Pharmacodynamics of vicadrostat for aldosterone synthase inhibition in patients with CKD

Aldosterone synthase inhibition may affect cortisol synthesis due to homology between CYP11B2 (aldosterone synthase) and CYP11B1. The selectivity of vicadrostat, a highly selective aldosterone synthase inhibitor, for aldosterone suppression was evaluated by corticosteroid assessment in participants with albuminuric CKD (with or without T2D) in a randomized, double-blind, placebo-controlled phase 2 trial (NCT05182840).

After randomization to receive empagliflozin 10 mg once-daily or matched placebo for an 8-week run-in (plus renin-angiotensin system inhibitors), 586 participants were re-randomized to receive vicadrostat (3, 10, or 20 mg once-daily) or matched placebo for 14 weeks, with a 4-week follow-up. Our analysis included 410 participants who completed treatment. Plasma corticosteroids (aldosterone, cortisol, corticosterone, 11-deoxycorticosterone, and 11-deoxycortisol) were measured using liquid chromatography tandem mass spectrometry. Effects were evaluated via mixed effects models for repeated measures.

Dose-dependent suppression of plasma aldosterone was observed, with maximum suppression at week 14 resulting in geometric mean changes of -49.5% (95% CI: -68.7, -18.5) and -52.1% (-70.7, -21.6) for vicadrostat 20 mg given with and without empagliflozin, respectively. From baseline to week 14, increases were observed in mean plasma corticosterone, 11-deoxycorticosterone, and 11-deoxycortisol. Plasma 11-deoxycorticosterone increased by 222.8% (95% CI: 103.2, 412.7) and 231.5% (95% CI: 106.4, 432.2) for vicadrostat 20 mg given with or without empagliflozin, respectively, and plasma 11-deoxycortisol increased by 112.5% (95% CI: 36.0, 231.9) and 121.0% (95% CI: 40.0, 249.0) for the same dose groups. No increase or decrease in plasma cortisol was observed across vicadrostat dose groups with or without empagliflozin. Aldosterone suppression was sustained to 4 weeks post-treatment, while precursor levels normalized within 1 week of treatment cessation.

Vicadrostat, with or without background empagliflozin, selectively suppressed aldosterone over cortisol. These findings will be explored in a phase 3 trial program.