Esaxerenone: A Comprehensive Clinical and Pharmacological Profile

1. Executive Summary

Esaxerenone is a novel, orally administered, non-steroidal, selective mineralocorticoid receptor (MR) antagonist. Developed by Daiichi Sankyo, it has received its first global approval in Japan for the treatment of hypertension and is under investigation for diabetic nephropathy. Its distinct chemical structure and high selectivity for the MR aim to overcome limitations associated with older, steroidal MRAs, particularly concerning hormonal side effects.

Pharmacokinetically, esaxerenone exhibits high oral bioavailability, a long plasma half-life supporting once-daily administration, and multiple metabolic pathways (primarily CYP3A-mediated oxidation, glucuronidation, and hydrolysis), which suggest a low potential for significant drug-drug interactions. Its disposition is largely unaffected by food or mild-to-moderate hepatic impairment. Pharmacodynamically, esaxerenone effectively blocks MR activation, leading to reduced blood pressure, natriuresis, and a decrease in urinary albumin-to-creatinine ratio (UACR) in relevant patient populations.

Clinical trials, predominantly in Japanese patients, have demonstrated esaxerenone's efficacy in essential hypertension, where it showed non-inferiority and, at higher doses, superiority to eplerenone in blood pressure reduction. In patients with type 2 diabetes and microalbuminuria, esaxerenone significantly improved UACR and reduced progression to overt nephropathy. Preliminary data also suggest potential benefits in heart failure with reduced ejection fraction.