No Evidence of QTc Interval Prolongation With Baxdrostat Treatment: Concentration–QTc Modeling Assessment

TL;DR

Baxdrostat, a new drug for hypertension and kidney disease, does not cause QTc interval prolongation, a heart rhythm issue, even at high doses.

Contribution

This study provides new evidence using concentration–QTc modeling to confirm the safety of baxdrostat on heart rhythm.

Findings

Baxdrostat did not cause QTc interval prolongation at therapeutic and supratherapeutic doses.

Upper bounds of the 90% confidence interval for ΔΔQTcF mean estimates were less than 10 ms.

Pharmacokinetic data and tolerability were as expected for the tested doses.

Abstract

Baxdrostat is a novel, highly potent, selective, competitive inhibitor of human aldosterone synthase currently under development for the treatment of uncontrolled and resistant hypertension and chronic kidney disease. We assessed the risk of QTc‐interval prolongation with baxdrostat using concentration‐QTc (C‐QTc) modeling in healthy adult participants using data from two placebo‐controlled Phase 1 studies: a multiple‐ascending dose (MAD) study of baxdrostat 0.5–5 mg (N = 56; NCT05500820) and a Phase 1 four‐way crossover thorough QT/QTc (TQT) study assessing the pharmacokinetics, pharmacodynamics, safety and tolerability of baxdrostat at supratherapeutic doses of 16 and 32 mg (N = 28; NCT06194032). In the TQT study, 28 participants were randomized to one of four treatment sequences (each n = 7) of baxdrostat 16 mg, baxdrostat 32 mg, placebo and open‐label moxifloxacin 400 mg. Digital electrocardiogram and pharmacokinetic data were collected at baseline and up to 48 h post dose. Dependent and independent variables of the pre‐specified linear mixed‐effect model were placebo‐corrected baseline‐adjusted ΔΔQTcF and baxdrostat plasma concentrations, respectively. Results were consistent between the two C‐QTc modeling analyses. Baxdrostat treatment did not produce QT‐interval prolongation, both at concentrations of interest and geometric mean of the maximum observed plasma concentration. Upper bounds of the two‐sided 90% confidence interval for the ΔΔQTcF mean estimates were < 10 ms. Pharmacokinetic data for the 16 and 32 mg doses in the TQT study were as expected, and both doses were well tolerated. These data illustrate that baxdrostat is not associated with the risk of QT‐interval prolongation at therapeutic and supra‐therapeutic concentrations.

We present concentration‐QTc modeling analyses from two phase 1 studies of the novel, highly selective aldosterone synthase inhibitor, baxdrostat. The assessments presented here confirm the lack of QT‐interval prolongation risk with baxdrostat at therapeutic and supra‐therapeutic concentrations.

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