European journal of endocrinology · 2026
Pharmacodynamics of vicadrostat for aldosterone synthase inhibition in patients with CKD.
СтатьяРандомизированное исследованиеКлиническое исследование II фазыНазвание и аннотация: Перевод в очереди
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Gashaw Isabella A, Tuttle Katherine R, Monroy Kuhn Manuel, Pleiner Sina, Delic Denis, Cronin Lisa, Shah Shimoli V, Rossing Peter
Аннотация
OBJECTIVE: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Vicadrostat, with or without background empagliflozin, selectively suppressed aldosterone over cortisol. These findings will be explored in a phase 3 trial program.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Vicadrostat, with or without background empagliflozin, selectively suppressed aldosterone over cortisol. These findings will be explored in a phase 3 trial program.