ing o se um po assium le els and enal
unc ion 28, which may ep esen a p ac ical impedimen o ou ine clinical p esc ip ion.
Pa ien s wi h an S810L gain-o - unc ion mu a ion wi hin he MR, which con ibu es o ea ly-
onse o ges a ional hype ension, a e also ineligible o MR an agonis he apy, since bo h
eple enone and spi onolac one pa adoxically enhance signalling h ough his mu an ecep o
o p omo e hype ension 33, 34. Fu he , olde pa ien s (75 yea s) appea o be a signi ican ly
ele a ed isk o hype kalaemia- ela ed hospi al admissions and subsequen in-hospi al dea hs
ollowing MR an agonis he apy 35. Ne e heless, se e al isk- o-bene i assessmen s
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ul ima ely suppo he use o MR an agonis s in pa ien s ac oss a spec um o low-, medium-,
and high- isk.
Fine enone, an al e na i e non-s e oidal MR an agonis
The molecula s uc u e o MR an agonis s can impac he p o ile o biodis ibu ion, po ency,
selec i i y, physicochemis y and, ul ima ely, he balance be ween clinical e icacy and side
e ec s 24. Thus, in an e o o maximise ca diac and/o ascula ac i i y and minimise
dis up ions in enal sodium/po assium homeos asis, he de elopmen o nex -gene a ion MR
an agonis s has ocussed on non-s e oidal compounds. This app oach has he po en ial o
ex end he ca diop o ec i e bene i s o MR an agonis s o mul iple pa ien popula ions ha a e
cu en ly con aindica ed o his he apy 36. In pa icula , dihyd opy idines, adi ionally
known o hei u ili y as L- ype calcium channel an agonis s, ha e been iden i ied as a new
class o non-s e oidal MR an agonis s 37.
Fine enone (BAY94-8862) is a hi d-gene a ion po en , speci ic, o ally bioa ailable, non-
s e oidal MR an agonis ha was gene a ed du ing high- h oughpu sc eening and subsequen
emodelling o cyano-1,4-dihyd opy idine compounds 38. Fine enone is accommoda ed in he
MR ligand binding ca i y in a dis inc manne om s e oid-based MR an agonis s, and shows
good s e ic binding wi h a MR IC50 o 17.8 nM (Table 1) 38, 39. Impo an ly, ine enone is o e
500- old mo e selec i e o he MR e sus s e oid ecep o s wi hin he same supe amily,
including he glucoco icoid ecep o (GR), and ogen ecep o (AR), and p oges e one
ecep o (PR) (Table 1). S uc u al s udies sugges ha his selec i i y is p edominan ly
media ed h ough a hyd ogen bond dono in e ac ion wi h he unique MR-speci ic esidue,
Se 810 38. Fu he , ine enone has no obse ed o - a ge in e ac ions wi h o e 65 biological
ecep o s and ion channels 38, and lacks he abili y o block L- ype calcium channels, which is
associa ed wi h many o he dihyd opy idine-based MR an agonis s 38, 40, 41.
Fine enone displays subs an ially al e ed biochemical and biophysical p ope ies compa ed o
spi onolac one and eple enone (Table 1). O gan dis ibu ion o adioac i ely-labelled
ine enone one hou a e o al adminis a ion in Wis a a s is p edominan ly con ined o he
ascula and in e s i ial spaces, and can be clea ly de ec ed in well- ascula ised o gans such
as he hea , lung, li e , and kidney 42. While adi ional s e oid-based MR an agonis s
ypically build up o highe concen a ions in he kidney e sus he hea 24, a p ope y ha
may con ibu e o hype kalaemic side e ec s, ine enone achie es an equi alen dis ibu ion
be ween ca diac and enal compa men s 42. In heal hy subjec s, he plasma hal li e o
ine enone is ~2 h, much sho e han spi onolac one (~15 h) 24, 43 al hough oughly equi alen
o eple enone (4–6 h). The ela i ely long hal -li e o spi onolac one has he pha macokine ic

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consequence o a slow onse o ac ion, and e ec s ha pe sis o se e al days ollowing d ug
discon inua ion 44. Howe e , he kine ics o he downs eam e ec s o ine enone on a ge
o gans has no been ex ensi ely s udied 24. Finally, he me abolic consequences o ine enone
o al applica ion ha e ye o be explo ed. Thus i emains o be de e mined i his d ug b eaks
down o gene a e mul iple ac i e me aboli es (simila o spi onolac one) o emains
essen ially in ac (simila o eple enone).
In heal hy a s, ine enone has li le impac on he o al u ina y olume (excep a e y high
doses [100 mg/kg]), and no measu able impac on u ina y po assium le els 42. Howe e , a
models a e ypically esis an o he de elopmen o hype kalaemia ollowing RAAS
inhibi ion 45. Con e sely, na iu e ic esponses, which can ac as a su oga e ma ke o enal
elec oly e homeos asis in a models, inc ease in a dose-dependen manne ollowing
ine enone he apy 42. In a di ec compa ison wi h he s e oid-based MR an agonis ,
eple enone, equi alen na iu e ic esponses we e obse ed a 1 mg/kg ine enone and 10–30
mg/kg eple enone 42, sugges ing ha ine enone ep esen s a mo e po en MR an agonis .
P e-clinical assessmen o ine enone in models o ca dio ascula and enal disease
Fine enone has been es ed in se e al p e-clinical a models o ca dio enal disease in
compa ison o he adi ional s e oid-based MR an agonis , eple enone. These include a model
o hype aldos e onism-induced end-o gan damage (induced by a 10-week ea men wi h
deoxyco icos e one-ace a e (DOCA)/sal ) 42, a model o pos -MI HF (induced by co ona y
a e y liga ion) 42, and a model o se e e a e ial hype ension (induced by main aining
spon aneously hype ensi e, s oke-p one a s (SHRSP) on a 7-week high-sal die ) 46.
In a model o hype aldos e onism-induced end-o gan damage, low doses o ine enone
ou pe o med eple enone in p o ec ing bo h he hea and kidney agains s uc u al and
unc ional damage 42. Di ec compa isons we e d awn be ween ou comes wi h equi alen
na iu e ic doses o ine enone (1–10 mg/kg) and eple enone (30–100 mg/kg). In he hea ,
ine enone ea men dec eased sys olic BP (SBP) and minimised ca diac hype ophy a he
ul as uc u al le el 42. Eple enone had no signi ican impac on ca diac hype ophy.
Simila ly, ine enone signi ican ly educed plasma le els o p oho mone o b ain na iu e ic
pep ide (p o-BNP), a pa hological ma ke o en icula emodelling and myoca dial
ischaemia, beyond he le el obse ed wi h eple enone, sugges ing lowe le els o hea s ess
42. A he kidney le el, his ological analysis demons a ed less glome ula and
ubuloin e s i ial damage, and less kidney hype ophy ollowing ine enone ea men 42.
Fine enone also educed le els o geno oxic damage, cha ac e ised by double-s and DNA
b eaks, in enal cells 47. Con e sely, eple enone and placebo g oups displayed mo e e idence
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o glome ula scle osis, ubula degene a ion, ubula dila ion, and p o einu ia cas s 42.
P o einu ia was also amelio a ed o a g ea e deg ee ollowing ine enone ea men compa ed
o eple enone. Finally, he exp ession le els o genes in ol ed in p o-in lamma o y and p o-
ib o ic p ocesses in he kidney, including PAI-1, MCP-1, os eopon in, and MMP-2, we e
educed o he g ea es deg ee ollowing ine enone ea men 42.
In a model o pos -MI HF, lowe doses o ine enone (0.1, 0.3, o 1 mg/kg/day) we e di ec ly
compa ed wi h eple enone (100 mg/kg/day). Fine enone ea men achie ed clinical e icacy
a a dose o 1 mg/kg/day; lowe doses had no impac , equi alen o eple enone 42. Bo h
sys olic and dias olic le en icula unc ion was imp o ed ollowing ine enone
adminis a ion, wi h signi ican enhancemen s in ca diac con ac ili y and elaxa ion.
Simila ly, ine enone educed plasma le els o p o-BNP wi hou impac ing BP 42. Plasma
le els o aldos e one we e also analysed as an indi ec measu e o ine enone occupancy a
he MR, since an agonism o he MR ypically inc eases ci cula ing le els o unbound
aldos e one 48, and he magni ude o his inc ease can e lec he e iciency and ex en o MR
blockade. Fine enone signi ican ly inc eased ci cula ing le els o aldos e one compa ed o
placebo con ols 42. Eple enone achie ed a simila inc ease in plasma aldos e one
concen a ions, sugges ing ha while eple enone was capable o e ec i ely blocking he MR,
his was ul ima ely no ansla ed in o a downs eam impac on ca diop o ec i e pa ame e s.
Finally, doses o ine enone a 10 mg/kg/day we e epo ed o signi ican ly imp o e he
su i al o se e ely hype ensi e a s compa ed o ei he eple enone (30 mg/kg/day) o
spi onolac one (30 mg/kg/day) 46. Bo h s e oid-based MR an agonis s had no signi ican
impac on mo ali y a es. Simul aneous educ ions in u ina y p o ein/c ea inine a ios and
os eopon in exp ession le els ollowing ine enone ea men indica ed a bene icial impac on
kidney heal h 46. This was suppo ed by his opa hological analysis demons a ing ha
ine enone ea men educed ascula , glome ula , and ubuloin e s i ial damage. In con as ,
no such e ec s we e ound on analysis o animals ea ed wi h ei he spi onolac one o
eple enone.
P og ess o ine enone o clinical ials
ARTS
Fine enone has been es ed h ough phase I sa e y and ole abili y s udies o phase IIb sa e y
and e icacy ials (Table 2). The phase II Mine aloco icoid Recep o An agonis Tole abili y
S udy (ARTS) ep esen s he mos ex ensi e published ial o ine enone in pa ien s wi h HF
wi h a educed ejec ion ac ion (HFREF) and mild- o-mode a e CKD 49. ARTS was designed
as a 4-week andomised, double-blind, placebo-con olled, pa allel-g oup, sa e y and
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ole abili y s udy ha was di ided in o wo pa s. The i s pa compa ed ine enone (2.5, 5,
o 10 mg pe day) s. placebo in 65 pa ien s wi h HF and mild CKD. The second pa
compa ed ine enone (2.5, 5, o 10 mg o (2 × 5 mg) pe day) s. spi onolac one (25 o 50 mg
pe day) s. placebo in 392 pa ien s wi h HF and mode a e CKD 50. P ima y ou come
measu emen s cen ed on enal pa ame e s, including se um po assium le els and ma ke s o
kidney heal h and unc ion, such as u ina y albumin o c ea inine a io (UACR) and es ima ed
glome ula il a ion a e (eGFR). Seconda y ou comes included changes in ma ke s o
ca diac heal h, pha macokine ic p o iles, and sa e y and ole abili y 49. Ou come
measu emen s we e made a isi 4 (d15  1; app oxima ely hal way h ough he ial) and
isi 7 (d29  2; a he conclusion o he ial).
Mean inc eases in se um po assium concen a ions we e signi ican ly lowe in all ine enone
g oups compa ed o spi onolac one (Figu e 2) 50. Indeed, a 2.5 mg and 5 mg daily doses o
ine enone, he e was no signi ican change in se um po assium le els compa ed o placebo
con ols. Minimal ine enone dis up ions in se um po assium le els we e also e iden in sub-
analyses o ei he olde (>75 yea s) pa ien s, indi iduals wi h HFREF o g ea e se e i y
(NYHA class III), o pa ien s who had p e ious expe ience wi h MR an agonis he apy. The
lack o obse ed hype kalaemia in aged indi iduals ecei ing ine enone he apy was
pa icula ly impo an , since spi onolac one has p e iously been associa ed wi h inc eased
hype kalaemia-associa ed mo ali y in his popula ion 26.
Al hough no s a is ically signi ican , he e was a end owa ds a educ ion in he UACR
ac oss all ea men g oups ( ine enone and spi onolac one) compa ed o placebo 50.
Spi onolac one (25 o 50 mg pe day) signi ican ly educed eGFR compa ed o placebo
con ols, indica ing a nega i e impac on kidney unc ion a his clinically ele an dose 10. On
he o he hand, o ine enone, eGFR only de e io a ed signi ican ly a he highes dose
p esc ibed (10 mg/day) (Figu e 2) 50. All o he ine enone doses (2.5 mg, 5 mg, (2 × 5mg) pe
day) demons a ed no signi ican de ia ion in eGFR om placebo con ol. Ul ima ely,
acking degene a ion o enal unc ion ei he h ough changes in se um c ea inine le els o
eGFR ollowing ine enone ea men demons a ed simila changes o placebo con ols.
Wo sening enal unc ion was obse ed in <11% o pa ien s ac oss bo h he placebo and all
ine enone g oups, bu in 38% o pa ien s ecei ing spi onolac one.
No signi ican changes in bioma ke s o hea heal h we e obse ed ollowing ine enone o
spi onolac one he apy 50. In pa ien s ecei ing >2.5mg ine enone o spi onolac one (25 o 50
mg), he e was a end owa ds dec eased median concen a ions o bo h N- e minal p o-BNP
(NT-p o-BNP) and BNP i sel compa ed o placebo con ols. NT-p o-BNP le els a e s ongly
p edic i e o long- e m mo ali y in pa ien s wi h hea disease 51. SBP emained a highly
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a iable measu emen wi hin each pa ien g oup. Only pa ien s ecei ing spi onolac one
demons a ed a signi ican educ ion in SBP compa ed o placebo con ols; no an i-
hype ensi e e ec s we e obse ed ac oss ine enone ea men g oups 50.
Indi ec e ec s o ine enone we e also analysed by measu ing aldos e one le els in plasma.
All ine enone doses abo e 2.5 mg we e associa ed wi h signi ican inc eases in se um
aldos e one le els 50. Ye he mos subs an ial inc ease was obse ed ollowing spi onolac one
he apy, almos ce ainly as a consequence o he highe dosage e lec ing a g ea e
occupancy o MR si es. Since ine enone achie ed mo e subs an ial bene i s on bioma ke s o
ca diac heal h han spi onolac one, despi e ha ing less impac on plasma aldos e one le els,
his sugges s an uncoupling o he ela ionship be ween ci cula ing aldos e one le els and
ca diop o ec i e/neph op o ec i e e ec s.
Finally, and o c ucial clinical impo ance, he majo i y o ine enone ea men -associa ed
ad e se e en s we e mild. Se ious ad e se e en s ac oss all ea men g oups (including
spi onolac one) we e obse ed in 25/457 pa ien s (5.5%). In pos -hoc analyses ac oss all
ine enone g oups, a es o hype kalaemia, enal impai men , o enal ailu e we e no
signi ican ly di e en om placebo con ols 50. Unexpec edly, his di e ence was e en
smalle when compa ing only he highes ine enone dose g oups (5 mg o 10 mg pe day).
Con e sely, a es o hype kalaemia- ela ed enal dys unc ion we e signi ican ly ele a ed in
pa ien s ecei ing spi onolac one. Due o limi a ions o he ARTS clinical s udy design
(including he numbe o ec ui ed pa ien s and he ela i ely sho clinical schedule o
he apy), he abili y o ine enone o p o ec agains majo ca dio ascula e en s and imp o e
su i al a es could no be in es iga ed. This limi a ion also p e en ed he analysis o a es o
gynaecomas ia, impo ence, and ameno hoea, which ep esen common side e ec s o
spi onolac one he apy.
ARTS-DN
Following on om he ARTS ial, a simila s udy was ca ied ou o compa e he e ec s o
ine enone wi h placebo in pa ien s wi h ype 2 diabe es and diabe ic neph opa hy 52. Pa ien s
we e andomised o ecei e once daily doses o ine enone (7.5, 10, 15, o 20 mg) o placebo.
The p ima y endpoin was he a io o UACR om baseline o he end o he 90-day ollow-
up pe iod, wi h o he endpoin s including se um po assium le els, eGFR, and ad e se e en s.
Fo he pa ien s ecei ing ine enone, he a io o UACR om 90 days o baseline dec eased
in a dose-dependen manne , a end which was main ained when he alues we e adjus ed by
hose o he placebo g oup (Figu e 3) 53. By he end o he s udy, a educ ion in UACR o
≥50% om baseline was achie ed o 17.2%, 17.2%, 33.6%, and 40.2% o he pa ien s in he
Page 16 o 26
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Page 20 o 26
Figu es
Figu e 1. Molecula s uc u es o na u al MR ligands and syn he ic MR an agonis s.
Page 21 o 26
Figu e 2. E ec o ine enone on kidney unc ion in he ARTS ial.
Legend: Selec ed esul s om he ARTS ial. A) Change in se um po assium le els om
baseline o isi 4 and 6/7, B) Change in eGFR om baseline o isi 4 and 6/7. Rep oduced
om 50.

Page 22 o 26
Figu e 3. Change in u ina y albumin o c ea inine a io in he ARTS-DN ial
Legend: Rep oduced om 53
Page 23 o 26
Figu e 4. P opo ion o pa ien s achie ing a >30% dec ease in NT-p oBNP le els du ing
he 90-day ARTS-HF ial
Legend: Adap ed om 55.
Page 24 o 26
Tables
Table 1. Cha ac e is ics o i s -, second-, and hi d-gene a ion MR an agonis s
Spi onolac one
Eple enone
Fine enone
T ade name(s)
Aldac one
Insp a
Class
S e oidal
S e oidal
Dihyd opy idine
MR IC50 (nM)
24
990
17.8
AR IC50 (nM)
77
≥21,240
≥10,000
GR IC50 (nM)
2,410
≥21,980
≥10,000
PR EC50 (nM)
740
≥31,210
≥10,000
Hal -li e (h)
1.4 (ac i e me aboli es 12–35)
4–6 h
1.7–2.8
Legend: MR, mine aloco icoid ecep o ; AR, and ogen ecep o ; GR, glucoco icoid ecep o ; PR, p oges e one ecep o ; IC50, concen a ion o an agonis
equi ed o inhibi 50% ac i a ion o ecep o ; EC50, concen a ion o ligand equi ed o achie e 50% ac i a ion o he ecep o . (Adap ed om 38, 39, 43)
Page 25 o 26
Table 2. Fine enone in clinical ials
Clinical T ial
Iden i ie
Phase
S udy
Pa ien Popula ion
Es ima ed
Pa ien
G oup
Size
Daily
Fine enone
Dose
(mg)
Time
F ame
Compa a o
A m(s)
P ima y (1°) and
Seconday (2°) Ou come
Measu es
T ial S a
Da e
Publica ions
NCT01473108
I
Sa e y, Tole abili y,
Pha macokine ics &
Pha macodynamics a e
Adminis a ion wi h
0.5mg Flud oco isone
Heal hy male
subjec s
n = 67
2.5, 5, 10, 15
o 20
Single
dose,
moni o ed
up o 28
days
Placebo
Eple enone
50mg/day
1° Pha macodynamics
(na iu esis)
2° Pha macokine ics
(maximum concen a ion
[Cmax] & a ea-unde -
cu e [AUC]) & ad e se
e en s
Ma ch
2010
43
NCT01687920
I
Dose P opo ion
Heal hy male
subjec s
n = 25
1.25, 2.5, 5,
7.5 o 10
Single
dose,
moni o ed
up o 48h
N/A
1° Pha macokine ic dose
p opo ionali y
2° Ad e se e en s
Sep embe
2012
NCT01345656
II
Sa e y and Tole abili y
(ARTS)
Pa A: Subjec s
wi h s able ch onic
HF wi h le
en icula sys olic
dys unc ion and
mild CKD
Pa B: Subjec s
wi h s able ch onic
HF wi h le
en icula sys olic
dys unc ion and
mode a e CKD
n = 457
2.5, 5, 10 o
(5 x 2)
Daily dose
o 4
weeks,
moni o ed
up o 4
weeks
Placebo
Spi onolac one
25-50mg/day
1° Change in se um
po assium
2° Change in se um
magnesium, BP & hea
a e
May 2011
49, 50
NCT01874431
II
Sa e y and E icacy
(ARTS-DN)
Subjec s wi h Type
2 diabe es melli us
and diabe ic
neph opa hy
n = 821
1.25, 2.5, 5,
7.5, 10, 15
o 20
Daily dose
o 90 days,
moni o ed
up o 120
days
Placebo
1° Change in UACR
2° Change in se um
po assium, enal unc ion,
quali y-o -li e & ad e se
e en s
June 2013
52, 53
NCT01968668
II
Sa e y and E icacy
(ARTS-DN Japan)
Japanese subjec s
wi h Type 2 diabe es
melli us
& diabe ic
neph opa hy
n = 96
1.25, 2.5, 5,
7.5, 10, 15
o 20
Daily dose
o 90 days,
moni o ed
up o 90
days
Placebo
1° Change in UACR
2° Change in se um
po assium
Oc obe
2013