Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers

Abstract

Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and were placed on either a low-salt or normal-salt diet for the duration of the study. Blood samples were collected before and after dosing on days 1 and 10 to characterize pharmacokinetics and pharmacodynamics. Safety was assessed by adverse events, physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Plasma levels of baxdrostat increased proportionally with ascending doses, with peak concentrations observed within 4 h after dosing and a mean half-life of 26 to 31 h. A dose-dependent reduction of plasma aldosterone occurred with baxdrostat doses ≥1.5 mg, regardless of diet. Decreases in plasma aldosterone were sustained, with levels reduced by approximately 51 to 73% on day 10. Baxdrostat had no meaningful impact on plasma cortisol levels and resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels. Baxdrostat was safe and well tolerated with a half-life that supports once-daily dosing. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase.

Keywords: Aldosterone; Aldosterone synthase inhibitor; CYP11B2; Hypertension; Primary aldosteronism.

Fig. 1

Plasma Baxdrostat Concentration vs. Time on Days 1 and 10. Plasma baxdrostat concentration (ng/mL) by scheduled time point and treatment. Data are mean ± standard deviation

Fig. 2

Baxdrostat Reduces Plasma Aldosterone Levels in a Dose-dependent Manner. Estimated percentage change from baseline (day −1) in plasma aldosterone area under the pharmacodynamic effect-time curve from time 0 to 12 h postdose on day 1 and day 10. Data are least squares mean and 90% confidence intervals. AUC indicates area under the curve

Fig. 3

Baxdrostat Does Not Have a Significant Effect on Plasma Cortisol Levels. Estimated percentage change from baseline (day −1) in plasma cortisol (total) area under the pharmacodynamic effect-time curve from time 0 to 12 h postdose on day 1 and day 10. Data are least squares mean and 90% confidence intervals. AUC indicates area under the curve

Fig. 4

Urinary Sodium and Potassium Concentrations Following Baxdrostat Administration. Urine sodium and potassium concentrations at baseline (BL), day 1, and day 10. Box whiskers show interquartile range (box) and minimum-maximum (whiskers) for sodium or potassium from 24 h urine collections