CURRENT OPINION Nonsteroidal Antagonists of the Mineralocorticoid Receptor
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REVIEW CURRENT OPINION Nonsteroidal antagonists of the mineralocorticoid receptor Peter Kolkhof a, Christina Nowackb, and Frank Eitner a Purpose of review The broad clinical use of steroidal mineralocorticoid receptor antagonists (MRAs) is limited by the potential risk of inducing hyperkalemia when given on top of renin–angiotensin system blockade. Drug discovery campaigns have been launched aiming for the identification of nonsteroidal MRAs with an improved safety profile. This review analyses the evidence for the potential of improved safety profiles of nonsteroidal MRAs and the current landscape of clinical trials with nonsteroidal MRAs. Recent findings At least three novel nonsteroidal MRAs have reportedly demonstrated an improved therapeutic index (i.e. less risk for hyperkalemia) in comparison to steroidal antagonists in preclinical models. Five pharmaceutical companies have nonsteroidal MRAs in clinical development with a clear focus on the treatment of chronic kidney diseases. No clinical data have been published so far for MT-3995 (Mitsubishi), SC-3150 (Daiichi- Sankyo), LY2623091 (Eli Lilly) and PF-03882845 (Pfizer). In contrast, data from two clinical phase II trials are available for finerenone (Bayer) which demonstrated safety and efficacy in patients with heart failure and additional chronic kidney diseases, and significantly reduced albuminuria in patients with diabetic nephropathy. Neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Summary Novel, nonsteroidal MRAs are currently tested in clinical trials. Based on preclinical and first clinical data, these nonsteroidal MRAs might overcome the limitations of today’s steroidal antagonists. Keywords aldosterone, hyperkalemia, mode of action INTRODUCTION reported in up to 36% among unselected elderly Pathological overactivation of the mineralocorti- heart failure outpatients with about 10% developing coid receptor plays a critical and causative role in potential life-threatening serum potassium levels of the pathogenesis of a variety of different cardiovas- greater than 6 mmol/l [7,8]. cular diseases [1&&,2,3]. Accordingly, blockade of Consequently, drug discovery programs within mineralocorticoid receptor has proven clinical effi- several pharmaceutical companies are aiming to cacy in patients with heart failure with reduced identify novel nonsteroidal MRAs with potentially ejection fraction, arterial hypertension and chronic different pharmacodynamic properties. Recent kidney diseases (CKD) [1&&,4&,5&]. Current attempts reviews have already addressed some aspects of to block aldosterone’s action at the mineralocorti- coid receptor by using the available steroidal mineralocorticoid receptor antagonists (MRAs) spi- aGlobal Drug Discovery, Cardiology Research and bGlobal Clinical ronolactone or eplerenone might, however, cause a Development, Bayer Healthcare Pharmaceuticals, Wuppertal, Germany dilemma for the responsible physician; although Correspondence to Dr Peter Kolkhof, Cardiology Research, Bayer these drugs could be a life-saving therapy for Healthcare Pharmaceuticals, Building 500, Aprather Weg 18a, 42096 Wuppertal, Germany. Tel: +49 202365475; fax: +49 202368009; patients with heart failure [6], they may also induce e-mail: [email protected] severe hyperkalemia and kidney dysfunction, Curr Opin Nephrol Hypertens 2015, 24:417–424 particularly when given on top of standard of care DOI:10.1097/MNH.0000000000000147 angiotensin converting enzyme inhibitors or angio- This is an open-access article distributed under the terms of the Creative tensin receptor blockers to ‘real life’ patients, typi- Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where cally with variable degrees of concomitant kidney it is permissible to download and share the work provided it is properly dysfunction. In fact, hyperkalemic episodes were cited. The work cannot be changed in any way or used commercially. 1062-4821 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-nephrolhypertens.com Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pharmacology and therapeutics whereas treatment with spironolactone decreased KEY POINTS blood pressure at doses of 100 and 300 mg/kg with The broad clinical use of steroidal MRAs spironolactone concomitant elevation of serum potassium at and eplerenone is limited by the potential risk of 300 mg/kg [27]. These results may suggest an inducing hyperkalemia when given on top of improved therapeutic index of SM-368229 in com- RAS blockade. parison to spironolactone. To date, no clinical study has, however, been announced for SM-368229. Very Novel, nonsteroidal MRAs are currently being & developed to overcome such limitations. recently, Nariai et al. [28 ] presented preclinical data of another Dainippon Sumitomo MRA called DSR- Nonsteroidal finerenone has different physicochemical 71167, which also weakly blocks carbonic anhydrase. and tissue distribution properties compared with DSR-71167, in contrast to spironolactone and epler- steroidal eplerenone or spironolactone. enone, did not cause elevation of serum potassium Finerenone demonstrated superior safety and efficacy levels in potassium-loaded rats. Carbonic anhydrase compared with spironolactone in patients with heart inhibition may increase urinary potassium and there- failure and CKD. fore may avoid the development of hyperkalemia, at least from a theoretical point of view. Researchers at Takeda identified benzoxazin- 3-one derivatives, as novel, nonsteroidal MRAs these efforts [9–12,13&]. This review will serve two [29–31]. Initially, selected lead compounds still key purposes: first, it provides a current overview of had moderate affinity at the progesterone receptor, preclinical and clinical studies using nonsteroidal whereas related dihydropyrrol-2-one derivatives MRAs with a particular focus on recent clinical trials, exhibited moderate and partial mineralocorticoid and second, it summarizes our current knowledge of receptor agonistic activity at higher concentrations differences in the mode of action between steroidal (30% activation at 10 mM). A novel, benzoxazin-3- MRAs and the novel, nonsteroidal MRA finerenone. one derivative has recently been presented which significantly lowered the blood pressure of deoxy- corticosterone acetate/salt hypertensive rats after PRECLINICAL AND CLINICAL ACTIVITIES oral application [31]. REPORTED ON NONSTEROIDAL LY2623091 (Eli Lilly, Table 1) entered clinical MINERALOCORTICOID RECEPTOR phase I trials in October 2010 and has been inves- ANTAGONISTS tigated in a small phase IIa trial in 48 patients with Table 1 summarizes the current landscape of non- CKD until March 2013. Recently, Lilly announced steroidal MRAs in clinical development [14–18]. At the start of a larger phase II trial, this time, however, least five pharmaceutical companies have novel, among 300 hypertensive patients, which may nonsteroidal MRAs in clinical study development indicate a refocussing of this nonsteroidal MRA (source: clinicaltrials.gov) with a clear focus on the on the therapy of arterial hypertension. Lilly has treatment of patients with CKD. Additional com- also investigated LY3045697 in two small phase I pounds are in preclinical development [13&]. The studies in healthy volunteers during 2013 in The chemical structures have only been revealed for two Netherlands. No published data on these novel compounds under clinical development (Table 2) MRAs are available. [19,20]: Bayer’s finerenone [21] and Pfizer’s PF- Mitsubishi is currently conducting its nonster- 03882845 [22]; however, more structural infor- oidal MRA MT-3995 in small phase IIa studies in mation is available for pharmaceutical compounds Japan and two studies in Eastern Europe (n ¼ 30–90) in preclinical studies. among patients with diabetic nephropathy [32] Researchers at Merck identified oxazolidine- (Table 1). dione derivatives as novel, nonsteroidal MRAs CS-3150 is a novel, nonsteroidal MRA which was [23,24]. Representative compounds demonstrated discovered by Exelixis and out-licensed to Daiichi- acceptable in-vitro potency and selectivity but Sankyo in 2006. In January 2015, Daiichi-Sankyo no pharmacodynamic in-vivo data have been announced the start of two different phase II studies: published. a dose-finding study in Japanese patients with Dainippon Sumitomo discovered the nonsteroi- T2DM and microalbuminuria [33] and a study to dal MRA SM-368229, possessing moderate selectivity evaluate efficacy and safety of CS-3150 in Japanese towards other steroid receptors [25,26]. In spon- patients with hypertension (estimated enrollment: taneously hypertensive rats, SM-368229 decreased 400 patients) [34] (Table 1). systolic blood pressure at doses between 1 and Pfizer investigated the nonsteroidal MRA PF- 10 mg/kg without serum potassium elevation, 03882845 (Tables 1 and 2) in preclinical as well in 418 www.co-nephrolhypertens.com Volume 24 Number 5 September 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Nonsteroidal antagonists of the mineralocorticoid receptor Kolkhof et al. Table 1. Current landscape of clinical trials with nonsteroidal mineralocorticoid receptor antagonists (source: clinicaltrials.gov) NCT# Phase Condition/study name No. enrolled Study begin Study completion Status/references Finerenone NCT01473108 1 Healthy 67 Mar 2010 Nov 2010 Completed NCT01687920 1 Healthy 25 Sep 2012 Nov 2012 Completed NCT01345656 2a ARTS 457 May 2011 Jun 2012 Completed [14,15] NCT01968668 2b ARTS-DN