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

Page 1 of 26 Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease Peter Bramlage 1,2, Stephanie Swift 1, Martin Thoenes 3, Joan Minguet 1, Carmen Ferrero 2, Roland E. Schmieder 4 1 Institute for Pharmacology and Preventive Medicine, Mahlow, Germany 2 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Sevilla, Spain 3 Léman Research Institute, Oberägeri, Switzerland 4 Department of Nephrology and Hypertension, University Hospital of the University Erlangen-Nürnberg, Erlangen, Germany Correspondence: Peter Bramlage, MD, PhD, FESC, FACC Institute for Pharmacology and Preventive Medicine Menzelstrasse 21, 15831 Mahlow, Germany Tel.: +49 3379 3147890 Fax: +49 3379 3147892 Email: [email protected] Journal: Eur J Heart Fail Version: 13.09.2015 Word count: 4,767 Abstract: 170 Tables: 2 Figures: 4 References: 65 Page 2 of 26 Abstract Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY94-8862) has emerged as a next-generation nonsteroidal dihydropyridine-based MR antagonist designed to minimise off-target effects while maintaining potent efficacy. In this review, the authors explore the outcomes of finerenone therapy in several diseases associated with MR activity. The authors compare the (pre-) clinical efficacy of finerenone with traditional steroid-based MR antagonists. Finally, the authors discuss recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy. Taken together preclinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared to traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease. Keywords: mineralocorticoid; receptor; antagonist; heart; kidney; failure; disease; finerenone; ARTS, BAY94-8862 Page 3 of 26 Introduction The specific intracellular steroidal mineralocorticoid receptor (MR) has a major role in the renin-angiotensin-aldosterone system (RAAS), which regulates sodium reabsorption and potassium leakage in nephrons, and achieves co-ordinated control of fluid, extracellular volume, and electrolyte balance to regulate blood pressure (BP) 1. The MR binds several ligands, including aldosterone and cortisol. Under normal conditions, aldosterone acts as a MR agonist, while cortisol acts as an antagonist 2, and both bind the MR with similar affinities 3. Several disease states are associated with elevated activation of the MR, including heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. Enhanced MR activity can be driven by increased levels of circulating aldosterone, switches in cortisol activity from MR antagonist to MR agonist, or elevated local expression of the MR 4. Such changes are observed following disruptions in hormonal homeostasis during cardiovascular, renal, or adrenal pathology 5. Pathophysiological levels of aldosterone or cortisol, especially in combination with inappropriate salt and redox status, can damage multiple tissues that express the MR 2, 6-8. Blockade of the aldosterone/cortisol signalling pathway through MR antagonism is a clinically effective method of preventing organ pathologies. MR antagonist therapy for cardiovascular and renal disease Current clinically-approved steroid-based MR antagonists, including spironolactone, canrenone and the later developed eplerenone, mimic the molecular structure of the natural MR ligands, aldosterone and cortisol (Figure 1) 9. These agents have demonstrated significant clinical efficacy in the treatment of several disease conditions, including chronic HF 10-14, CKD 15, 16, primary aldosteronism, and hypertension 17-21. Spironolactone and eplerenone are considered highly effective strategies for the management of cardiorenal disease, and current guidelines recommend the addition of MR antagonists during the management of symptomatic systolic HF in patients already receiving angiotensin-converting enzyme (ACE) inhibitors and beta-blockers 22. Yet, surprisingly, only low numbers (9–30%) of eligible hospitalised HF patients are prescribed MR antagonists 23. Despite these clear clinical benefits, there remains a bias that prevents the prescription of MR antagonists to patients displaying HF. Such bias is undoubtedly related to the side effects associated with spironolactone and eplerenone therapy. While the first-generation spironolactone displays significant MR antagonistic potency, it also antagonises the androgen receptor (AR) to drive the development Page 4 of 26 of gynaecomastia and impotence in men, and acts as an agonist of the progesterone receptor to cause amenorrhoea in pre-menopausal women (Table 1) 10, 23. These side effects typically limit patient adherence to therapy. While the second-generation eplerenone targets the MR with a greater specificity, leading to fewer side effects, it lacks the potency of spironolactone (Table 1) 18, 19. Finally, and perhaps of greatest clinical concern, blockade of MRs in the kidney increases sodium excretion with a subsequent reduction in blood volume, and a corresponding retention of potassium. This effect may be exacerbated by the biodistribution pattern of both spironolactone and eplerenone, which build up to higher concentrations in renal tissue compared to myocardium 24. Reduced renal elimination of potassium results in hyperkalaemia, where potassium levels in the blood increase to potentially pathological levels 10, 11, 16, 25. Incidence of hyperkalaemia in the Randomized Aldactone Evaluation Study (RALES) was only slightly greater in the spironolactone arm than in the placebo arm 10. In a subsequent assessment of the real world situation, however, significant hyperkalaemia-related morbidity and mortality correlated with an increase in the prescription rate of the drug 26. In a separate study involving a population of unselected heart failure patients treated with spironolactone, 36% reached a serum potassium level of >5 mmol/L 27. In the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), higher proportions of patients being treated with eplerenone were noted to have potassium levels > 5 mEq/L in comparison to those receiving a placebo (15.6 vs. 11.2%; p < 0.001) 28. A similar trend was found in the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF; 11.8 vs. 7.2% for eplerenone and placebo, respectively; p < 0.001) 25. These high rates of hyperkalaemia appear to be manageable in patients with normal kidney function or mild-to-moderate kidney disease. However, patients with conditions such as CKD or diabetes are at increased risk of developing elevated potassium levels, and display increased rates of hyperkalaemia-related hospitalisation and death following MR antagonist therapy 29-32. Ultimately, all patients receiving spironolactone or eplerenone therapy require careful serial monitoring of serum potassium levels and renal function 28, which may represent a practical impediment to routine clinical prescription. Patients with an S810L gain-of-function mutation within the MR, which contributes to earlyonset or gestational hypertension, are also ineligible for MR antagonist therapy, since both eplerenone and spironolactone paradoxically enhance signalling through this mutant receptor to promote hypertension 33, 34. Further, older patients (75 years) appear to be at significantly elevated risk of hyperkalaemia-related hospital admissions and subsequent in-hospital deaths following MR antagonist therapy 35. Nevertheless, several risk-to-benefit assessments Page 5 of 26 ultimately support the use of MR antagonists in patients across a spectrum of low-, medium-, and high-risk. Finerenone, an alternative non-steroidal MR antagonist The molecular structure of MR antagonists can impact the profile of biodistribution, potency, selectivity, physicochemistry and, ultimately, the balance between clinical efficacy and side effects 24. Thus, in an effort to maximise cardiac and/or vascular activity and minimise disruptions in renal sodium/potassium homeostasis, the development of next-generation MR antagonists has focussed on non-steroidal compounds. This approach has the potential to extend the cardioprotective benefits of MR antagonists to multiple patient populations that are currently contraindicated for this therapy 36. In particular, dihydropyridines, traditionally known for their utility as L-type calcium channel antagonists, have been identified as a new class of non-steroidal MR antagonists 37. Finerenone (BAY94-8862) is a third-generation potent, specific, orally bioavailable, nonsteroidal MR antagonist that was generated during high-throughput screening and subsequent remodelling of cyano-1,4-dihydropyridine compounds 38. Finerenone is accommodated in the MR ligand binding cavity in a distinct manner from steroid-based MR antagonists, and shows good steric binding with a MR IC50 of 17.8 nM (Table 1) 38, 39. Importantly, finerenone is over 500-fold more selective for the MR versus steroid receptors within the same superfamily, including the glucocorticoid receptor (GR), androgen receptor (AR), and progesterone receptor (PR) (Table 1). Structural studies suggest that this selectivity is predominantly mediated through a hydrogen bond donor interaction with the unique MR-specific residue, Ser810 38. Further, finerenone has no observed off-target interactions with over 65 biological receptors and ion channels 38, and lacks the ability to block L-type calcium channels, which is associated with many other dihydropyridine-based MR antagonists 38, 40, 41. Finerenone displays substantially altered biochemical and biophysical properties compared to spironolactone and eplerenone (Table 1). Organ distribution of radioactively-labelled finerenone one hour after oral administration in Wistar rats is predominantly confined to the vascular and interstitial spaces, and can be clearly detected in well-vascularised organs such as the heart, lung, liver, and kidney 42. While traditional steroid-based MR antagonists typically build up to higher concentrations in the kidney versus the heart 24, a property that may contribute to hyperkalaemic side effects, finerenone achieves an equivalent distribution between cardiac and renal compartments 42. In healthy subjects, the plasma half life of finerenone is ~2 h, much shorter than spironolactone (~15 h) 24, 43 although roughly equivalent to eplerenone (4–6 h). The relatively long half-life of spironolactone has the pharmacokinetic Page 6 of 26 consequence of a slow onset of action, and effects that persist for several days following drug discontinuation 44. However, the kinetics of the downstream effects of finerenone on target organs has not been extensively studied 24. Finally, the metabolic consequences of finerenone oral application have yet to be explored. Thus it remains to be determined if this drug breaks down to generate multiple active metabolites (similar to spironolactone) or remains essentially intact (similar to eplerenone). In healthy rats, finerenone has little impact on the total urinary volume (except at very high doses [100 mg/kg]), and no measurable impact on urinary potassium levels 42. However, rat models are typically resistant to the development of hyperkalaemia following RAAS inhibition 45. Conversely, natriuretic responses, which can act as a surrogate marker for renal electrolyte homeostasis in rat models, increase in a dose-dependent manner following finerenone therapy 42. In a direct comparison with the steroid-based MR antagonist, eplerenone, equivalent natriuretic responses were observed at 1 mg/kg finerenone and 10–30 mg/kg eplerenone 42, suggesting that finerenone represents a more potent MR antagonist. Pre-clinical assessment of finerenone in models of cardiovascular and renal disease Finerenone has been tested in several pre-clinical rat models of cardiorenal disease in comparison to the traditional steroid-based MR antagonist, eplerenone. These include a model of hyperaldosteronism-induced end-organ damage (induced by a 10-week treatment with deoxycorticosterone-acetate (DOCA)/salt) 42, a model of post-MI HF (induced by coronary artery ligation) 42, and a model of severe arterial hypertension (induced by maintaining spontaneously hypertensive, stroke-prone rats (SHRSP) on a 7-week high-salt diet) 46. In a model of hyperaldosteronism-induced end-organ damage, low doses of finerenone outperformed eplerenone in protecting both the heart and kidney against structural and functional damage 42. Direct comparisons were drawn between outcomes with equivalent natriuretic doses of finerenone (1–10 mg/kg) and eplerenone (30–100 mg/kg). In the heart, finerenone treatment decreased systolic BP (SBP) and minimised cardiac hypertrophy at the ultrastructural level 42. Eplerenone had no significant impact on cardiac hypertrophy. Similarly, finerenone significantly reduced plasma levels of prohormone of brain natriuretic peptide (pro-BNP), a pathological marker of ventricular remodelling and myocardial ischaemia, beyond the level observed with eplerenone, suggesting lower levels of heart stress 42. At the kidney level, histological analysis demonstrated less glomerular and tubulointerstitial damage, and less kidney hypertrophy following finerenone treatment 42. Finerenone also reduced levels of genotoxic damage, characterised by double-strand DNA breaks, in renal cells 47. Conversely, eplerenone and placebo groups displayed more evidence Page 7 of 26 of glomerular sclerosis, tubular degeneration, tubular dilation, and proteinuria casts 42. Proteinuria was also ameliorated to a greater degree following finerenone treatment compared to eplerenone. Finally, the expression levels of genes involved in pro-inflammatory and profibrotic processes in the kidney, including PAI-1, MCP-1, osteopontin, and MMP-2, were reduced to the greatest degree following finerenone treatment 42. In a model of post-MI HF, lower doses of finerenone (0.1, 0.3, or 1 mg/kg/day) were directly compared with eplerenone (100 mg/kg/day). Finerenone treatment achieved clinical efficacy at a dose of 1 mg/kg/day; lower doses had no impact, equivalent to eplerenone 42. Both systolic and diastolic left ventricular function was improved following finerenone administration, with significant enhancements in cardiac contractility and relaxation. Similarly, finerenone reduced plasma levels of pro-BNP without impacting BP 42. Plasma levels of aldosterone were also analysed as an indirect measure of finerenone occupancy at the MR, since antagonism of the MR typically increases circulating levels of unbound aldosterone 48, and the magnitude of this increase can reflect the efficiency and extent of MR blockade. Finerenone significantly increased circulating levels of aldosterone compared to placebo controls 42. Eplerenone achieved a similar increase in plasma aldosterone concentrations, suggesting that while eplerenone was capable of effectively blocking the MR, this was ultimately not translated into a downstream impact on cardioprotective parameters. Finally, doses of finerenone at 10 mg/kg/day were reported to significantly improve the survival of severely hypertensive rats compared to either eplerenone (30 mg/kg/day) or spironolactone (30 mg/kg/day) 46. Both steroid-based MR antagonists had no significant impact on mortality rates. Simultaneous reductions in urinary protein/creatinine ratios and osteopontin expression levels following finerenone treatment indicated a beneficial impact on kidney health 46. This was supported by histopathological analysis demonstrating that finerenone treatment reduced vascular, glomerular, and tubulointerstitial damage. In contrast, no such effects were found on analysis of animals treated with either spironolactone or eplerenone. Progress of finerenone to clinical trials ARTS Finerenone has been tested through phase I safety and tolerability studies to phase IIb safety and efficacy trials (Table 2). The phase II Mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) represents the most extensive published trial of finerenone in patients with HF with a reduced ejection fraction (HFREF) and mild-to-moderate CKD 49. ARTS was designed as a 4-week randomised, double-blind, placebo-controlled, parallel-group, safety and Page 8 of 26 tolerability study that was divided into two parts. The first part compared finerenone (2.5, 5, or 10 mg per day) vs. placebo in 65 patients with HF and mild CKD. The second part compared finerenone (2.5, 5, or 10 mg or (2 × 5 mg) per day) vs. spironolactone (25 or 50 mg per day) vs. placebo in 392 patients with HF and moderate CKD 50. Primary outcome measurements centred on renal parameters, including serum potassium levels and markers of kidney health and function, such as urinary albumin to creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Secondary outcomes included changes in markers of cardiac health, pharmacokinetic profiles, and safety and tolerability 49. Outcome measurements were made at visit 4 (d15  1; approximately half way through the trial) and visit 7 (d29  2; at the conclusion of the trial). Mean increases in serum potassium concentrations were significantly lower in all finerenone groups compared to spironolactone (Figure 2) 50. Indeed, at 2.5 mg and 5 mg daily doses of finerenone, there was no significant change in serum potassium levels compared to placebo controls. Minimal finerenone disruptions in serum potassium levels were also evident in subanalyses of either older (>75 years) patients, individuals with HFREF of greater severity (NYHA class III), or patients who had previous experience with MR antagonist therapy. The lack of observed hyperkalaemia in aged individuals receiving finerenone therapy was particularly important, since spironolactone has previously been associated with increased hyperkalaemia-associated mortality in this population 26. Although not statistically significant, there was a trend towards a reduction in the UACR across all treatment groups (finerenone and spironolactone) compared to placebo 50. Spironolactone (25 or 50 mg per day) significantly reduced eGFR compared to placebo controls, indicating a negative impact on kidney function at this clinically relevant dose 10. On the other hand, for finerenone, eGFR only deteriorated significantly at the highest dose prescribed (10 mg/day) (Figure 2) 50. All other finerenone doses (2.5 mg, 5 mg, (2 × 5mg) per day) demonstrated no significant deviation in eGFR from placebo control. Ultimately, tracking degeneration of renal function either through changes in serum creatinine levels or eGFR following finerenone treatment demonstrated similar changes to placebo controls. Worsening renal function was observed in <11% of patients across both the placebo and all finerenone groups, but in 38% of patients receiving spironolactone. No significant changes in biomarkers of heart health were observed following finerenone or spironolactone therapy 50. In patients receiving >2.5mg finerenone or spironolactone (25 or 50 mg), there was a trend towards decreased median concentrations of both N-terminal pro-BNP (NT-pro-BNP) and BNP itself compared to placebo controls. NT-pro-BNP levels are strongly predictive of long-term mortality in patients with heart disease 51. SBP remained a highly Page 9 of 26 variable measurement within each patient group. Only patients receiving spironolactone demonstrated a significant reduction in SBP compared to placebo controls; no antihypertensive effects were observed across finerenone treatment groups 50. Indirect effects of finerenone were also analysed by measuring aldosterone levels in plasma. All finerenone doses above 2.5 mg were associated with significant increases in serum aldosterone levels 50. Yet the most substantial increase was observed following spironolactone therapy, almost certainly as a consequence of the higher dosage reflecting a greater occupancy of MR sites. Since finerenone achieved more substantial benefits on biomarkers of cardiac health than spironolactone, despite having less impact on plasma aldosterone levels, this suggests an uncoupling of the relationship between circulating aldosterone levels and cardioprotective/nephroprotective effects. Finally, and of crucial clinical importance, the majority of finerenone treatment-associated adverse events were mild. Serious adverse events across all treatment groups (including spironolactone) were observed in 25/457 patients (5.5%). In post-hoc analyses across all finerenone groups, rates of hyperkalaemia, renal impairment, or renal failure were not significantly different from placebo controls 50. Unexpectedly, this difference was even smaller when comparing only the highest finerenone dose groups (5 mg or 10 mg per day). Conversely, rates of hyperkalaemia-related renal dysfunction were significantly elevated in patients receiving spironolactone. Due to limitations of the ARTS clinical study design (including the number of recruited patients and the relatively short clinical schedule for therapy), the ability of finerenone to protect against major cardiovascular events and improve survival rates could not be investigated. This limitation also prevented the analysis of rates of gynaecomastia, impotence, and amenorrhoea, which represent common side effects for spironolactone therapy. ARTS-DN Following on from the ARTS trial, a similar study was carried out to compare the effects of finerenone with placebo in patients with type 2 diabetes and diabetic nephropathy 52. Patients were randomised to receive once daily doses of finerenone (7.5, 10, 15, or 20 mg) or placebo. The primary endpoint was the ratio of UACR from baseline to the end of the 90-day followup period, with other endpoints including serum potassium levels, eGFR, and adverse events. For the patients receiving finerenone, the ratio of UACR from 90 days to baseline decreased in a dose-dependent manner, a trend which was maintained when the values were adjusted by those of the placebo group (Figure 3) 53. By the end of the study, a reduction in UACR of ≥50% from baseline was achieved for 17.2%, 17.2%, 33.6%, and 40.2% of the patients in the Page 16 of 26 24. Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. 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Meyers MJ, Arhancet GB, Hockerman SL, Chen X, Long SA, Mahoney MW, Rico JR, Garland DJ, Blinn JR, Collins JT, Yang S, Huang HC, McGee KF, Wendling JM, Dietz JD, Payne MA, Homer BL, Heron MI, Reitz DB, Hu X. Discovery of (3S,3aR)-2-(3-chloro-4cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g] indazole-7-carboxylic acid (PF3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy. J Med Chem 2010;53(16):5979-6002. 65. Orena S, Maurer TS, She L, Eudy R, Bernardo V, Dash D, Loria P, Banker ME, Tugnait M, Okerberg CV, Qian J, Boustany-Kari CM. PF-03882845, a non-steroidal mineralocorticoid receptor antagonist, prevents renal injury with reduced risk of hyperkalemia in an animal model of nephropathy. Front Pharmacol 2013;4:115. Page 20 of 26 Figures Figure 1. Molecular structures of natural MR ligands and synthetic MR antagonists. Page 21 of 26 Figure 2. Effect of finerenone on kidney function in the ARTS trial. Legend: Selected results from the ARTS trial. A) Change in serum potassium levels from baseline to visit 4 and 6/7, B) Change in eGFR from baseline to visit 4 and 6/7. Reproduced from 50. Page 22 of 26 Figure 3. Change in urinary albumin to creatinine ratio in the ARTS-DN trial Legend: Reproduced from 53 Page 23 of 26 Figure 4. Proportion of patients achieving a >30% decrease in NT-proBNP levels during the 90-day ARTS-HF trial Legend: Adapted from 55. Page 24 of 26 Tables Table 1. Characteristics of first-, second-, and third-generation MR antagonists Spironolactone Eplerenone Finerenone Trade name(s) Aldactone Inspra Class Steroidal Steroidal Dihydropyridine 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 Half-life (h) 1.4 (active metabolites 12–35) 4–6 h 1.7–2.8 Legend: MR, mineralocorticoid receptor; AR, androgen receptor; GR, glucocorticoid receptor; PR, progesterone receptor; IC50, concentration of antagonist required to inhibit 50% activation of receptor; EC50, concentration of ligand required to achieve 50% activation of the receptor. (Adapted from 38, 39, 43) Page 25 of 26 Table 2. Finerenone in clinical trials Clinical Trial Identifier Phase Study Patient Population Estimated Patient Group Size Daily Finerenone Dose (mg) Time Frame Comparator Arm(s) Primary (1°) and Seconday (2°) Outcome Measures Trial Start Date Publications NCT01473108 I Safety, Tolerability, Pharmacokinetics & Pharmacodynamics after Administration with 0.5mg Fludrocortisone Healthy male subjects n = 67 2.5, 5, 10, 15 or 20 Single dose, monitored up to 28 days Placebo Eplerenone 50mg/day 1° Pharmacodynamics (natriuresis) 2° Pharmacokinetics (maximum concentration [Cmax] & area-undercurve [AUC]) & adverse events March 2010 43 NCT01687920 I Dose Proportion Healthy male subjects n = 25 1.25, 2.5, 5, 7.5 or 10 Single dose, monitored up to 48h N/A 1° Pharmacokinetic dose proportionality 2° Adverse events September 2012 NCT01345656 II Safety and Tolerability (ARTS) Part A: Subjects with stable chronic HF with left ventricular systolic dysfunction and mild CKD Part B: Subjects with stable chronic HF with left ventricular systolic dysfunction and moderate CKD n = 457 2.5, 5, 10 or (5 x 2) Daily dose for 4 weeks, monitored up to 4 weeks Placebo Spironolactone 25-50mg/day 1° Change in serum potassium 2° Change in serum magnesium, BP & heart rate May 2011 49, 50 NCT01874431 II Safety and Efficacy (ARTS-DN) Subjects with Type 2 diabetes mellitus and diabetic nephropathy n = 821 1.25, 2.5, 5, 7.5, 10, 15 or 20 Daily dose for 90 days, monitored up to 120 days Placebo 1° Change in UACR 2° Change in serum potassium, renal function, quality-of-life & adverse events June 2013 52, 53 NCT01968668 II Safety and Efficacy (ARTS-DN Japan) Japanese subjects with Type 2 diabetes mellitus & diabetic nephropathy n = 96 1.25, 2.5, 5, 7.5, 10, 15 or 20 Daily dose for 90 days, monitored up to 90 days Placebo 1° Change in UACR 2° Change in serum potassium October 2013