Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease

Page 1 o 26 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 Page 2 o 26 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 Page 3 o 26 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 Page 4 o 26 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 Page 5 o 26 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 Page 6 o 26 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 Page 7 o 26 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 Page 8 o 26 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 Page 9 o 26 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 24. Kolkho P, Bo den SA. Molecula pha macology o he mine aloco icoid ecep o : p ospec s o no el he apeu ics. Mol Cell Endoc inol 2012;350(2):310-7. 25. Zannad F, McMu ay JJ, K um H, an Veldhuisen DJ, Swedbe g K, Shi H, Vincen J, Pocock SJ, Pi B. Eple enone in pa ien s wi h sys olic hea ailu e and mild symp oms. N Engl J Med 2011;364(1):11-21. 26. Juu link DN, Mamdani MM, Lee DS, Kopp A, Aus in PC, Laupacis A, Redelmeie DA. Ra es o hype kalemia a e publica ion o he Randomized Aldac one E alua ion S udy. N Engl J Med 2004;351(6):543-51. 27. S ensson M, Gus a sson F, Gala ius S, Hildeb and PR, A a D. How p e alen is hype kalemia and enal dys unc ion du ing ea men wi h spi onolac one in pa ien s wi h conges i e hea ailu e? J Ca d Fail 2004;10(4):297-303. 28. Pi B, Bak is G, Ruilope LM, DiCa lo L, Mukhe jee R. Se um po assium and clinical ou comes 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). Ci cula ion 2008;118(16):1643-50. 29. Schepkens H, Vanholde R, Billiouw JM, Lamei e N. Li e- h ea ening hype kalemia du ing combined he apy wi h angio ensin-con e ing enzyme inhibi o s and spi onolac one: an analysis o 25 cases. Am J Med 2001;110(6):438-41. 30. W enge E, Mulle R, Moesen hin M, Wel e T, F olich JC, Neumann KH. In e ac ion o spi onolac one wi h ACE inhibi o s o angio ensin ecep o blocke s: analysis o 44 cases. BMJ 2003;327(7407):147-9. 31. Einho n LM, Zhan M, Hsu VD, Walke LD, Moen MF, Selige SL, Wei MR, Fink JC. The equency o hype kalemia and i s signi icance in ch onic kidney disease. A ch In e n Med 2009;169(12):1156-62. 32. Eschalie R, McMu ay JJ, Swedbe g K, an Veldhuisen DJ, K um H, Pocock SJ, Shi H, Vincen J, Rossignol P, Zannad F, Pi B. Sa e y and e icacy o eple enone in pa ien s a high isk o hype kalemia and/o wo sening enal unc ion: analyses o he EMPHASIS-HF s udy subg oups (Eple enone in Mild Pa ien s Hospi aliza ion And Su I al S udy in Hea Failu e). J Am Coll Ca diol 2013;62(17):1585-93. 33. Gelle DS, Fa hi A, Pinke on N, F adley M, Mo i z M, Spi ze A, Meinke G, Tsai FT, Sigle PB, Li on RP. Ac i a ing mine aloco icoid ecep o mu a ion in hype ension exace ba ed by p egnancy. Science 2000;289(5476):119-23. 34. Hul man ML, K asnope o a NV, Li S, Du S, Xia C, Die z JD, Lala DS, Welsch DJ, Hu X. The ligand-dependen in e ac ion o mine aloco icoid ecep o wi h coac i a o and co ep esso pep ides sugges s mul iple ac i a ion mechanisms. Mol Endoc inol 2005;19(6):1460-73. 35. Rossignol P, Dob e D, McMu ay JJ, Swedbe g K, K um H, an Veldhuisen DJ, Shi H, Messig M, Vincen J, Gi e d N, Bak is G, Pi B, Zannad F. Incidence, de e minan s, and Page 17 o 26 p ognos ic signi icance o hype kalemia and wo sening enal unc ion in pa ien s wi h hea ailu e ecei ing he mine aloco icoid ecep o an agonis eple enone o placebo in addi ion o op imal medical he apy: esul s om he Eple enone in Mild Pa ien s Hospi aliza ion and Su i al S udy in Hea Failu e (EMPHASIS-HF). Ci c Hea Fail 2014;7(1):51-8. 36. Baue sachs J. The ARTS o hi d-gene a ion mine aloco icoid ecep o an agonis s: achie ing ca dio ascula bene i wi h minimized enal side e ec s? Eu Hea J 2013;34(31):2426-8. 37. E gueden J-K, Kolkho P, Kuhl A, Pook E, Sandne P, Schlemme K-H, S asch J-P. Fluo enone 1, 4,-dihyd opy idin de i a i es. In: Baye Heal hca e AG., Ge many; 2005. 38. Bä acke L, Kuhl A, Hillisch A, G osse R, Figue oa-Pe ez S, Heck o h H, Ni sche A, E guden JK, Gielen-Hae wig H, Schlemme KH, Mi endo J, Paulsen H, Pla zek J, Kolkho P. Disco e y o BAY 94-8862: a nons e oidal an agonis o he mine aloco icoid ecep o o he ea men o ca dio enal diseases. ChemMedChem 2012;7(8):1385-403. 39. Faga J, Hillisch A, Huye J, Ba acke L, Fay M, Pleiss U, Pook E, Scha e S, Ra es in-Oblin ME, Kolkho P. A new mode o mine aloco icoid ecep o an agonism by a po en and selec i e nons e oidal molecule. J Biol Chem 2010;285(39):29932-40. 40. A hance GB, Wooda d SS, Die z JD, Ga land DJ, Wagne GM, Iyana K, Collins JT, Blinn JR, Numann RE, Hu X, Huang HC. S e eochemical equi emen s o he mine aloco icoid ecep o an agonis ac i i y o dihyd opy idines. J Med Chem 2010;53(10):4300-4. 41. Die z JD, Du S, Bol en CW, Payne MA, Xia C, Blinn JR, Funde JW, Hu X. A numbe o ma ke ed dihyd opy idine calcium channel blocke s ha e mine aloco icoid ecep o an agonis ac i i y. Hype ension 2008;51(3):742-8. 42. Kolkho P, Delbeck M, K e schme A, S einke W, Ha mann E, Ba acke L, Ei ne F, Alb ech -Kuppe B, Scha e S. Fine enone, a no el selec i e nons e oidal mine aloco icoid ecep o an agonis p o ec s om a ca dio enal inju y. J Ca dio asc Pha macol 2014;64(1):69-78. 43. Len ini S, Kimmeskamp-Ki schbaum N, Wensing G, Heinig R. BAY 94-8862 Exe s a Po en Na iu e ic E ec in Heal hy Male Subjec s P e- ea ed Wi h Flud oco isone: Findings F om a P oo -o -concep S udy. Ci cula ion 2012;126(A10732). 44. Sica DA. Pha macokine ics and pha macodynamics o mine aloco icoid blocking agen s and hei e ec s on po assium homeos asis. Hea Fail Re 2005;10(1):23-9. 45. Ga cia NH, Baigo ia ST, Juncos LI. Hype kalemia, enal ailu e, and con e ing- enzyme inhibi ion: an o e a ed connec ion. Hype ension 2001;38(3 P 2):639-44. 46. Kolkho P, K e schme A, Ba acke L, Ha mann E, Scha e S. Imp o ed su i al and neph op o ec ion in hype ensi e a s by BAY 94-8862, a no el non-s e oidal Page 18 o 26 mine aloco icoid ecep o an agonis . 2012: Abs ac 33 (suppl.1), p. 978-979. Eu opean Hea Jou nal. 47. Schupp N, Kolkho P, Queisse N, Bä acke L, K e schme A, Ha mann E, Schä e S, S oppe H. Aldos e one causes DNA damage in i o and in kidneys o DOCA/sal a s, media ed by he mine aloco icoid ecep o . Toxicology Le e s 2009(189S):S98. 48. Eudy RJ, Sahas abudhe V, Sweeney K, Tugnai M, King-Ahmad A, Nea K, Lo ia P, Banke ME, Pio owski DW, Bous any-Ka i CM. The use o plasma aldos e one and u ina y sodium o po assium a io as ansla able quan i a i e bioma ke s o mine aloco icoid ecep o an agonism. J T ansl Med 2011;9:180. 49. Pi B, Filippa os G, Gheo ghiade M, Kobe L, K um H, Ponikowski P, Nowack C, Kolkho P, Kim SY, Zannad F. Ra ionale and design o ARTS: a andomized, double-blind s udy o BAY 94-8862 in pa ien s wi h ch onic hea ailu e and mild o mode a e ch onic kidney disease. Eu J Hea Fail 2012;14(6):668-75. 50. Pi B, Kobe L, Ponikowski P, Gheo ghiade M, Filippa os G, K um H, Nowack C, Kolkho P, Kim SY, Zannad F. Sa e y and ole abili y o he no el non-s e oidal mine aloco icoid ecep o an agonis BAY 94-8862 in pa ien s wi h ch onic hea ailu e and mild o mode a e ch onic kidney disease: a andomized, double-blind ial. Eu Hea J 2013;34(31):2453-63. 51. Omland T, Pe sson A, Ng L, O'B ien R, Ka lsson T, He li z J, Ha o d M, Caidahl K. N- e minal p o-B- ype na iu e ic pep ide and long- e m mo ali y in acu e co ona y synd omes. Ci cula ion 2002;106(23):2913-8. 52. Ruilope LM, Aga wal R, Chan JC, Coope ME, Ganse oo RT, Halle H, Remuzzi G, Rossing P, Schmiede RE, Nowack C, Fe ei a AC, Piepe A, Kimmeskamp-Ki schbaum N, Bak is GL. Ra ionale, design, and baseline cha ac e is ics o ARTS-DN: a andomized s udy o assess he sa e y and e icacy o ine enone in pa ien s wi h ype 2 diabe es melli us and a clinical diagnosis o diabe ic neph opa hy. Am J Neph ol 2014;40(6):572-81. 53. Bak is GL, Aga wal R, Chan JC, Coope ME, Ganse oo RT, Halle H, Remuzzi G, Rossing P, Schmiede RE, Nowack C, Kolkho P, Joseph A, Piepe A, Kimmeskamp- Ki schbaum N, Ruilope LM. E ec o Fine enone on Albuminu ia in Pa ien s Wi h Diabe ic Neph opa hy: A Randomized Clinical T ial. JAMA 2015;314(9):884-94. 54. Pi B, Anke SD, Bohm M, Gheo ghiade M, Kobe L, K um H, Maggioni AP, Ponikowski P, Voo s AA, Zannad F, Nowack C, Kim SY, Piepe A, Kimmeskamp- Ki schbaum N, Filippa os G. Ra ionale and design o Mine Aloco icoid Recep o an agonis Tole abili y S udy-Hea Failu e (ARTS-HF): a andomized s udy o ine enone s. eple enone in pa ien s who ha e wo sening ch onic hea ailu e wi h diabe es and/o ch onic kidney disease. Eu J Hea Fail 2015;17(2):224-32. Page 19 o 26 55. Filippa os G, Anke SD, Böhm M, Gheo ghiade M, Kobe L, K um H, Maggioni AP, Ponikowski P, Voo s AA, Zannad F, Kim SY, Nowack C, Palombo G, Kolkho P, Kimmeskamp-Ki schbaum N, Piepe A, Pi B. Resul s o ARTS-HF: ine enone e sus eple enone in pa ien s wi h wo sening ch onic hea ailu e and diabe es and/o ch onic kidney disease. 2015. 56. Mena d J. The 45-yea s o y o he de elopmen o an an i-aldos e one mo e speci ic han spi onolac one. Mol Cell Endoc inol 2004;217(1-2):45-52. 57. Yang J, Young MJ. The mine aloco icoid ecep o and i s co egula o s. J Mol Endoc inol 2009;43(2):53-64. 58. Tama go J, Solini A, Ruilope LM. Compa ison o agen s ha a ec aldos e one ac ion. Semin Neph ol 2014;34(3):285-306. 59. Le y DG, Rocha R, Funde JW. Dis inguishing he an ihype ensi e and elec oly e e ec s o eple enone. J Clin Endoc inol Me ab 2004;89(6):2736-40. 60. Kjeldsen S, Feldman RD, Lisheng L, Mou ad JJ, Chiang CE, Zhang W, Wu Z, Li W, Williams B. Upda ed Na ional and In e na ional Hype ension Guidelines: A Re iew o Cu en Recommenda ions. D ugs 2014. 61. Schupp N, Kolkho P, Queisse N, Ga ne S, Schmid U, K e schme A, Ha mann E, Oli RG, Scha e S, S oppe H. Mine aloco icoid ecep o -media ed DNA damage in kidneys o DOCA-sal hype ensi e a s. Faseb j 2011;25(3):968-78. 62. Na iai T, Fuji a K, Mo i M, Ka ayama S, Ho i S, Ma sui K. SM-368229, a no el selec i e and po en non-s e oidal mine aloco icoid ecep o an agonis wi h s ong u ina y Na+ exc e ion ac i i y. J Pha macol Sci 2011;115(3):346-53. 63. Na iai T, Fuji a K, Mo i M, Ka ayama S, Ho i S, Ma sui K. An ihype ensi e and ca dio enal p o ec i e e ec s o SM-368229, a no el mine aloco icoid ecep o an agonis , in aldos e one/sal - ea ed a s. Pha macology 2012;89(1-2):44-52. 64. Meye s MJ, A hance GB, Hocke man SL, Chen X, Long SA, Mahoney MW, Rico JR, Ga land DJ, Blinn JR, Collins JT, Yang S, Huang HC, McGee KF, Wendling JM, Die z JD, Payne MA, Home BL, He on MI, Rei z DB, Hu X. Disco e y o (3S,3aR)-2-(3-chlo o-4- cyanophenyl)-3-cyclopen yl-3,3a,4,5- e ahyd o-2H-benzo[g] indazole-7-ca boxylic acid (PF- 3882845), an o ally e icacious mine aloco icoid ecep o (MR) an agonis o hype ension and neph opa hy. J Med Chem 2010;53(16):5979-6002. 65. O ena S, Mau e TS, She L, Eudy R, Be na do V, Dash D, Lo ia P, Banke ME, Tugnai M, Oke be g CV, Qian J, Bous any-Ka i CM. PF-03882845, a non-s e oidal mine aloco icoid ecep o an agonis , p e en s enal inju y wi h educed isk o hype kalemia in an animal model o neph opa hy. F on Pha macol 2013;4:115. 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