bay-94-8862 and Cardio-Renal-Syndrome

Characterization of mice with cell-specific deletion or overexpression of the mineralocorticoid receptor (MR) shed a new light on its role in health and disease. Pathophysiological MR activation contributes to a plethora of deleterious molecular mechanisms in the development of cardiorenal diseases like chronic kidney disease (CKD) and heart failure (HF). Accordingly, the available steroidal MR antagonists (MRAs) spironolactone (first generation MRA) and eplerenone (second generation MRA) have been shown to be effective in reducing cardiovascular (CV) mortality and morbidity in patients with chronic HF and a reduced left ventricular ejection fraction (HFrEF). However, they remain underutilized, in large part owing to the risk inducing severe adverse events including hyperkalemia and worsening of kidney function, particularly when given on top of inhibitors of the renin angiotensin system (RAS) to patients with concomitant kidney dysfunction. Novel, potent, and selective non-steroidal MRAs (third generation) were identified in drug discovery campaigns and a few entered clinical development recently. One of these is finerenone with different physicochemical, pharmacokinetics, and pharmacological properties in comparison with the steroidal MRAs. Available data from five clinical phase II trials with finerenone in more than 2,000 patients with HF and additional CKD and/or diabetes as well as in patients with diabetic kidney disease demonstrated that neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Moreover, finerenone demonstrated a nominally improved outcome compared to eplerenone in a phase IIb trial with 1,066 patients with HFrEF and concomitant type 2 diabetes mellitus (T2DM) and/or CKD.

Topics: Animals; Cardio-Renal Syndrome; Diabetic Nephropathies; Endothelial Cells; Eplerenone; Fibroblasts; Heart Failure; Humans; Macrophages; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Myocytes, Cardiac; Myocytes, Smooth Muscle; Naphthyridines; Receptors, Mineralocorticoid; Spironolactone; Stroke Volume

Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), but their use is limited by hyperkalaemia and/or worsening renal function (WRF). BAY 94-8862 is a highly selective and strongly potent non-steroidal MRA. We investigated its safety and tolerability in patients with HFrEF associated with mild or moderate chronic kidney disease (CKD).. This randomized, controlled, phase II trial consisted of two parts. In part A, the safety and tolerability of oral BAY 94-8862 [2.5, 5, or 10 mg once daily (q.d.)] was assessed in 65 patients with HFrEF and mild CKD. In part B, BAY 94-8862 (2.5, 5, or 10 mg q.d., or 5 mg twice daily) was compared with placebo and open-label spironolactone (25 or 50 mg/day) in 392 patients with HFrEF and moderate CKD. BAY 94-8862 was associated with significantly smaller mean increases in serum potassium concentration than spironolactone (0.04-0.30 and 0.45 mmol/L, respectively, P < 0.0001-0.0107) and lower incidences of hyperkalaemia (5.3 and 12.7%, respectively, P = 0.048) and WRF. BAY 94-8862 decreased the levels of B-type natriuretic peptide (BNP), amino-terminal proBNP, and albuminuria at least as much as spironolactone. Adverse events related to BAY 94-8862 were infrequent and mostly mild.. In patients with HFrEF and moderate CKD, BAY 94-8862 5-10 mg/day was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of haemodynamic stress, but it was associated with lower incidences of hyperkalaemia and WRF.

Topics: Administration, Oral; Aged; Albuminuria; Aldosterone; Blood Pressure; Cardio-Renal Syndrome; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Male; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Peptide, Brain; Peptide Fragments; Potassium

Topics: Cardio-Renal Syndrome; Female; Humans; Male; Mineralocorticoid Receptor Antagonists; Naphthyridines