SUN-254 - Effect of the Aldosterone Synthase Inhibitor Baxdrostat on Aldosterone and its Precursors in the BaxHTN Trial

Background: Aldosterone synthase (CYP11B2) catalyzes the final steps in aldosterone biosynthesis: conversion of 11-deoxycorticosterone (11-DOC) to corticosterone, corticosterone to 18-hydroxycorticosterone (18-OHB), and 18-OHB to aldosterone. We assessed the effect of the highly selective aldosterone synthase inhibitor baxdrostat on aldosterone and its precursors in the BaxHTN trial.

Methods: BaxHTN enrolled adults with seated systolic blood pressure (sSBP) ≥140– < 170 mmHg despite having 2 or ≥3 antihypertensive treatments. After placebo run in, those with sSBP ≥135 mmHg were randomized to baxdrostat 1 mg, baxdrostat 2 mg, or placebo once daily for a 12-week double-blind period. A 12-week open-label period followed, where those on baxdrostat 2 mg continued treatment, and those on baxdrostat 1 mg or placebo were re-randomized to baxdrostat 2 mg or standard of care (SOC). At Week (W) 24, participants on baxdrostat 2 mg were re-randomized to baxdrostat 2 mg or placebo for an 8-week randomized withdrawal (RWD) period. Serum concentrations of aldosterone and its precursors were measured up to W32 using liquid chromatography–tandem mass spectrometry. Change from baseline to W12 and W24, and from W24 to W32, are reported as median percentage change (Q1, Q3). For the analysis, the baxdrostat 1 mg and 2 mg groups were pooled (n=192) and compared with placebo/SOC (n=123), including only patients who did not switch between baxdrostat and placebo during the study. The RWD period analysis included baxdrostat 2 mg (n=172) and placebo (n=85) groups.

Results: In the pooled baxdrostat group, change from baseline to W12 and W24 was 194.8% (60.9, 441.0) and 207.0% (59.1, 404.1) for 11-DOC, 69.2% (2.3, 187.3) and 112.4% (13.1, 240.5) for corticosterone, −25.1% (−52.9, 11.9) and −24.6% (−56.1, 14.0) for 18-OHB, and −67.5% (−83.8, −36.6) and −78.0% (−91.5, −55.4) for aldosterone. In the placebo/SOC group, change from baseline to W12 and W24 was −11.5% (−39.9, 41.8) and 13.8% (−29.1, 84.1) for 11-DOC, −13.9% (−54.5, 57.8) and 25.5% (−31.8, 95.5) for corticosterone, −16.4% (−39.7, 32.6) and 10.9% (−13.1, 45.3) for 18-OHB, and 1.3% (−27.5, 43.3) and 3.6% (−26.4, 68.0) for aldosterone.

During the RWD period (W24 to W32), there was little change in the levels of aldosterone or its precursors in the baxdrostat 2 mg group; in the placebo (baxdrostat withdrawal) group, the change from W24 to W32 was −57.0% (−70.4, −32.0) for 11-DOC, −41.7% (−67.1, 8.6) for corticosterone, 28.2% (−20.7, 119.9) for 18-OHB, and 171.2% (0, 359.6) for aldosterone.

Conclusion: Changes in aldosterone and its precursors in BaxHTN indicate that administration of baxdrostat for up to 32 weeks primarily inhibits conversion of corticosterone to 18-OHB, 18-OHB to aldosterone, and to a lesser extent 11-DOC to corticosterone, consistent with in vitro and phase I study results. These changes were not fully reversed 8 weeks after baxdrostat withdrawal.

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