Dean’s Seminar Series featuring Peter Kolkhof, PhD & Amer Joseph, MBBS – The basic science and clinical applications of mineralocorticoid receptors and antagonists
Dean’s Seminar Series
Peter Kolkhof, PhD
Amer Joseph, MBBS
Global Clinical Leader, Cardiology & Nephrology Clinical Development
The basic science and clinical applications of mineralocorticoid receptors and antagonists.
Part One Title and Abstract:
“From steroidal aldosterone antagonists to novel non-steroidal antagonists of the Mineralocorticoid Receptor”
During the recent 30 years, there has been a dramatic increase in knowledge about the role of aldosterone and the mineralocorticoid receptor (MR) in the pathophysiology of cardiovascular and kidney diseases. The scientific perspective on the aldosterone/MR ensemble extended from a previously renal epithelial-centered focus on sodium-potassium exchange to a broader view as systemic modulators of extracellular matrix, inflammation and fibrosis. Spironolactone was launched as the first aldosterone antagonist 27 years before the MR was cloned in 1987 while the second steroidal aldosterone antagonist eplerenone was developed at a time when the role of aldosterone and MR in cardiac fibrosis was rediscovered. The constraint of developing potentially life-threatening hyperkalaemia when used in combination with other inhibitors of the renin-angiotensin-system in patients with reduced kidney function initiated extensive research and development activities with the goal to identify novel nonsteroidal MR antagonists with an improved benefit-risk ratio.
A cluster of dihydropyridines (DHPs) acting as MRAs in vitro were identified in an ultrahigh throughput screening program of ca. 1 million compounds at Bayer. This finding was very surprising as DHPs constitute the known class of L-type calcium channel blockers like nifedipine. Chemical optimization of DHP-based compounds led to a novel series of heterobicyclic analogs of naphthyridine derivatives. The dihydronaphthyridine finerenone was identified as a potent and selective, ‘bulky’, nonsteroidal MRA with different physicochemical, pharmacokinetic and pharmacodynamic properties in comparison to steroidal MRAs.
Part Two Title and Abstract:
“Clinical outcomes with the selective nonsteroidal MRA finerenone in patients with CKD and T2D”
The selective, nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone was investigated in two parallel complementary studies in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the largest CKD program performed to date. The FIDELIO-DKD and FIGARO-DKD studies were both randomized double-blind placebo-controlled phase 3 trials that analyzed a total of 13,026 patients across 48 countries.
Both studies met their primary objectives, and in combination demonstrated that finerenone significantly reduced the progression of kidney disease and the risk of cardiovascular events compared to placebo, with all patients treated with optimized renin-angiotensin system inhibitors. In major subgroups the cardiorenal benefit of finerenone was preserved, and there was an indication of an independent treatment benefit irrespective of SGLT-2i use at baseline. The safety profile was in line with the mechanism of action of an MRA with the most prominent adverse effect being an increased incidence of hyperkalemia, however this was largely manageable with few events leading to discontinuation of study regimen or hospitalization.
Overall, the program has demonstrated that selective MR blockade with finerenone is efficacious and safe in reducing cardiorenal risk in patients with CKD and T2D. The results of the pivotal FIDELIO-DKD trial has led to the first global approval of finerenone (trade name Kerendia) by the US FDA in July 2021, with approvals in other regions underway.